Hisanori Uehara and Tetsuyuki Takahashi : Soluble EP2 inhibits osteolytic tumor growth by neutralizing prostaglandin E2-induced cell signaling, Transworld Research Network, 2010.
3.
Keisuke Izumi, Yoshifumi Nakajima, Keisuke Kitaura, Takanori Minami, Kazuhiro Hayashi, Takeshi Tsuchigauchi, Eiko Takishita, Tokiko Nakai and Hisanori Uehara : Cancer susceptibilities to chemical carcinogens in Long-Evans Cinnamon (LEC), Long-Evans Agouti (LEA) and F344 rats. In: Tanaka Takuji, Tsuda Hiroyuki, eds. Carcinogenesis and Modification of Carcinogenesis, Research Signpost, Kerala, India, 2005.
Academic Paper (Judged Full Paper):
1.
Kengo ATSUMI, 松本 穣, Michiko Yamashita, 西村 碧 フィリーズ, 佐藤 康晴, Yoshimi Bando and Hisanori Uehara : A case of adult T-cell leukemia/lymphoma showing CD8 positive and CD25 negative by immunohistochemistry, 診断病理, Vol.41, No.4, 2024.
Yasuyuki Okada, Koichi Okamoto, 谷 直也, 和田 浩典, Tomoyuki Kawaguchi, 野田 和克, 宮本 佳彦, 春藤 譲治, Hisanori Uehara and Tetsuji Takayama : A CASE OF GASTRIC NEUROENDOCRINE TUMOR IN A PATIENT WITH AUTOIMMUNE GASTRITIS COMPLICATED BY TYPE 3 AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 3, Gastroenterological Endoscopy, Vol.66, No.3, 259-265, 2024.
Masayuki Takahashi, Kei Daizumoto, Tomoya Fukawa, Yayoi Fukuhara, Yoshimi Bando, Minoru Kowada, Tsogt-Ochir Dondoo, Yutaro Sasaki, Ryotaro Tomida, Yoshiteru Ueno, Megumi Tsuda, Yoshito Kusuhara, Kunihisa Yamaguchi, Yasuyo Yamamoto, Hisanori Uehara and Hiroomi Kanayama : Insulin receptor expression to predict resistance to axitinib and elucidation of the underlying molecular mechanism in metastatic renal cell carcinoma., British Journal of Cancer, 2023.
(Summary)
Decreased INSR in RCC could be a biomarker to predict axitinib resistance. Regarding the resistant mechanism, vascular endothelial cells with decreased INSR in RCC may secrete interferon-β and induce PD-L1.
Satoshi Sumida, Mayuko Shimizu, Yuko Miyakami, Takumi Kakimoto, Tomoko Kobayashi, Yasuyo Saijo, Minoru Matsumoto, Hirohisa Ogawa, Takeshi Oya, Yoshimi Bando, Hisanori Uehara, Shu Taira, Mitsuo Shimada and Koichi Tsuneyama : Histological and immunohistochemical analysis of epithelial cells in epidermoid cysts in intrapancreatic accessory spleen., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 251-259, 2023.
(Summary)
Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023.
Takayoshi Shinya, Tomoki MATSUSHITA, Yuka HIROSHIMA, Youichi Otomi, Yasuhisa Kanematsu, Yoshimi Bando, Hisanori Uehara, Yoshiaki Kitamura and Masafumi Harada : Imaging features of a myoepithelial carcinoma of the nasal cavity: A case report and literature review, Radiology Case Reports, Vol.18, No.1, 386-391, 2022.
(Summary)
Myoepithelial carcinoma of the nasal cavity is extremely rare. We report the case of a 66-year-old man with myoepithelial carcinoma of the nasal cavity. Computed tomography (CT) and magnetic resonance imaging revealed a lobulated soft tissue mass with central necrosis and hemorrhage, as well as an invasion of the skull base and left orbit. The patient presented with continuous nasal congestion and heavy head and had no elevated level of squamous cell carcinoma-related antigen. CT, magnetic resonance imaging, or F-fluorodeoxyglucose (FDG) positron emission tomography/CT revealed no evidence of a metastatic lesion. F-FDG accumulation in the tumor was inhomogeneous and moderate. Histopathological examination of the resected specimen confirmed a well-circumscribed solid tumor with septa, a small area of hemorrhage, and necrosis. The subsequent diagnosis was a myoepithelial carcinoma of the left nasal cavity. This case shows that nasal myoepithelial carcinoma might appear as a well-defined lobulated mass with hemorrhagic necrosis and intense contrast enhancement in the solid component. We conjecture that hemorrhagic necrosis and intense enhancement values may be potential markers of nasal myoepithelial carcinoma.
Kouki Tada, Kei Daizumoto, Masayuki Takahashi, Hisanori Uehara, Megumi Tsuda, Yoshito Kusuhara, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi and Hiro-omi Kanayama : Recurrent multiple liver metastases of clear cell renal cell carcinoma with a significant response to sunitinib after nivolumab treatment., IJU Case Reports, Vol.6, No.1, 41-44, 2022.
(Summary)
Sunitinib after an IO-drug showed a significant effect in spite of only slight efficacy with other VEGFR-TKIs, which may have occurred through the alteration of the immunological microenvironment.
Souichiro Sasa, Hiroaki Inoue, INUI Tomohiro, Naoki Miyamoto, Mariko Aoyama, Kazumasa Okumura, Hiroaki Toba, Takahiro Yoshida, Tezuka Miki, Hirose Chieko, Yasuyo Saijo, Hisanori Uehara, Izumori Ayumi, Takahashi Masako, Sasa Mitsunori and Hiromitsu Takizawa : Axillary lymphangioma that developed following COVID-19 vaccination: a case report, Surgical Case Reports, Vol.8, No.1, 131, 2022.
(Summary)
Extensive vaccination programs are being implemented worldwide for coronavirus disease 2019 (COVID-19). With the spread of vaccination, swelling of the lymph nodes after vaccination is frequently seen. We encountered a patient who developed left axillary lymphadenoma following vaccine administration. The patient was a Japanese woman in her 80 s who had previously undergone surgery for right breast cancer. She received two injections of the Pfizer-BioNTech COVID-19 vaccine in her left arm. Approximately 3 months later, she complained of left axillary swelling, and imaging resulted in a diagnosis of left axillary lymphangioma. In accordance with the patient's wishes, we performed axillary mass resection. The pathological diagnosis was lymphangioma. Our examination findings indicated that congestion of the axillary lymph vessels might have been caused by upper-arm injections of the COVID-19 vaccine.
Yusuke Fukatani, Kei Daizumoto, Fumiya Kadoriku, 山本 拓, Yutaro Sasaki, 尾﨑 啓介, 上野 恵輝, Megumi Tsuda, Yoshito Kusuhara, Tomoya Fukawa, Yasuyo Yamamoto, Kunihisa Yamaguchi, Masayuki Takahashi, Hiro-omi Kanayama, Mariko Niki and Hisanori Uehara : A Case of Pappilary Renal Cell Caircinoma which Responded Well to the Combination Therapy of Ipilimumab and Nivolumab --A CASE REPORT--, Acta Urologica Japonica, Vol.68, No.4, 107-111, 2022.
(Summary)
We report a case of papillary renal cell carcinoma that responded well to the combination of ipilimumab and nivolumab. The patient was a 68-year-old male who was being followed up for a small left renal mass without treatment. Two years later, computed tomography (CT) showed enlarged cervical and para-aortic lymph nodes, and lymph node biopsy suggested metastases of the cancer. After resection of the renal tumor, we performed pararenal aortic lymph node biopsy, and we diagnosed the case as papillary renal cell carcinoma type 1 with lymph node metastasis. The combination of ipilimumab and nivolumab each metastatic site showed regression on CT. Since immune-related adverse events occurred during the therapy nivolumab was discontinued, but partial response of the metastases was maintained.
(Keyword)
Papillary renal cell carcinoma / Ipilimumab and nivolumab / 494.9
Takahiro Yoshida, Takeshi Nishino, Masakazu Goto, Seiya Inoue, Satoshi Fujiwara, Hiromitsu Takizawa, Akira Tangoku, Hisanori Uehara and Yoshimi Bando : ypN0 in Patients with Definitive cN-positive Status After Preoperative Treatment Is a Prognostic Factor in Esophageal Cancer, Anticancer Research, Vol.42, No.1, 195-203, 2022.
(Summary)
Histopathological tumor regression grade is applied not to lymph nodes but primary tumors modified by preoperative treatments. This study focused on patients whose pathological examination at the time of surgery showed no residual tumor after chemo(radio)therapy in the primary lesion (ypT0) or lymph nodes (ypN0). A total of 87 patients with clinical stage II/III thoracic esophageal cancer underwent esophagectomy following preoperative treatments to evaluate significances between pathological response and clinical outcomes; 51 patients with clinically definitive lymph node metastasis (cN+) were analyzed as a subgroup. ypT0 rates were 20.7% and 23.5%, and ypN0 rates were 47.1% and 27.5% in the whole cohort and in the cN+ subgroup, respectively. Disease-free survival, from surgery to relapse or death, was significantly influenced by ypN status (p=0.035) but not by ypT status in the 51 patients with definitive cN+ disease. Preoperative chemoradiation was an independent favorable factor for achievement of ypN0 in the 51 patients (odds ratio=0.09; p=0.007). ypN status was a predictive factor for DFS in patients treated with docetaxel plus low-dose 5-fluorouracil and cisplatin combined chemotherapy, superior to ypT status, especially in patients with definitive cN+ disease.
Masahiro Sako, Hiroshi Nokihara, Kensuke Kondo, Atsushi Mitsuhashi, Ryohiko Ozaki, Yohei Yabuki, Akane Abe, Hiroto Yoneda, Hirokazu Ogino, Kenji Otsuka, Hisanori Uehara and Yasuhiko Nishioka : A case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia successfully treated with pembrolizumab., Thoracic Cancer, Vol.13, No.1, 129-132, 2021.
(Summary)
Pulmonary pleomorphic carcinoma is often refractory to chemotherapy and follows an aggressive clinical course. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced lung cancer, and a few cases with pleomorphic carcinoma have been reported to show tumor shrinkage after therapy with ICIs. When treating patients with ICIs, patient selection is essential, and monitoring and management of immune-related adverse events, including pneumonitis, are needed. We herein report a case of pulmonary pleomorphic carcinoma with preexisting interstitial pneumonia treated with pembrolizumab, antiprogrammed cell death 1 antibody. Our report highlights important considerations necessary when treating advanced pleomorphic carcinoma patients complicated with interstitial pneumonia. We also review the literature regarding the use of ICIs in such patients.
Toshifumi Tezuka, Masahiko Azuma, Hirohisa Ogawa, Mayo Kondou, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi and Yasuhiko Nishioka : A RAS inhibitor reduces allergic airway remodeling via regulating IL-33-derived type 2 innate lymphoid cells., Experimental Lung Research, Vol.47, No.9, 451-463, 2021.
(Summary)
The RAS signal pathway plays a crucial role in allergen-induced airway remodeling associated with ILC2s. XRP44X may have therapeutic potential for refractory asthma.
Michittra Boonchan, Hideki Arimochi, Kunihiro Otsuka, Tomoko Kobayashi, Hisanori Uehara, Thiranut Jaroonwitchawan, Yuki Sasaki, Shin-ichi Tsukumo and Koji Yasutomo : Necroptosis protects against exacerbation of acute pancreatitis., Cell Death & Disease, Vol.12, No.6, 601, 2021.
(Summary)
mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.
Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.
Shun Morizumi, Seidai Satou, Kazuya Koyama, Hiroyasu Okazaki, Yajuan Chen, Hisatsugu Goto, Kozo Kagawa, Hirohisa Ogawa, Haruka Nishimura, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara and Yasuhiko Nishioka : Blockade of Pan-Fibroblast Growth Factor Receptors Mediates Bidirectional Effects in Lung Fibrosis., American Journal of Respiratory Cell and Molecular Biology, Vol.63, No.3, 317-326, 2020.
(Summary)
H]thymidine incorporation assays. The expression of FGFR was analyzed using IB or flow cytometry. We also investigated the effect of BGJ398 on pulmonary fibrosis induced by bleomycin in mice. Both lung fibroblasts and AECs expressed FGFRs. BGJ398 significantly inhibited the proliferation and migration of lung fibroblasts stimulated with FGF2. BGJ398 also reduced the proliferation of AECs in response to FGF2. Although the administration of BGJ398 ameliorated pulmonary fibrosis in bleomycin-treated mice, it increased mortality resulting from alveolar injury and inhibition of AEC regeneration. These data suggest that the total inhibition of FGFR signaling can suppress lung fibrosis by inhibiting fibroblast activities, although alveolar injury is simultaneously caused.
高松 直子, Yusuke Osaki, Hiroki Yamazaki, Kazutaka Kuroda, Hirohisa Ogawa, Hisanori Uehara, Koichi Tsuneyama, Hiroyuki Nodera and Yuishin Izumi : A case of led to diagnosis of malignancy by brachial plexus ultrasonography, Neurosonology, Vol.33, No.2, 36-40, 2020.
(Summary)
A 72-year-old man admitted to our hospital due to severe pain and drop hand in the left arm. MRI and CT of the head and neck at an outside hospital showed no abnormality. Neurological findings revealed distal weakness in the left upper extremity, vague pain between the radial aspect of the left hand and the middle of the digits 1-3, as well as brisk reflexes in the left extremities. Small masses were palpable in the posterior neck, the lower jaw, and the left neck. Clinically, left radial neuropathy and cervical radiculopathy were suspected. We performed ultrasound of the nerve roots, brachial plexus, and the radial nerve. There was a mass compressing the left brachial plexus from the caudolateral direction. Additionally, nerve swelling in the left arm was identified. Skin biopsy over the mass suggested metastatic adenocarcinoma. Chest CT scan showed a mass in the upper right lobe suggestive of a lung cancer. We concluded that the pain was due to radial neuropathy and upper and middle trunk disturbance of the left brachial plexopathy, of which neuromuscular ultrasound was useful in diagnosis.
Akio Takezaki, Shin-ichi Tsukumo, Yasuhiro Setoguchi, G Julie Ledford, Hisatsugu Goto, Kazuyoshi Hosomichi, Hisanori Uehara, Yasuhiko Nishioka and Koji Yasutomo : A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis., The Journal of Experimental Medicine, Vol.216, No.12, 2724-2735, 2019.
(Summary)
promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.
These results suggest that the β-catenin/CBP inhibitor PRI-724 is a potent antifibrotic agent that acts by modulating the activity of macrophages in the lungs.
Ayumi Sasaki, Mayumi Sugimoto, Narumi Tokaji, Makoto Irahara, Koichi Okamoto, Hisanori Uehara and Shoji Kagami : Efficacy of an elimination diet in a patient with eosinophilic gastroenteritis : a pediatric case with multiple food allergies., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 201-204, 2019.
Hirokazu Taniguchi, Tadaaki Yamada, Rong Wang, Keiko Tanimura, Yuta Adachi, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, H Luiz Araujo, Mariana Boroni, Akihiro Yoshimura, Shinsuke Shiotsu, Isao Matsumoto, Satoshi Watanabe, Toshiaki Kikuchi, Satoru Miura, Hiroshi Tanaka, Takeshi Kitazaki, Hiroyuki Yamaguchi, Hiroshi Mukae, Junji Uchino, Hisanori Uehara, Koichi Takayama and Seiji Yano : AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells., Nature Communications, Vol.10, No.1, 2019.
(Summary)
A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
Masami Kishi, Yoshinori Aono, Seidai Satou, Kazuya Koyama, Momoyo Azuma, Shuichi Abe, Hiroshi Kawano, Jun Kishi, Yuko Toyoda, Hiroyasu Okazaki, Hirohisa Ogawa, Hisanori Uehara and Yasuhiko Nishioka : Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice., PLoS ONE, Vol.13, No.12, 2018.
(Summary)
Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of pulmonary fibrosis. Nintedanib, a multi-kinase inhibitor that targets several tyrosine kinases, including PDGF receptor (PDGFR), was recently approved as an anti-fibrotic agent to reduce the deterioration of FVC in patients with idiopathic pulmonary fibrosis (IPF). However, the effects of PDGFR-α or -β on pulmonary fibrosis remain unclear. In an attempt to clarify their effects, we herein used blocking antibodies specific for PDGFR-α (APA5) and -β (APB5) in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. The effects of these treatments on the growth of lung fibroblasts were examined using the 3H-thymidine incorporation assay in vitro. The anti-fibrotic effects of these antibodies were investigated with the Ashcroft score and collagen content of lungs treated with BLM. Their effects on inflammatory cells in the lungs were also analyzed using bronchoalveolar lavage fluid. We investigated damage to epithelial cells and the proliferation of fibroblasts in the lungs. APA5 and APB5 inhibited the phosphorylation of PDGFR-α and -β as well as the proliferation of lung fibroblasts induced by PDGF-AA and BB. The administration of APB5, but not APA5 effectively inhibited BLM-induced pulmonary fibrosis in mice. Apoptosis and the proliferation of epithelial cells and fibroblasts were significantly decreased by the treatment with APB5, but not by APA5. The late treatment with APB5 also ameliorated fibrosis in lungs treated with BLM. These results suggest that PDGFR-α and -β exert different effects on BLM-induced pulmonary fibrosis in mice. A specific approach using the blocking antibody for PDGFR-β may be useful for the treatment of pulmonary fibrosis.
Yuko Miyakami, Shingen Nakamura, Masahiro Oura, Yasunobu Okamoto, 高橋 真美子, Kimiko Sogabe, 岩佐 昌美, Takeshi Harada, Shiroh Fujii, Hirokazu Miki, Kumiko Kagawa, Hisanori Uehara and Masahiro Abe : De novo CD 20-negative diffuse large B-cell lymphoma developed with sustained fever and markedly high C-reactive protein level, Shikoku Acta Medica, Vol.74, No.5-6, 193-200, 2018.
(Summary)
A 68-year-old woman presented with sustained fever for more than 1 month and admitted due to hematemesis and systemic edema. Computed tomography scan revealed swelling of the cervical, paraaortic lymph nodes. Blood test results showed severe anemia, elevation of white blood cell count, elevation of liver enzyme and coagulopathy with high C-reactive protein. Biopsy of the right cervical lymph node showed proliferation of abnormal lymphoid cells with necrosis and hemorrhage, which are positive for CD79α, CD30, MUM-1, and bcl-6 and negative for CD20, CD5, CD10, ALK, CD38, CD138, and EBER. Gene rearrangement of immunoglobulin heavy chain was detected in tumor cells. Bone marrow aspiration showed tumor involvement. The patient was diagnosed with de novo CD20-negative diffuse large B-cell lymphoma(DLBCL)stage IV B. Reduced CHOP therapy was performed under artificial respiration due to pulmonary edema and takotsubo cardiomyopathy. Although her general condition and high CRP levels temporarily improved, she died 47 days after admission due to rapid relapse. De novo CD20-negative DLBCL was rare and presented with high CRP levels and rapid progression, and was thought to be clinically different from the existing DLBCL. It is imperative to elucidate molecular pathophysiology and establish new treatment strategy for de novo CD20-negative DLBCL.
(Keyword)
CD20 / fever of unknown origin / diffuse large B-cell lymphoma / CRP
Yuishin Izumi, Ryosuke Miyamoto, Koji Fujita, Yuki Yamamoto, Hirotsugu Yamada, Tomoyasu Matsubara, Yuki Unai, Ai Tsukamoto, Naoko Takamatsu, Hiroyuki Nodera, Shinya Hayashi, Masaya Oda, Atsuko Mori, Yoshihiko Nishida, Shunsuke Watanabe, Hirohisa Ogawa, Hisanori Uehara, Shigeo Murayama, Masataka Sata and Ryuji Kaji : Distinct Incidence of Takotsubo Syndrome Between Amyotrophic Lateral Sclerosis and Synucleinopathies: A Cohort Study., Frontiers in Neurology, Vol.9, 1099, 2018.
(Summary)
Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by regional left ventricular dysfunction with a peculiar circumferential pattern, which typically results in apical ballooning. Evidence indicates a pivotal role of catecholamines in TTS, and researchers have discussed multiple hypotheses on the etiology, including multivessel coronary spasm, myocardial stunning, excessive transient ventricular afterload, and cardiac sympathetic overactivity with local noradrenaline spillover. Although central nervous system disorders, such as stroke and epilepsy, are known to trigger TTS, the incidence and clinical features of TTS in neurodegenerative disorders are poorly understood. Here, we retrospectively examined TTS cases in a single-center cohort composed of 250 patients with amyotrophic lateral sclerosis (ALS) and 870 patients with synucleinopathies [582 patients with Parkinson's disease (PD), 125 patients with dementia with Lewy bodies (DLB), and 163 patients with multiple system atrophy (MSA)] and identified 4 (1.6%, including 2 women) cases with ALS and no cases with synucleinopathies. Two ALS patients underwent autopsy and the pathological findings were compatible with the chronological changes identified in catecholamine-induced cardiomyopathy. A literature review identified 16 TTS cases with ALS, 1 case each with PD and DLB, and no cases with MSA. When current and previous TTS cases with ALS were concatenated: 55% (11/20) were female; 35% (7/20) had a bulbar-onset and 45% (9/20) had a limb-onset; the mean age of TTS onset was 63.3 ± 9.0 years and the mean interval time from ALS onset to TTS development was 4.9 ± 3.0 years; no (0/16) patients developed TTS within 12 months after ALS onset; 50% (10/20) underwent artificial ventilations; the mortality was 17% (3/18); and most cases had precipitating factors, and TTS development was associated with gastrostomy, tracheostomy, or infections in 45% (9/20) of the patients. This study demonstrated that ALS is a considerable predisposing factor of TTS and that synucleinopathies rarely cause TTS. The distinct TTS incidence between ALS and synucleinopathies may be due to cardiac sympathetic overactivity in ALS and may also be affected by cardiac sympathetic denervation in synucleinopathies. Moreover, the etiology of TTS in ALS may be reasonably explained by the two-hit theory.
Atsuro Saijo, Hisatsugu Goto, Nakano Mayuri, Mitsuhashi Atsushi, Yoshinori Aono, Masaki Hanibuchi, Hirohisa Ogawa, Hisanori Uehara, Kazuya Kondo and Yasuhiko Nishioka : Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells., Cancer Letters, Vol.421, 17-27, 2018.
(Summary)
Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches.
Kei Daizumoto, Tetsuro Yoshimaru, Yosuke Matsushita, Tomoya Fukawa, Hisanori Uehara, Masaya Ono, Masato Komatsu, Hiro-omi Kanayama and Toyomasa Katagiri : A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer, Cancer Research, Vol.78, No.9, 2233-2247, 2018.
(Summary)
The p53 and EGFR pathways are frequently altered in bladder cancer, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle-invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31-bound mutp53/SP1 enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31/NCL interaction resulted in downregulation of EGFR/Akt signaling, eliciting an antitumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31/NCL formation may lead to potential treatment strategies for advanced MIBC. DDX31 cooperates with mutp53 and EGFR to promote progression of muscle invasive bladder cancer. .
Hitoshi Nishijima, Tatsuya Kajimoto, Yoshiki Matsuoka, Yasuhiro Mouri, Junko Morimoto, Minoru Matsumoto, Hiroshi Kawano, Yasuhiko Nishioka, Hisanori Uehara, Keisuke Izumi, Koichi Tsuneyama, Il-mi Okazaki, Taku Okazaki, Kazuyoshi Hosomichi, Ayako Shiraki, Makoto Shibutani, Kunitoshi Mitsumori and Mitsuru Matsumoto : Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)., Journal of Autoimmunity, Vol.86, 75-92, 2018.
(Summary)
Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire.
Seidai Satou, Shinohara Shintaro, Hayashi Shinya, Morizumi Shun, Abe Shuichi, Okazaki Hiroyasu, Chen Yanjuan, Hisatsugu Goto, Yoshinori Aono, Hirohisa Ogawa, Koyama Kazuya, Nishimura Haruka, Hiroshi Kawano, Yuko Toyoda, Hisanori Uehara and Yasuhiko Nishioka : Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity., Respiratory Research, Vol.18, No.1, 172, 2017.
(Summary)
Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear. Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin. Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects. These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.
(Keyword)
Animals / Cell Movement / Cells, Cultured / Dose-Response Relationship, Drug / Fibroblasts / Humans / Indoles / Male / Mice / Mice, Inbred C57BL / Pulmonary Fibrosis / Treatment Outcome / Vascular Endothelial Growth Factor A
Tetsuyuki Takahashi, Takeshi Nishida, Hayato Baba, Hideki Hatta, Johji Imura, Mitsuko Sutoh, Syunji Toyohara, Ryoji Hokao, Syunsuke Watanabe, Hirohisa Ogawa, Hisanori Uehara and Koichi Tsuneyama : Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse)., Molecular and Clinical Oncology, Vol.5, No.2, 267-270, 2016.
(Summary)
We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of -catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.
Miwako Kagawa, Yasuteru Fujino, Naoki Muguruma, Noriaki Murayama, Koichi Okamoto, Shinji Kitamura, Tetsuo Kimura, Kazuhiro Kishi, Hiroshi Miyamoto, Hisanori Uehara and Tetsuji Takayama : Localized amyloidosis of the stomach mimicking a superficial gastric cancer., Clinical Journal of Gastroenterology, Vol.9, No.3, 109-113, 2016.
(Summary)
A 73-year-old man was referred to our hospital for further examination of a depressed lesion in the stomach found by cancer screening gastroscopy. A barium upper gastrointestinal series showed an area of irregular mucosa measuring 15 mm on the anterior wall of the gastric body. Esophagogastroduodenoscopy revealed a 15 mm depressed lesion on the anterior wall of the lower gastric body. We suspected an undifferentiated adenocarcinoma from the appearance and took some biopsies. However, histology of the specimens revealed amyloidal deposits in the submucosal layer without malignant findings. Congo red staining was positive for amyloidal protein and green birefringence was observed under polarized light microscopy. Congo red staining with prior potassium permanganate incubation confirmed the light chain (AL) amyloid type. There were no amyloid deposits in the colon or duodenum. Computed tomography of the chest, abdomen, and pelvis showed no remarkable findings. Thus, this case was diagnosed as a localized gastric amyloidosis characterized by AL type amyloid deposition in the mucosal or submucosal layer. As the clinical outcome of gastric AL amyloidosis seems favorable, this case is scheduled for periodic examination to recognize potential disease progression and has been stable for 2 years.
Mitsuhashi Atsushi, Hisatsugu Goto, Atsuro Saijo, Trung The Van, Yoshinori Aono, Hirokazu Ogino, Kuramoto Takuya, Tabata Sho, Hisanori Uehara, Keisuke Izumi, Mitsuteru Yoshida, Kobayashi Hiroaki, Takahashi Hidefusa, Gotoh Masashi, Kakiuchi Soji, Masaki Hanibuchi, Seiji Yano, Yokomise Hiroyasu, Shoji Sakiyama and Yasuhiko Nishioka : Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab, Nature Communications, Vol.6, 8792, 2015.
(Summary)
Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy.
Toshifumi Tezuka, Hirohisa Ogawa, Masahiko Azuma, Hisatsugu Goto, Hisanori Uehara, Yoshinori Aono, Masaki Hanibuchi, Yamaguchi Yoichi, Fujikawa Tomoyuki, Itai Akiko and Yasuhiko Nishioka : IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators, PLoS ONE, Vol.10, No.3, e0121615, 2015.
(Summary)
Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.
Yasuteru Fujino, Naoki Muguruma, Shinji Kitamura, Yasuhiro Mitsui, Tetsuo Kimura, Hiroshi Miyamoto, Hisanori Uehara, Koichi Kataoka and Tetsuji Takayama : Perineurioma in the sigmoid colon diagnosed and treated by endoscopic resection, Clinical Journal of Gastroenterology, Vol.7, No.5, 392-396, 2014.
(Summary)
Perineuriomas are rare benign peripheral nerve sheath tumors in the gastrointestinal tract. We recently encountered a submucosal lesion in the sigmoid colon that was resected by endoscopic mucosal resection and was then diagnosed as perineurioma by immunohistochemistry. A 51-year-old female with a positive test for fecal occult blood was referred to our hospital for screening colonoscopy. Colonoscopy identified a submucosal lesion, approximately 15 mm in diameter, in the sigmoid colon. Endoscopic ultrasound showed a 15-mm tumor with a strong acoustic shadow. Endoscopic mucosal resection was performed in order to make a precise diagnosis as well as removal. The specimen revealed spindle cell proliferation without atypia, and immunostaining revealed that the spindle cells were positive for collagen type IV and glut-1, and the lesion was diagnosed as a colonic perineurioma with no malignancy. Gastroenterologists as well as pathologists should be aware of this type of submucosal lesion, and immunohistochemical evaluation is highly recommended when an unusual mesenchymal tumor is found.
Hisanori Uehara, Tetsuyuki Takahashi, Mina Oha, Hirohisa Ogawa and Keisuke Izumi : Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression., International Journal of Cancer, Vol.135, No.11, 2558-2568, 2014.
(Summary)
Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum-induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three-dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase-3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor-treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity-prostate cancer progression link.
Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara, Hiroyuki Furumoto and Masafumi Harada : Clear cell adenocarcinoma arising from clear cell adenofibroma of the ovary: value of DWI and DCE-MRI., Magnetic Resonance in Medical Sciences, Vol.12, No.4, 305-308, 2013.
(Summary)
Clear cell adenofibroma (CCAF) is a rare surface epithelial-stromal tumor of the ovary and recently considered another precursor of clear cell adenocarcinoma (CCA) other than endometrioma. We report magnetic resonance (MR) findings of a borderline CCAF that contained a small CCA focus. The tumor manifested a characteristic "black sponge" appearance. The CCA focus showed high signal intensity on diffusion-weighted imaging (DWI) and early enhancement on dynamic contrast-enhanced (DCE) MR imaging (DCE-MRI), and the CCAF components showed low signal intensity on DWI and gradually increasing contrast enhancement on DCE-MRI.
Katsuhiro Kinoshita, Yoshinori Aono, Momoyo Azuma, Jun Kishi, Akio Takezaki, Masami Kishi, Hideki Makino, Hiroyasu Okazaki, Hisanori Uehara, Keisuke Izumi, Saburo Sone and Yasuhiko Nishioka : Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice., American Journal of Respiratory Cell and Molecular Biology, Vol.49, No.4, 536-543, 2013.
(Summary)
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of -smooth muscle actin induced by transforming growth factor , indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.
Tetsuyuki Takahashi, Hisanori Uehara and Keisuke Izumi : Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and utility of TMPRSS4 as a conbinatorial molecular target, International Journal of Oncology, Vol.43, 416-424, 2013.
(Summary)
We have previously reported that FuEP2/Ex2, a soluble decoy receptor for PGE2, suppresses tumor growth in an orthotopic xenograft model. To examine whether it has further uses, we examined the effect of FuEP2/Ex2 in an intraperitoneal metastasis model of ovarian cancer cells. We established FuEP2/Ex2-expressing ovarian cancer cells (SKOV/ip-FuEP2/Ex2) and injected them intraperitoneally into female nude mice. Mice injected with SKOV/ip-FuEP2/Ex2 had no ascitic fluid and showed smaller tumor lesions compared to mice injected with vector control cells, with decreased microvessel density and M2 macrophages. To identify molecular targets for combination treatment, we conducted cDNA microarray analysis and found three genes encoding enzyme [matrix metalloproteinase-7 (MMP-7), transmembrane protease serin 4 (TMPRSS4) and cytocrome P450 1B1 (CYP1B1)] to be upregulated in SKOV/ip-FuEP2/Ex2-derived tumors. Administration of TMPRSS4 inhibitor further reduced tumor weight and decreased the number of Ki-67-positive cells in SKOV/ip-FuEP2/Ex2-injected mice. These data indicate a possible EP-targeting strategy using FuEP2/Ex2 in the treatment of ovarian cancer and suggest that dual targeting of EP-mediated signaling and TMPRSS4 may enhance therapeutic value.
Hisanori Uehara, Tetsuyuki Takahashi and Keisuke Izumi : Induction of retinol-binding protein 4 and placenta-specific 8 expression in human prostate cancer cells remaining in bone following osteolytic tumor growth inhibition by osteoprotegerin, International Journal of Oncology, Vol.43, No.2, 365-374, 2013.
(Summary)
New drugs that inhibit the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL)/RANK pathway have demonstrated efficacy for the treatment of bone metastasis. Toxicities induced by these drugs, however, including osteonecrosis of the jaw and hypocalcemia, may adversely affect therapy. The aim of this study was to identify additional therapeutic targets that can be combined with OPG/RANKL/RANK pathway inhibition in the treatment of prostate cancer bone metastasis. We established a stable transfectant that produces high levels of OPG mRNA and protein from PC-3 human prostate cancer cells (PC3-OPG). The culture medium of PC3-OPG cells significantly inhibited the differentiation of mouse monocytes into mature osteoclasts. Furthermore, when PC3-OPG cells were injected into the bones of nude mice, bone destruction and tumor-induced osteoclast formation were reduced. Injection into bone of the mixtures containing equal amounts of green fluorescent protein (GFP)-expressing PC-3 cells (PC3-GFP) and PC3-OPG cells also reduced bone destruction, compared to the control mixture. PC3-GFP cells were subsequently isolated from bone tumors and used for microarray analysis to assess changes in gene expression following osteolytic tumor growth inhibition by OPG. We selected the top 10 upregulated genes based on results from microarrays and confirmed mRNA expression of each gene by RT-PCR. The expression patterns of retinol-binding protein 4 (RBP4) and placenta-specific 8 (PLAC8) were consistent with microarray results. Expression of these genes was also increased in the bone tumors of PC3-GFP/PC3-OPG-injected mice. Knockdown of both RBP4 and PLAC8 by siRNA inhibited the growth of PC-3 cells in vitro. Thus, RBP4 and PLAC8 may become new therapeutic targets for prostate cancer bone metastasis, in combination with OPG/RANKL/RANK pathway inhibition.
Atsushi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Sho Tabata, Sawaka Yukishige, Shinji Abe, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, G Julie Ledford, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages., The American Journal of Pathology, Vol.182, No.5, 1843-1853, 2013.
(Summary)
Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-A-expressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-A-expressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs.
Hideki Makino, Yoshinori Aono, Momoyo Azuma, Masami Kishi, Yuki Yokota, Katsuhiro Kinoshita, Akio Takezaki, Jun Kishi, Hiroshi Kawano, Hirohisa Ogawa, Hisanori Uehara, Keisuke Izumi, Saburo Sone and Yasuhiko Nishioka : Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice., The Journal of Medical Investigation : JMI, Vol.60, No.1-2, 127-137, 2013.
(Summary)
Circulating fibrocytes had been reported to migrate into the injured lungs, and contribute to fibrogenesis via chemokine-chemokine receptor systems including CXCL12-CXCR4 axis. Here we hypothesized that blockade of CXCR4 might inhibit the migration of fibrocytes to the injured lungs and the subsequent pulmonary fibrosis. To explore the antifibrotic effects of blockade of CXCR4, we used a specific antagonist for CXCR4, AMD3100, in bleomycin-induced pulmonary fibrosis model in mice. Administration of AMD3100 significantly improved the loss of body weight of mice treated with bleomycin, and inhibited the fibrotic lesion in subpleural areas of the lungs. The quantitative analysis demonstrated that treatment with AMD3100 reduced the collagen content and fibrotic score (Aschcroft score) in the lungs. Although AMD3100 did not affect cell classification in bronchoalveolar lavage fluid on day 7, the percentage of lymphocytes was reduced by AMD3100 on day 14. AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleocmycin in vivo. These results suggest that the blockade of CXCR4 might be useful strategy for therapy of patients with pulmonary fibrosis via inhibiting the migration of circulating fibrocytes.
Tomoya Fukawa, Masaya Ono, Taisuke Matsuo, Hisanori Uehara, Tsuneharu Miki, Yusuke Nakamura, Hiro-omi Kanayama and Toyomasa Katagiri : DDX31 regulates the p53-HDM2 pathway and rRNA gene transcription through its interaction with NPM1 in renal cell carcinomas, Cancer Research, Vol.72, No.22, 5867-5877, 2012.
(Summary)
Studies of renal cell carcinoma (RCC) have led to the development of new molecular-targeted drugs but its oncogenic origins remain poorly understood. Here, we report the identification and critical roles in renal carcinogenesis for DDX31, a novel nucleolar protein upregulated in the vast majority of human RCC. Immunohistochemical overexpression of DDX31 was an independent prognostic factor for patients with RCC. RNA interference (RNAi)-mediated attenuation of DDX31 in RCC cells significantly suppressed outgrowth, whereas ectopic DDX31 overexpression in human 293 kidney cells drove their proliferation. Endogenous DDX31 interacted and colocalized with nucleophosmin (NPM1) in the nucleoli of RCC cells, and attenuation of DDX31 or NPM1 expression decreased pre-ribosomal RNA biogenesis. Notably, in DDX31-attenuated cells, NPM1 was translocated from nucleoli to the nucleoplasm or cytoplasm where it bound to HDM2. As a result, HDM2 binding to p53 was reduced, causing p53 stablization with concomitant G(1) phase cell-cycle arrest and apoptosis. Taken together, our findings define a mechanism through which control of the DDX31-NPM1 complex is likely to play critical roles in renal carcinogenesis.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Atsuro Saijo, Souji Kakiuchi, Yoichi Maekawa, Koji Yasutomo, Masaki Hanibuchi, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-Notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, Molecular Cancer Therapeutics, Vol.11, No.12, 2578-2587, 2012.
(Summary)
Notch signaling regulates cell-fate decisions during development and postnatal life. Little is known, however, about the role of Delta-like-4 (Dll4)-Notch signaling between cancer cells, or how this signaling affects cancer metastasis. We, therefore, assessed the role of Dll4-Notch signaling in cancer metastasis. We generated a soluble Dll4 fused to the IgG1 constant region (Dll4-Fc) that acts as a blocker of Dll4-Notch signaling and introduced it into human small cell lung cancer (SCLC) cell lines expressing either high levels (SBC-3 and H1048) or low levels (SBC-5) of Dll4. The effects of Dll4-Fc on metastasis of SCLC were evaluated using a mouse model. Although Dll4-Fc had no effect on the liver metastasis of SBC-5, the number of liver metastasis inoculated with SBC-3 and H1048 cells expressing Dll4-Fc was significantly lower than that injected with control cells. To study the molecular mechanisms of the effects of Dll4-Fc on liver metastasis, a PCR array analysis was conducted. Because the expression of NF-κB target genes was affected by Dll4-Fc, we conducted an electrophoretic mobility shift assay and observed that NF-κB activities, both with and without stimulation by TNF-α, were downregulated in Dll4-Fc-overexpressing SBC-3 and H1048 cells compared with control cells. Moreover, Dll4-Fc attenuates, at least in part, the classical and alternative NF-κB activation pathway by reducing Notch1 signaling. These results suggest that Dll4-Notch signaling in cancer cells plays a critical role in liver metastasis of SCLC by regulating NF-κB signaling.
(Keyword)
Animals / apoptosis / Cell Growth Processes / Cell Movement / Down-Regulation / Humans / Liver Neoplasms, Experimental / Lung Neoplasms / Male / Mice / Mice, SCID / NF-kappa B / Receptors, Notch / Recombinant Fusion Proteins / signal transduction / Small Cell Lung Carcinoma / Transfection / Xenograft Model Antitumor Assays
Yoshimi Bando, Tetsuyuki Takahashi, Hisanori Uehara, Teruyoshi Kageji, Shinji Nagahiro and Keisuke Izumi : Autopsy case of amebic granulomatous meningoencephalitis caused by Balamuthia mandrillaris in Japan, Pathology International, Vol.62, No.6, 418-423, 2012.
(Summary)
Balamuthia mandrillaris is a free-living ameba that causes amebic encephalitis. Herein, we report an autopsy case of Balamuthia encephalitis proven with polymerase chain reaction (PCR) and immunohistochemistry from paraffin-embedded brain biopsy specimens. A 68-year-old Japanese male presented at a hospital with progressive right hemiparesis approximately 3 months before his death. An open-brain biopsy specimen showed diffuse meningitis with massive coagulative necrosis. The perivascular spaces contained numerous lymphocytes, histiocytes and giant cells, although the etiology was not determined. The patient deteriorated into coma and died from cerebral herniation. Autopsy revealed abundant trophozoites and cysts in the subarachnoid and Virchow-Robin's spaces. Electron-micrographs of the amebic cysts showed a characteristic triple-walled envelope. The amebas were identified as Balamuthia mandrillaris based on immunohistochemical analysis from the autopsy and biopsy specimens. Primer sets designed to amplify approximately 200 bp bands of mitochondrial 16S rRNA gene of Balamuthia by PCR produced positive results from the biopsy specimens but negative results from the autopsy specimens. In summary, PCR to amplify shorter segments of DNA may be of diagnostic value in detecting suspected cases of balamuthiasis in formalin-fixed, paraffin-embedded specimens. Increased awareness and timely diagnosis of Balamuthia encephalitis might lead to earlier initiation of therapy and improved outcome.
(Keyword)
Amebiasis / Balamuthia mandrillaris / Brain / Central Nervous System Protozoal Infections / Fatal Outcome / Humans / Japan / Magnetic Resonance Imaging / Male / Treatment Failure
Hirohisa Ogawa, Masahiko Azuma, Hisanori Uehara, Tetsuyuki Takahashi, Yasuhiko Nishioka, Saburo Sone and Keisuke Izumi : Nerve growth factor derived from bronchial epithelium afer chronic mite antigen exposure contributes to airway hyperresponsiveness by inducing hyperinnervaiton, and is inhibited by in vivo siRNA., Clinical and Experimental Allergy, Vol.42, No.3, 460-470, 2012.
(Summary)
Bronchial asthma is a chronic allergic airway inflammatory disease. Neurotrophins, including nerve growth factor (NGF), play an important role in the pathogenesis of asthma. However, the effects of NGF derived from epithelium on airway hyperresponsiveness (AHR) after antigen sensitization/exposure remain uncertain. In this study, we examined the role of NGF on AHR after chronic antigen exposure and the effect of inhibiting NGF by in vivo siRNA on AHR exacerbation. We generated chronic mouse models of bronchial asthma using house-dust mite antigen (Dermatophagoides pteronyssinus; Dp). NGF concentrations in bronchoalveolar lavage fluid (BALF), lung histopathology, hyperresponsiveness, and related neuronal peptides and cytokines in supernatants of lung homogenates were determined. NGF in BALF was increased in a dose- and time-dependent manner, and was expressed primarily in bronchial epithelium. Nerve fibres and substance P-positive fibres were detected in subepithelium of Dp-sensitized and challenged mice over 4 weeks of mite antigen exposure. AHR was positively correlated with NGF concentration and nerve fibre innervation. AHR, modulation of innervation, and increased substance P were inhibited by in vivo administration of siRNA that targeted NGF, although the inhibition of NGF did not affect allergic inflammation and subepithelial fibrosis. These findings suggest that NGF derived from bronchial and alveolar epithelium plays an important role in AHR after chronic exposure to mite antigen. NGF inhibition could potentially manage bronchial asthma, including AHR.
Ezar Hafez, Tetsuyuki Takahashi, Tokiko Nakai, Hirohisa Ogawa, Makoto Sato, Chie Takasu, Hisanori Uehara and Keisuke Izumi : High susceptibility to zymbal gland and intestinal carcinogenesis in diabetic Otsuka Long-Evans Tokushima Fatty rats., Journal of Toxicologic Pathology, Vol.24, No.4, 187-193, 2011.
(Summary)
Diabetes mellitus (DM) and obesity are believed to be risk factors for colorectal cancer in humans. In experiment 1, male nondiabetic Long-Evans Tokushima Otsuka (LETO) rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model animal of type 2 DM, were whole-body X-irradiated (4 Gy) at 6 and 8 weeks of age and euthanized at 78 weeks of age (n=15, respectively). The incidences of small intestine adenocarcinoma in LETO and OLETF rats were 0% and 30%, respectively. In experiment 2, male LETO and OLETF rats (n=24, respectively) were given s.c. injections of 15 mg/kg azoxymethane (AOM) once weekly for 3 weeks and euthanized at 36 weeks of age. The incidences of Zymbal gland tumors in LETO and OLETF rats were 0% and 67%, respectively (P<0.001), whereas those of small intestine adenocarcinoma were 0% and 43% (P<0.001) and those of cecum/colon adenocarcinoma were 46% and 79% (P<0.05), respectively. Fatty change of hepatocytes was common in OLETF rats (63%) but not in LETO rats. Serum triglyceride and free fatty acid levels in OLETF rats were significantly higher than in LETO rats at sacrifice, whereas serum insulin levels in OLETF rats were very diverse. These data suggest that hyperlipidemia plays a significant role in high susceptibility to lower intestinal tract carcinogenesis in OLETF rats; this strain is susceptible to AOM-induced Zymbal gland carcinogenesis.
Mayumi Takeuchi, Kenji Matsuzaki and Hisanori Uehara : Primary carcinoid tumor of the ovary: Magnetic resonance imaging characteristics with pathologic correlation, Magnetic Resonance in Medical Sciences, Vol.10, No.3, 205-209, 2011.
(Summary)
Ovarian carcinoid tumor is a rare neoplasm that may appear as a solid mass or often combined with teratomas or mucinous tumors. We report 2 cases associated with mucinous cystadenomas and describe their magnetic resonance imaging characteristics. On T(2)-weighted images, the tumors appeared as multilocular cystic masses with hypointense solid components as a result of abundant fibrous stroma induced by serotonin. Demonstration of prominent hypervascularity of the tumors following contrast administration on dynamic study may be the clue to differential diagnosis.
Akiko Kitamura, Yoichi Maekawa, Hisanori Uehara, Keisuke Izumi, Izumi Kawachi, Masatoyo Nishizawa, Yasuko Toyoshima, Hitoshi Takahashi, M Daron Standley, Keiji Tanaka, Jun Hamazaki, Shigeo Murata, Koji Obara, Itaru Toyoshima and Koji Yasutomo : A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans., The Journal of Clinical Investigation, Vol.121, No.10, 4150-4160, 2011.
(Summary)
Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional subunits, expression of which is induced by IFN-, are substituted for their constitutively expressed counterparts, the structure is converted to an immunoproteasome. However, the underlying roles of immunoproteasomes in human diseases are poorly understood. Using exome analysis, we found a homozygous missense mutation (G197V) in immunoproteasome subunit, type 8 (PSMB8), which encodes one of the subunits induced by IFN- in patients from 2 consanguineous families. Patients bearing this mutation suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was highly expressed, and there was reduced expression of PSMB8. Downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. These findings identify PSMB8 as an essential component and regulator not only of inflammation, but also of adipocyte differentiation, and indicate that immunoproteasomes have pleiotropic functions in maintaining the homeostasis of a variety of cell types.
Qi Li, Wei Wang, Tadaaki Yamada, Kunio Matsumoto, Katsuya Sakai, Yoshimi Bando, Hisanori Uehara, Yasuhiko Nishioka, Saburo Sone, Shotaro Iwakiri, Kazumi Itoi, Teruhiro Utsugi, Kazuo Yasumoto and Seiji Yano : Pleural mesothelioma instigates tumor-associated fibroblasts to promote progression via a malignant cytokine network., The American Journal of Pathology, Vol.179, No.3, 1483-1493, 2011.
(Summary)
The tumor microenvironment is crucial to the progression of various malignancies. Malignant pleural mesothelioma (MPM), which originates from the pleura, grows aggressively in the thoracic cavity. Here we describe an orthotopic implantation SCID mouse model of MPM and demonstrate that α-SMA-positive fibroblast-like cells accumulate in the tumors produced by the human MPM cell lines MSTO-211H and Y-Meso-14. We assessed the interaction between MPM cells and their microenvironments, focusing on tumor-associated fibroblasts. MSTO-211H and Y-Meso-14 cells produced fibroblast growth factor-2 (FGF-2) and/or platelet-derived growth factor-AA (PDGF-AA); they also enhanced growth, migration, and production of hepatocyte growth factor (HGF) by human lung fibroblast MRC-5 cells. MRC-5 cells stimulated HGF-mediated growth and migration of MSTO-211H and Y-Meso-14 cells in an in vitro coculture system. In the orthotopic model, tumor formation by MSTO-211H and Y-Meso-14 cells was significantly inhibited by TSU-68, an inhibitor of FGF, VEGF, and PDGF receptors; imatinib, an inhibitor of PDGF receptors; and NK4, an antagonist of HGF. Histological analyses of clinical specimens from 51 MPM patients revealed considerable tumor-associated fibroblasts infiltration and expression of HGF, together with FGF-2 or PDGF-AA, in tumors. These findings indicate that MPM instigates tumor-associated fibroblasts, promoting tumor progression via a malignant cytokine network. Regulation of this cytokine network may be therapeutically useful for controlling MPM.
Hongchao Shan, Tetsuyuki Takahashi, Yoshimi Bando, Keisuke Izumi and Hisanori Uehara : Inhibitory effect of soluble PDGFRbeta on intraosseous growth of breast cancer cells in nude mice, Cancer Science, Vol.102, No.10, 1904-1910, 2011.
(Summary)
Bone metastasis is a frequent complication of advanced breast cancer. On the basis of functional and molecular evidence, signaling mediated by the binding of platelet-derived growth factor (PDGF)-BB and -DD to PDGF receptor β (PDGFRβ) is critical for the survival and growth of metastatic breast cancer cells within the bone microenvironment. In this study, we propose a new approach to blocking PDGFRβ signaling using soluble PDGFRβ (sPDGFRβ) as a decoy receptor for PDGF-BB and -DD secreted from tumor cells and bone marrow stromal cells. A bone-seeking TNBCT/Bo cell line was established by in vivo selection from TNBCT human breast cancer cells, which are negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 protein expression. The TNBCT/Bo cells were transfected with a mammalian expression vector encoding the extracellular domain of PDGFRβ. A stable transfectant (TNBCT/Bo-sPDGFRβ) grew at a similar rate to that of control cells under normal culture conditions, although growth stimulation of human fibroblasts with PDGF-BB was neutralized by the culture medium from TNBCT/Bo-sPDGFRβ cells. Intratibial injection of TNBCT/Bo-sPDGFRβ cells into athymic nude mice resulted in a significant decrease in tumor incidence compared with control mice (P < 0.01). This attenuated growth correlated with decreased cancer cell proliferation, angiogenesis, and recruitment of stromal cells, and with an increase in the number of apoptotic cells. These findings suggest that sPDGFRβ is useful for the treatment of breast cancer bone metastasis.
Tetsuyuki Takahashi, Hirohisa Ogawa, Keisuke Izumi and Hisanori Uehara : The solubla EP2 receptor FuEP2/Ex2 suppresses endometrial cancer cell growth in an orthotopic xenograft model in nude mice, Cancer Letters, Vol.306, No.1, 67-75, 2011.
(Summary)
Endometrial cancer is one of the most common gynecologic malignancies and many factors influence in its growth and development. As in many other types of cancer, prostaglandin E(2) (PGE(2)) is thought to be an accelerator of cell proliferation and endometrial cancer progression. In this study, we examined the effect of FuEP2/Ex2, a soluble decoy receptor for PGE(2) on growth of endometrial cancer cells. A stable transfectant expressing FuEP2/Ex2 was established from human endometrial cancer Ishikawa cells (Ish-FuEP2/Ex2). Ish-FuEP2/Ex2 cells expressed FuEP2/Ex2 mRNA and protein. Expression levels of E-prostanoid receptor 1 (EP1), EP2, EP3, EP4, and F-prostanoid receptor (FP) were almost the same in Ish-FuEP2/Ex2 and vector control cells. Growth rates of Ish-FuEP2/Ex2 under normal culture conditions were also similar to vector control cells, although PGE(2)-induced growth stimulation was completely inhibited in Ish-FuEP2/Ex2 or by Ish-FuEP2/Ex2 culture medium. Moreover, phosphorylation of extracellular signal-regulated kinase (ERK) and induction of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), cyclin D1, and c-fos mRNA by PGE(2) were not observed in Ish-FuEP2/Ex2 and Ish-FuEP2/Ex2 culture medium-treated vector control cells, although they were found when treated with prostaglandin F(2α). An orthotopic xenograft model in athymic nude mice revealed that Ish-FuEP2/Ex2-injected mice had significantly decreased mean tumor area. The proportion of Ki-67-positive cells in the tumor lesion was also significantly lower in Ish-FuEP2/Ex2-injected mice. These findings suggest that an EP-targeting strategy using FuEP2/Ex2 may be of use in the treatment of endometrial cancer.
Jun Kishi, Yasuhiko Nishioka, Tomomi Kuwahara, Souji Kakiuchi, Momoyo Azuma, Yoshinori Aono, Hideki Makino, Katsuhiro Kinoshita, Masami Kishi, R Batmunkh, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice., The European Respiratory Journal, Vol.38, No.2, 415-424, 2011.
(Summary)
Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.
Avirmed Shiirevnyamba, Tetsuyuki Takahashi, Hongchao Shan, Hirohisa Ogawa, Seiji Yano, Hiro-omi Kanayama, Keisuke Izumi and Hisanori Uehara : Enhancement of osteoclastogenic activity in osteolytic prostate cancer cells by physical contact with osteoblasts, British Journal of Cancer, Vol.104, No.3, 505-513, 2011.
(Summary)
The interaction between prostate cancer cells and osteoblasts is critical for the development of bone metastasis. Metastatic cancer cells may physically contact osteoblasts in the bone microenvironment; however, the biological significance of this interaction is not fully understood. Human prostate cancer cells (the osteolytic cell line PC-3 and the osteoblastic cell line MDA-PCa 2b) and human osteoblasts (hFOB1.19) were cocultured under two different conditions (bilayer and contact conditions). Differential gene expression profiles of prostate cancer cells were then investigated using microarray analysis. Differentially expressed genes were analysed using RT-PCR and western blotting, and the effect of anti-cadherin neutralising antibodies on their expression was assayed. The osteoclastogenic activity of cells grown under these different conditions was also investigated using an in vitro assay. When PC-3 or MDA-PCa 2b cells were cocultured with hFOB1.19 cells under contact conditions, the expression of eight genes was upregulated and that of one gene was downregulated in PC-3 cells compared with gene expression in bilayer culture. No differentially expressed genes were detected in MDA-PCa 2b cells. Four of the eight upregulated genes (interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), IL-6 and the third component of complement (C3)) have already been reported to participate in osteoclastogenesis. Indeed, a cell lysate of PC-3 cells grown under contact coculture conditions significantly enhanced osteoclastogenesis in vitro (P<0.005). neutralisation of cadherin-11 with a specific antibody inhibited upregulation of COX-2 and C3 mRNA in PC-3 cells. In contrast, neutralisation of N-cadherin induced upregulation of COX-2 mRNA. Physical contact between osteolytic prostate cancer cells and osteoblasts may upregulate osteoclastogenesis-related gene expression in prostate cancer cells and enhance osteoclastogenesis. Additionally, cadherin-11 and N-cadherin are involved in this process. These data provide evidence supporting new therapies of prostate cancer bone metastasis that target direct cancer-cell-osteoblast cell-cell contact.
Aki Fuminori, Yoshimi Bando, Tetsuyuki Takahashi, Hisanori Uehara, Numoto Satoshi, Ito Sueyoshi, Sasa Mitsunori and Keisuke Izumi : A retrospective study on TS mRNA expression and prediction of the effects of adjuvant oral 5-fluorouracil in breast cancer, Oncology Letters, Vol.1, No.6, 981-988, 2010.
(Summary)
Nucleic acid-metabolizing enzymes, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT), have attracted attention as candidates for response determinants of 5-fluorouracil (5-FU). Whether the expression levels of these enzymes can be adopted as valuable parameters for 5-FU sensitivity in breast cancer has yet to be elucidated. In the present study, intratumoral mRNA expression of TS, DPD, TP and OPRT were determined in formalin-fixed paraffin-embedded surgical specimens collected from 217 breast cancer patients, using the Danenberg Tumor Profile method, which combines microdissection and real-time-polymerase chain reaction. The significance of these enzymes as prognostic and 5-FU efficacy-predicting factors was evaluated. Our data showed that a low DPD expression is related to a high nuclear grade and other factors including hormone receptor-negativity. Low expression levels of TP were found in hormone receptor-negative tumors. TS and OPRT expression were not related to various clinicopathological factors, but patients with a high TS mRNA expression showed a significantly poorer prognosis in cases where 5-FU was not administered. The efficacy of 5-FU was more significant when administered for more than 6 months in the group with a high TS mRNA expression. These data suggest that TS mRNA expression in breast cancer tissue is an ideal predictor of outcomes for patients with no administration of 5-FU, and of the efficacy of 5-FU.
Hirohisa Ogawa, Masahiko Azuma, S Muto, Yasuhiko Nishioka, A Honjo, T Tezuka, Hisanori Uehara, Keisuke Izumi, A Itai and Saburo Sone : IκB kinase β inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma, Clinical and Experimental Allergy, Vol.41, No.1, 104-115, 2010.
(Summary)
Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) β is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKβ-NF-κB pathway may be an ideal strategy for the management of airway remodelling. We examined the effects of a newly synthesized IKKβ inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-β, via inhibition of IKKβ. IMD-0354 inhibited IL-13 and IL-1β production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness. IKKβ plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKβ inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.
Satoshi Sakaguchi, Hisatsugu Goto, Masaki Hanibuchi, Shinsaku Otsuka, Hirokazu Ogino, Souji Kakiuchi, Hisanori Uehara, Seiji Yano, Yasuhiko Nishioka and Saburo Sone : Gender difference in bone metastasis of human small cell lung cancer, SBC-5 cells in natural killer-cell depleted severe combined immunodeficient mice., Clinical & Experimental Metastasis, Vol.27, No.5, 351-359, 2010.
(Summary)
Lung cancer frequently develops multiple organ metastases, which thus makes this disease a leading cause of malignancy-related death worldwide. A gender difference is reported to affect the incidence and mortality of lung cancer; however, whether and how the gender difference is involved in lung cancer metastasis is unclear. This study evaluated the gender difference in multiple organ metastases in human small cell lung cancer (SBC-5) cells by using natural killer cell-depleted severe combined immunodeficient mice. Among multiple organ metastases, only bone metastasis formation significantly increased in female mice in comparison to males, while no significant difference was observed in the metastases to the liver and lungs. The suppression of androgen by castration or androgen receptor antagonist treatment in male mice also induced a significant increase of bone metastases. The number of osteoclasts in the bone metastatic lesions was greater in female mice and in mice with androgen suppression than in control male. However, there was no significant difference in the serum concentration of parathyroid hormone-related protein (PTHrP) associated with gender or androgen suppression. An in vitro study also indicated that sex steroid treatment had no effect on the proliferation or PTHrP production in SBC-5 cells. These results indicate that the balance of sex steroids therefore plays an important role in the formation of bone metastasis in small cell lung cancer, and suggests diverse mechanisms of interaction between cancer cells and host cells in the bone microenvironment.
(Keyword)
Androgens / Animals / Base Sequence / Bone Neoplasms / Carcinoma, Small Cell / Cell Line, Tumor / Cell Proliferation / DNA Primers / female / Humans / Killer Cells, Natural / Lung Neoplasms / Male / Mice / Mice, SCID / Orchiectomy / Parathyroid Hormone-Related Protein / Reverse Transcriptase Polymerase Chain Reaction / Sex Factors
Yoko Abe, Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara, Hiroyuki Furumoto and Hiromu Nishitani : A case of metastatic malignant melanoma of the ovary with a multilocular cystic appearance on MR imaging., Japanese Journal of Radiology, Vol.27, No.10, 458-461, 2009.
(Summary)
Ovarian metastasis from malignant melanoma is rare and usually appears as a solid ovarian mass. We report a case of ovarian metastasis from cutaneous malignant melanoma that proved to be a diagnostic dilemma. The ovarian metastasis exhibited a multilocular cystic appearance on magnetic resonance imaging, mimicking a mucinous ovarian tumor with massive ascites.
Takeshi Tsuchigauchi, Tetsuyuki Takahashi, Takamasa Ohnishi, Hirohisa Ogawa, Yoshimi Bando, Hisanori Uehara, Tamatsu Takizawa, Shinya Kaneda, Tokiko Nakai, Hiroshi Shiota and Keisuke Izumi : Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats, The Journal of Medical Investigation : JMI, Vol.56, No.3-4, 93-98, 2009.
(Summary)
The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats.
Tetsuyuki Takahashi, Hisanori Uehara, Yoshimi Bando and Keisuke Izumi : Soluble EP2 neutralizes prostaglandin E2-induced cell signaling and inhibits osteolytic tumor growth, Molecular Cancer Therapeutics, Vol.7, No.9, 2807-2816, 2008.
(Summary)
Prostaglandin E2 (PGE2) plays a key role in osteolytic bone metastasis as well as roles in inflammation, cell growth, and tumor development. PGE2 exerts its effects by binding and activating E-prostanoid receptor (EP). In this study, we propose a new approach for blocking EP-mediated cell signaling using a soluble chimeric EP2 fragment. Mammalian expression vectors encoding several human EP2 cDNAs were introduced into 293 cells and the culture medium was tested for their function as a decoy receptor for PGE2. PGE2 binding assays revealed that culture medium containing the second extracellular region of EP2 (FuEP2/Ex2) had binding activity. FuEP2/Ex2 neutralized PGE2-induced cyclic AMP production, cyclic AMP-responsive element binding protein phosphorylation, and subsequent induction of cyclooxygenase-2, interleukin (IL)-1beta, and IL-6 mRNAs. In human osteoblasts, this culture medium neutralized the induction of receptor activator of nuclear factor-kappaB ligand mRNA. A stable transfectant expressing FuEP2/Ex2 was established from human prostate cancer PC-3 cells (PC3-FuEP2/Ex2). PC3-FuEP2/Ex2 cells grew at similar rates to vector control cells under normal culture conditions, although PGE2-induced growth stimulation was suppressed. Intraosseous injection of PC3-FuEP2/Ex2 cells into the tibia of athymic nude mice revealed that the degrees of tumor growth and osteolysis were decreased compared with control cell-injected mice, with decreased osteoclasts and increased apoptotic cells. Furthermore, the cyclooxygenase-2, IL-1beta, and IL-6 mRNA levels were reduced in the tumor lesions. These data suggest that FuEP2/Ex2 is useful for treating osteolytic bone metastasis and cancers that depend on EP signaling for their growth and development.
Mayumi Takeuchi, Kenji Matsuzaki, Hiromu Nishitani and Hisanori Uehara : Ancient schwannoma of the female pelvis, Abdominal Imaging, Vol.33, No.2, 247-252, 2008.
(Summary)
BACKGROUND: The objective of this article is to define the imaging characteristics of ancient schwannoma, which is a rare variant of benign schwannoma with degenerative changes, arising in the female pelvis simulating ovarian tumors. METHODS: Eleven surgically proven ancient schwannomas of the female pelvis were evaluated retrospectively on the basis of CT and MR findings. RESULTS: Typical intra-pelvic schwannoma was a neurologically asymptomatic large mass, which may situate at presacral or lateral pelvic region with the continuity to the nerve or neural foramen. Ancient schwannomas manifested as encapsulated solid masses with random or eccentric cystic areas, or as cystic masses with marginal crescent-shaped or nodular solid components. Hemorrhagic changes and calcifications were often observed on MRI and CT respectively. To detect ipsilateral normal ovary and to demonstrate centripetal displacement of the adjacent rectum or iliac vessels were helpful to diagnose the tumor as an extra-ovarian mass situated at the extraperitoneal region. CONCLUSIONS: Diagnosis of ancient schwannoma before surgical treatment is important and should be made by its characteristic clinical and imaging findings.
Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara and Hiromu Nishitani : Malignant transformation of pelvic endometriosis: MR imaging findings and pathologic correlation, Radiographics, Vol.26, No.2, 407-417, 2006.
(Summary)
Malignant transformation is a rare complication of endometriosis. Endometriosis-associated ovarian cancers are seen more often in younger women than are ovarian cancers without endometriosis, and early detection is important to improve the prognosis and preserve fertility. However, normal decidual change of the ectopic endometrium in an endometrioma during pregnancy must be differentiated from malignant transformation. The finding that is most important for a diagnosis of malignant change is the presence of one or more contrast material-enhanced mural nodules within a cystic mass at magnetic resonance (MR) imaging. Dynamic subtraction MR imaging is useful in depicting small contrast-enhanced nodules within the hyperintense endometrioma on T1-weighted images. Intracystic coagulate may mimic a mural nodule; the absence of contrast enhancement is the diagnostic clue to its benignity. Enlargement of the endometrioma and the disappearance of shading within the mass on T2-weighted images are suggestive of malignant transformation.
Seiji Yano, Hiroaki Muguruma, Yuka Matsumori, Hisatsugu Goto, Emiko Nakataki, Nobutaka Edakuni, Hideki Tomimoto, Soji Kakiuchi, Akihiko Yamamoto, Hisanori Uehara, Anderson Ryan and Saburo Sone : Antitumor Vascular Strategy for Controlling Experimental Metastatic Spread of Human Small-Cell Lung Cancer Cells with ZD6474 in Natural Killer Cell Depleted Severe Combined Immunodeficient Mice, Clinical Cancer Research, Vol.11, No.24, 8789-8798, 2005.
(Summary)
Small-cell lung cancer is often characterized by rapid growth and metastatic spread. Because tumor growth and metastasis are angiogenesis dependent, there is great interest in therapeutic strategies that aim to inhibit tumor angiogenesis. The effect of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor tyrosine kinases, was studied in experimental multiple-organ metastasis models with human small-cell lung cancer cell lines (SBC-3 or SBC-5) in natural killer cell-depleted severe combined immunodeficient mice. Intravenously inoculated SBC-5 cells produced experimental metastases in the liver, lung, and bone whereas SBC-3 cells produced the metastases in the liver, systemic lymph nodes, and kidneys. Daily oral treatment with ZD6474 (50 mg/kg), started on day 14 (after the establishment of micrometastases), significantly reduced the frequency of large (>3 mm) metastatic colonies (in the liver and lymph nodes) and osteolytic bone lesions. ZD6474 treatment did not significantly reduce the frequency of small (<2-3 mm) metastatic lesions found in the lung (SBC-5) or kidney (SBC-3), consistent with an antiangiogenic mechanism of action. Immunohistochemical analysis of SBC-5 metastatic deposits in the liver showed that ZD6474 treatment inhibited VEGFR-2 activation and induced apoptosis of tumor-associated endothelial cells, resulting in decreasing tumor microvessel density. ZD6474 treatment was also associated with a decrease in tumor cell proliferation and an increase in tumor cell apoptosis. The antitumor effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib, a small-molecule inhibitor of epidermal growth factor receptor tyrosine kinase, was inactive in these models. These results suggest that ZD6474 may be of potential therapeutic value in inhibiting the growth of metastatic small-cell lung cancer in humans. Phase II trials with ZD6474 are currently ongoing in a range of solid tumors.
Yoshinori Aono, Yasuhiko Nishioka, Mami Inayama, Jun Kishi, Momoyo Ugai, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Imatinib as a Novel Antifibrotic Agent in Bleomycin-induced Pulmonary Fibrosis in Mice, American Journal of Respiratory and Critical Care Medicine, Vol.171, No.11, 1279-1285, 2005.
(Summary)
Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara, Hideki Shimazu and Hiromu Nishitani : A case of adenomyomatous polyp of the uterus associated with tamoxifen therapy, Radiation Medicine, Vol.23, No.6, 432-434, 2005.
(Summary)
A case of adenomyomatous polyp of the uterine endometrium is reported. The patient was 64-year-old woman treated with tamoxifen. Ultrasonography demonstrated a heterogeneous hyperechoic mass with small cystic spaces in the uterus. On magnetic resonance imaging (MRI), a thick stalk with many thin restiform branches within a large solid and cystic endometrial mass showed dendriform low intensity on T2-weighted images and intense enhancement on contrast-enhanced T1-weighted images. The prominent dendriform central fibrous core on MRI reflected a thick stalk originating from the myometrium with numerous branches containing abundant smooth muscle fibers, and may represent the pathologic feature of adenomyomatous polyp.
Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara, Shusaku Yoshida, Hiromu Nishitani and Hideki Shimazu : Pathologies of the uterine endometrial cavity and unusual manifestations and pitfalls on, European Radiology, Vol.15, No.11, 2244-2255, 2005.
(Summary)
The endometrial cavity may demonstrate various imaging manifestations such as normal, reactive, inflammatory, and benign and malignant neoplasms. We evaluated usual and unusual magnetic resonance imaging (MRI) findings of the uterine endometrial cavity, and described the diagnostic clues to differential diagnoses. Surgically proven pathologies of the uterine endometrial cavity were evaluated retrospectively with pathologic correlation. The pathologies included benign endometrial neoplasms such as endometrial hyperplasia and polyp, malignant endometrial neoplasms such as endometrial carcinoma and carcinosarcoma, endometrial-myometrial neoplasm such as endometrial stromal sarcoma, pregnancy-related lesions in the endometrial cavity such as gestational trophoblastic diseases (hydatidiform mole, invasive mole and choriocarcinoma) and placental polyp, myometrial lesions simulating endometrial lesions such as submucosal leiomyoma and some adenomyosis, endometrial neoplasms simulating myometrial lesions such as adenomyomatous polyp and endometrial lesions arising in the hemicavity of a septate/bicornate uterus, and fluid collections in the uterine cavity (hydro/hemato/pyometra). It is important to recognize various imaging findings in these diseases, in order to make a correct preoperative diagnosis.
Akira Hirata, Hisanori Uehara, Keisuke Izumi, Seiji Naito, Michihiko Kuwano and Mayumi Ono : Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib ('Iressa', ZD1839), Cancer Science, Vol.95, No.7, 614-618, 2004.
(Summary)
The development of gefitinib ('Iressa', ZD1839) by targeting the EGFR tyrosine kinase is a recent therapeutic highlight. We have reported that gefitinib is antiangiogenic in vitro, as well as in vivo. In this study, we asked if the anti-angiogenic action of gefitinib is due to a direct effect on activation of vascular endothelial cells by EGF. EGF, as well as VEGF, caused pronounced angiogenesis in an avascular area of the mouse cornea, and i.p. administration of gefitinib almost completely blocked the response to EGF, but not to VEGF. Immunohistochemical analysis demonstrated phosphorylation of EGFR by EGF in the neovasculature, and gefitinib markedly reduced this effect. Gefitinib also inhibited downstream activation of ERK 1/2 via EGFR in cultured microvascular endothelial (HMVE) cells. These findings suggest that the anti-angiogenic effect of gefitinib in the vascular endothelial cells of neo-vasculature is partly attributable to direct inhibition of EGFR activation, and that endothelial cells in malignant tumors play a critical role in the cancer therapeutic efficacy of gefitinib.
Sun-Jin Kim, Hisanori Uehara, Sertac Yazici, Robert R Langley, Junqin He, Rachel Tsan, Dominic Fan, Jerald J. Killion and Isaiah J. Fidler : Simultaneous blockade of platelet-derived growth factor-receptor and epidermal growth factor-receptor signaling and systemic administration of paclitaxel as therapy for human prostate cancer metastasis in bone of nude mice, Cancer Research, Vol.64, No.12, 4201-4208, 2004.
(Summary)
Once prostate cancer metastasizes to bone, conventional chemotherapy is largely ineffective. We hypothesized that inhibition of phosphorylation of the epidermal growth factor receptor (EGF-R) and platelet-derived growth factor receptor (PDGF-R) expressed on tumor cells and tumor-associated endothelial cells, which is associated with tumor progression, in combination with paclitaxel would inhibit experimental prostate cancer bone metastasis and preserve bone structure. We tested this hypothesis in nude mice, using human PC-3MM2 prostate cancer cells. PC-3MM2 cells growing adjacent to bone tissue and endothelial cells within these lesions expressed phosphorylated EGF-R and PDGF-R alpha and -beta on their surfaces. The percentage of positive endothelial cells and the intensity of receptor expression directly correlated with proximity to bone tissue. Oral administration of PKI166 inhibited the phosphorylation of EGF-R but not PDGF-R, whereas oral administration of STI571 inhibited the phosphorylation of PDGF-R but not EGF-R. Combination therapy using oral PKI166 and STI571 with i.p. injections of paclitaxel induced a high level of apoptosis in tumor vascular endothelial cells and tumor cells in parallel with inhibition of tumor growth in the bone, preservation of bone structure, and reduction of lymph node metastasis. Collectively, these data demonstrate that blockade of phosphorylation of EGF-R and PDGF-R coupled with administration of paclitaxel significantly suppresses experimental human prostate cancer bone metastasis.
Mayumi Takeuchi, Kenji Matsuzaki, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Imaging findings of urachal mucinous cystadenocarcinoma associated with pseudomyxoma peritonei., Acta Radiologica, Vol.45, No.3, 348-350, 2004.
(Summary)
Pseudomyxoma peritonei is an uncommon neoplastic condition in which gelatinous fluid-like materials are observed in the peritoneal cavity caused by the dissemination of mucinous adenocarcinoma. Although ruptured appendiceal mucocele is the most common cause, tumors arising from other organs may also cause pseudomyxoma peritonei. We report the imaging findings of an extremely rare case of urachal mucinous adenocarcinoma associated with pseudomyxoma peritonei on computed tomography and magnetic resonance imaging with histopathologic correlation.
(Keyword)
Aged / Aged, 80 and over / Cystadenocarcinoma, Mucinous / Humans / Magnetic Resonance Imaging / Male / Neoplasms, Multiple Primary / Peritoneal Neoplasms / Pseudomyxoma Peritonei / Tomography, X-Ray Computed / Urachus
Yoshiko Kanezaki, Toshiyuki Obata, Rie Matsushima, Asako Minami, Tomoyuki Yuasa, Kazuhiro Kishi, Yoshimi Bando, Hisanori Uehara, Keisuke Izumi, Tasuku Mitani, Mitsuru Matsumoto, Yukari Takeshita, Yutaka Nakaya, Toshio Matsumoto and Yousuke Ebina : KATP Channel Knockout Mice Crossbred with Transgenic Mice Expressing a Dominant-Negative Form of Human Insulin Receptor have Glucose Intolerance but not Diabetes, Endocrine Journal, Vol.51, No.2, 133-144, 2004.
(Summary)
Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.
Mayumi Takeuchi, Kenji Matsuzaki, Hideki Shimazu, Hiromu Nishitani and Hisanori Uehara : A case of urachal xanthogranuloma containing a calculus: CT and MRI findings, European Journal of Radiology Extra, Vol.49, No.3, 107-109, 2004.
(Summary)
We report a rare case of an urachal xanthogranuloma containing a urinary calculus, which was considered to have originated from vesicourachal diverticulum. The patient was a 66-year old woman with hematuria and pyuria. Computed tomography (CT) revealed a midline-situated supravesical cavitary mass containing a calculus. Sagittal images of magnetic resonance imaging (MRI) revealed continuity of the mass with the umbilicus. Fatty components of the xanthogranuloma showed low attenuation on CT and hyperintensity on T1-weighted images of MRI. The presence of a large calculus in the vesicourachal diverticulum may have caused continuous irritation resulting in the xanthogranulomatous formation.
Seiji Yano, Helong Zhang, Masaki Hanibuchi, Toyokazu Miki, Hisatsugu Goto, Hisanori Uehara and Saburo Sone : Combined therapy with a new bisphosphonate, minodronate (YM529), and chemotherapy for multiple organ metastases of small cell lung cancer cells in severe combined immunodeficient mice., Clinical Cancer Research, Vol.9, No.14, 5380-5385, 2003.
(Summary)
Lung cancer in the advanced stage frequently metastasizes to multiple organs, including the liver, lungs, lymph nodes, and bone. Bisphosphonates have been widely used to treat osteolytic bone metastasis in the past years; however, many studies have implicated that a single use of bisphosphonates could not prolong the survival of patients. In the present study, using a multiple-organ metastasis model of human lung cancer cells, we examined the effect of combined therapy with a new bisphosphonate (YM529) and etoposide (VP-16). Human small cell lung cancer (SBC-5) cells i.v. inoculated into natural killer cell-depleted severe combined immunodeficient mice metastasized to multiple organs, including the lungs, liver, kidneys, lymph nodes, and bone. SBC-5-bearing mice were treated with YM529 and/or VP-16 and sacrificed 5 weeks after tumor cell inoculation. Bone metastasis was assessed by X-ray photographs, and visceral metastasis was evaluated macroscopically. The number of osteoclasts in the bone lesions was examined by tartrate-resistant acid phosphatase staining. Monotherapy with YM529 suppressed the production of bone metastases, but not visceral metastasis. Histological analyses revealed that the number of osteoclasts in bone lesions was lower in YM526-treated mice, compared with control mice. VP-16 inhibited both bone metastasis and visceral (lung and liver) metastasis. However, neither YM529 alone nor VP-16 alone significantly prolonged the survival of SBC-5-bearing mice. Combined use of YM529 and VP-16 further inhibited the production of bone metastasis and significantly prolonged survival. Combined therapy with bisphosphonate and chemotherapy may be useful for small cell lung cancer patients with multiple organ metastases including bone metastasis.
Sun-Jin Kim, Marjorie Johnson, Kristen Koterba, Matthew H Herynk, Hisanori Uehara and Gary E Gallick : Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model, Clinical Cancer Research, Vol.9, No.14, 5161-5170, 2003.
(Summary)
The expression of c-Met, the receptor protein tyrosine kinase for hepatocyte growth factor/scatter factor, frequently increases during prostate tumor progression. However, whether reduced c-Met expression inhibits tumor growth and metastasis has not been ascertained. c-Met expression was reduced by infection of an adenovirus expressing a c-Met ribozyme into the highly metastatic human prostate cancer cell line PC3-LN4. In vitro, effects on c-Met, Akt, and extracellular signal-regulated kinase 1/2 expression and phosphorylation, Src expression and activity, and vascular endothelial growth factor expression were determined, as were effects on cell migration and invasion. Prostate tumor formation and metastasis to regional lymph nodes in nude mice were examined after both ex vivo and in vivo infection of cells. Infection of PC3-LN4 cells with the Ad-c-Met-expressing ribozyme decreased steady-state c-Met levels, decreased Src kinase activity, decreased vascular endothelial growth factor expression, and decreased migration and invasion versus the pU1 (control) virus. Significant inhibition of tumorigenicity (histologically confirmed tumors in only 1 of 10 mice) and consequent lymph node metastasis were observed upon ex vivo infection of Ad-c-Met. Similarly, gene therapy experiments led to complete inhibition of tumor growth in 7 of 8 mice. Reduction in c-Met expression substantially inhibits both tumor growth and lymph node metastasis of PC3-LN4 cells in orthotopic nude mouse models. Therefore, targeting the c-Met signaling pathways may be important in controlling tumor growth and metastasis in human prostate cancers.
Seiji Yano, Kanematsu Takahori, Toyokazu Miki, Aono Yoshinori, Masahiko Azuma, Akihiko Yamamoto, Hisanori Uehara and Saburo Sone : A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 ("Iressa")., Cancer Science, Vol.94, No.5, 453-458, 2003.
(Summary)
Bronchioloalveolar carcinoma (BAC), a form of pulmonary adenocarcinoma, presents unique clinical features, such as endobronchial spread and bronchorrhea in advanced stages. The prognosis for BAC patients in advanced stages is poor, as is the case for patients with other non-small-cell lung cancer (NSCLC) types, because of low susceptibility to conventional chemotherapy. Recently, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), ZD1839 ("Iressa"), has been investigated in phase II clinical studies (IDEAL 1 and IDEAL 2) as monotherapy against chemotherapy-refractory NSCLC, and provided clinically significant antitumor activity. In this study, we examined the therapeutic efficiency of ZD1839 in chemotherapy-refractory BAC patients with bronchorrhea. Two female BAC patients with bronchorrhea were treated once daily with ZD1839 (250 mg/day). In both cases, serous sputum production was dramatically reduced within 3 days of starting the treatment, and hypoxia and radiographic signs of bilateral lung consolidation were visibly improved within 7 days. Following more than 8 months of treatment, no evidence of recurrence or severe adverse events has been observed. These results suggest that this selective EGFR-TKI, ZD1839, may be a powerful agent for treatment of chemotherapy-refractory BAC patients with bronchorrhea.
Hisanori Uehara, Sun-Jin Kim, Takashi Karashima, David L. Shepherd, Dominic Fan, Rachel Tsan, Jerald J. Killion, Christopher Logothetis, Paul Mathew and Isaiah J Fidler : Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases, Journal of the National Cancer Institute, Vol.95, No.6, 458-470, 2003.
(Summary)
Expression of platelet-derived growth factor (PDGF) and activation (by autophosphorylation) of its receptor (PDGF-R), a tyrosine kinase, are associated with the growth of metastatic prostate tumor cells in the bone parenchyma. The tyrosine kinase inhibitor STI571 blocks the PDGF signaling pathway by inhibiting PDGF-R autophosphorylation. We examined the effects of STI571, given alone or with paclitaxel (Taxol), on tumor growth in a mouse model of prostate cancer metastasis. Human prostate cancer PC-3MM2 cells were injected into the tibias of male nude mice. Three days later the mice (20 per group) were randomly assigned to 5 weeks of treatment with oral and injected water (control), daily oral STI571, weekly injected paclitaxel, or STI571 plus paclitaxel. Lesions in bone and the surrounding muscles were then harvested and analyzed by histology, western blotting (for PDGF-R phosphorylation), immunohistochemistry (for expression of proangiogenic molecules), and double immunofluorescence (to identify endothelial cells and apoptotic tumor cells). Growth of bone lesions was monitored by digital radiography. Bone lesions from control mice were used to establish short-term cell cultures for analysis of PDGF-R phosphorylation. All statistical tests were two-sided. PC-3MM2 cells cultured from bone lesions and treated in vitro with STI571 had less phosphorylated PDGF-R than untreated cells. In control mice, bone lesions expressed high levels of PDGF and activated (i.e., phosphorylated) PDGF-R, whereas lesions in the adjacent musculature did not. Activated PDGF-R was present on the surface of endothelial cells within the bone lesions but not in endothelial cells of uninjected bone. Mice treated with STI571 or STI571 plus paclitaxel had a lower tumor incidence, smaller tumors, and less bone lysis and lymph node metastasis than mice treated with water or paclitaxel alone (P<.001 for all). Mice treated with STI571 or STI571 plus paclitaxel had less phosphorylated PDGF-R on tumor cells and tumor-associated endothelial cells, less tumor cell proliferation, statistically significantly more apoptotic tumor cells (all P<.001), and fewer tumor-associated endothelial cells (P<.001) than control mice. Endothelial cells appear to express phosphorylated PDGF-R when they are exposed to tumor cells that express PDGF. Using STI571 to inhibit PDGF-R phosphorylation may, especially in combination with paclitaxel, produce substantial therapeutic effects against prostate cancer bone metastasis.
Seiji Yano, Hiroshi Nokihara, Akihiko Yamamoto, Hisatsugu Goto, Hirohisa Ogawa, Takanori Kanematsu, Toyokazu Miki, Hisanori Uehara, Yasuo Saijo, Toshihiro Nukiwa and Saburo Sone : Multifunctional interleukin-1beta promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules., Cancer Science, Vol.94, No.3, 244-252, 2003.
(Summary)
We examined whether interleukin-1 (IL-1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL-1beta enhanced expression of various cytokines (IL-6, IL-8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule-1 (ICAM-1) by A549, PC14, RERF-LC-AI, and SBC-3 cells expressing IL-1 receptors. A549 cells transduced with human IL-1beta-gene with the growth-hormone signaling-peptide sequence (A549/IL-1beta) secreted a large amount of IL-1beta protein. Overexpression of IL-1beta resulted in augmentation of expression of the cytokines, ICAM-1, and matrix metalloproteinase-2 (MMP-2). A549/IL-1beta cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti-IL-1beta antibody inhibited formation of lung metastasis by A549/IL-1beta cells. Moreover, A549/IL-1beta cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL-1beta cells. Histological analyses showed that more host-cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL-1beta cells, compared with tumors derived from control A549 cells. These findings suggest that IL-1beta facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis.
Sun-Jin Kim, Hisanori Uehara, Takashi Karashima, David L. Shepherd, Jerald J. Killion and Isaiah J Fidler : Blockade of Epidermal Growth Factor Receptor Signaling in Tumor Cells and Tumor-associated Endothelial Cells for Therapy of Androgen-independent Human Prostate Cancer Growing in the Bone of Nude Mice, Clinical Cancer Research, Vol.9, No.3, 1200-1210, 2003.
(Summary)
We determined whether blockade of the epidermal growth factor receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor (PKI 166) alone or in combination with injectable Taxol inhibits the growth of PC-3MM2 human prostate cancer cells in the bone of nude mice. Male nude mice implanted with PC-3MM2 cells in the tibia were treated with oral administrations of PKI 166 or PKI 166 plus injectable Taxol beginning 3 days after implantation. The incidence and size of bone tumors and destruction of bone were determined by digitalized radiography. Expression of epidermal growth factor (EGF), EGF-R, and activated EGF-R in tumor cells and tumor-associated endothelial cells was determined by immunohistochemistry. Oral administration of PKI 166 or PKI 166 plus injectable Taxol reduced the incidence and size of bone tumors and destruction of bone. Immunohistochemical analysis revealed that PC-3MM2 cells growing adjacent to the bone expressed high levels of EGF and activated EGF-R, whereas tumor cells in the adjacent musculature did not. Moreover, endothelial cells within the bone tumor lesions, but not in uninvolved bone or tumors in the muscle, expressed high levels of activated EGF-R. Treatment with PKI 166 and more so with PKI 166 plus Taxol significantly inhibited phosphorylation of EGF-R on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions. These data indicate that endothelial cells exposed to EGF produced by tumor cells express activated EGF-R and that targeting EGF-R can produce significant therapeutic effects against prostate cancer bone metastasis.
Mayumi Takeuchi, Kenji Matsuzaki, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Localized pseudomyxoma peritonei in the female pelvis simulating ovarian carcinomatous peritonitis., Journal of Computer Assisted Tomography, Vol.27, No.4, 622-625, 2003.
(Summary)
Two cases of localized pseudomyxoma peritonei in the female pelvic cavity associated with a ruptured appendiceal mucocele and ovarian involvement that mimicked ovarian carcinomatous peritonitis were evaluated. Subtle omental irregularity adjacent to the cecum may suggest the hidden appendiceal origin reflecting localized carcinomatous peritonitis caused by the occult rupture of the mucocele. Mucinous fluid-like materials were localized in the pelvic cavity with scalloping of the uterus, which may be the diagnostic finding of pseudomyxoma peritonei.
Mayumi Takeuchi, Kenji Matsuzaki, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Ovarian cystadenofibromas: characteristic magnetic resonance findings with pathologic correlation, Journal of Computer Assisted Tomography, Vol.27, No.6, 871-873, 2003.
(Summary)
Ovarian cystadenofibroma is a benign tumor and may appear as a multilocular cystic mass with solid nodular components mimicking malignant ovarian tumor. Preoperative diagnosis is required to avoid excess surgical procedure. We report characteristic magnetic resonance imaging (MRI) findings of 2 cases with pathologic correlation. On T2-weighted images, the solid components of the tumors showed very low intensity, in which very high intense tiny cysts were present reflecting dense fibrous stromal proliferation with scattered small cystic glandular structures. This "black sponge"-like appearance was considered to be diagnostic.
Takanori Kanematsu, Seiji Yano, Hisanori Uehara, Yoshimi Bando and Saburo Sone : Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients, Oncology Research, Vol.13, No.5, 289-298, 2003.
(Summary)
Epidermal growth factor receptor (EGFR) is commonly overexpressed in non-small cell lung cancer (NSCLC) and its tyrosine kinase phosphorylation is thought to be an ideal target in the treatment of patients with NSCLC. In the present study, we examined surgically obtained specimens from a series of 36 NSCLC patients for expression of EGFR, phosphorylated EGFR (p-EGFR), and HER2 by immunohistochemistry, and also examined the correlation with clinical characteristics. The positive rate of EGFR, p-EGFR, and HER2 was 97.2%, 44.4%, and 88.6%, respectively, and the overexpression rate was 80.6%, 0.0%, and 27.8%, respectively. EGFR overexpression and phosphorylation were seen at almost the same rate in each histological type of squamous and nonsquamous cell carcinoma (squamous vs. nonsquamous; 78.6% vs. 81.8% for EGFR, 35.7% vs. 50.0% for p-EGFR), while HER2 overexpression was seen less frequently in squamous cell carcinoma than in nonsquamous cell carcinoma (0.0% vs. 45.5%, P = 0.003). Univariate analysis revealed that EGFR overexpression was related to good performance status (P = 0.038) but not related to EGFR phosphorylation. EGFR phosphorylation was correlated to short time to progression (TTP) (P = 0.002) and poor prognosis (P = 0.002), although EGFR overexpression, HER2 overexpression, or EGFR-HER2 coexpression were not correlated to TTP or survival. Bivariate analysis showed EGFR phosphorylation was related to short TTP and poor prognosis both in early and advanced stages. Multivariate analyses confirmed that clinical stage, performance status, and p-EGFR expression were independently associated with increasing risk of short TTP and poor prognosis. These results suggest that phosphorylation, but not overexpression, of EGFR may be an important predictor for clinical outcome of NSCLCs.
Helong Zhang, Seiji Yano, Toyokazu Miki, Hisatsugu Goto, Takanori Kanematsu, Hiroaki Muguruma, Hisanori Uehara and Saburo Sone : A novel bisphosphonate minodronate (YM529) specifically inhibits osteolytic bone metastasis produced by human small-cell lung cancer cells in NK-cell depleted SCID mice., Clinical & Experimental Metastasis, Vol.20, No.2, 153-159, 2003.
(Summary)
In the present study, we examined the effects of a newly developed bisphosphonate, minodronate (YM529), on osteolytic bone metastasis caused by lung cancer. Human small-cell lung cancer (SBC-5) cells, injected intravenously into natural killer cell-depleted SCID mice, produced radiologically detectable bone metastasis by day 18 and macroscopically visible visceral metastases (lung, liver, kidney, systemic lymph node) by day 35. Prophylactic treatment with YM529 on day 1 significantly inhibited the formation of osteolytic bone metastasis evaluated on X-ray photographs in a dose-dependent manner. In addition, treatment with YM529 after establishment of bone metastasis (on day 21) also inhibited bone metastasis, although the treatment was more effective when started earlier. Single administration was as effective as repeated treatment, suggesting a sustained inhibitory effect of YM529 on bone metastasis. YM529 reduced the number of osteoclasts in the bone metastatic lesions in vivo, but had no effect on the proliferation or cytokine production of SBC-5 cells in vitro. These results suggest that YM529 is a potent inhibitor of bone metastasis of human lung cancer, probably by suppressing osteoclastic bone resorption. In contrast, treatment with YM529 had no effect on visceral metastasis, even if started on day 1, and did not prolong the survival of the mice. Therefore, development of a combined modality is necessary for prolonging the survival of small-cell lung cancer patients with multiple-organ metastasis.
Nobuo Satake, Hisanori Uehara, Nobuya Sano, Takayuki Kubo, Mitsunori Sasa and Keisuke Izumi : Cytological analysis of glycogen-rich carcinoma of the breast: report of two cases, The Journal of Medical Investigation : JMI, Vol.49, No.3-4, 193-196, 2002.
(Summary)
Glycogen-rich carcinoma is a rare special histologic subtype of breast cancer and its incidence is estimated to be 1.4% in breast malignancies. However, its precise characteristics in cytological specimens have not yet been fully clarified. Fifty-nine-year-old and 53-year-old women underwent fine-needle aspiration biopsy cytology (FNABC) of a breast tumor, confirming malignancy. A mastectomy with axillary dissection was performed. Cytologically, a moderate amount of eosinophilic, finely granular cytoplasm was seen in the majority of the tumor cells, however, foamy and vacuolated cytoplasm was noted in some tumor cells. Histologically, the tumor cells of both cases had clear and granular cytoplasm, which showed a positive reaction with periodic acid-Schiff, eliminated by diastase. While clear cytoplasm in the tumor cells in the FNABC seemed to be a pivotal cytological characteristic of glycogen-rich carcinoma, it may not be a major component of cytological specimens. Routine periodic acid-Schiff staining may be required to diagnose glycogen-rich carcinoma in cytological methods.
(Tokushima University Institutional Repository: 110654, PubMed: 12323010)
87.
Suyun Huang, Curtis A Pettaway, Hisanori Uehara, Corazon D Bucana and Isaiah J Fidler : Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis, Oncogene, Vol.20, No.31, 4188-4197, 2001.
(Summary)
Since the NF-κB/relA transcription factor is constitutively activated in human prostate cancer cells, we determined whether blocking NF-κB/relA activity in human prostate cancer cells affected their angiogenesis, growth, and metastasis in an orthotopic nude mouse model. Highly metastatic PC-3M human prostate cancer cells were transfected with a mutated IκBα (IκBαM), which blocks NF-κB activity. Parental (PC-3M), control vector-transfected (PC-3M-Neo), and IκBαM-transfected (PC-3M-IκBαM) cells were injected into the prostate gland of nude mice. PC-3M and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastasis, whereas PC-3M-IκBαM cells produced slow growing tumors with low metastatic potential. NF-κB signaling blockade significantly inhibited in vitro and in vivo expression of three major proangiogenic molecules, VEGF, IL-8, and MMP-9, and hence decreased neoplastic angiogenesis. Inhibition of NF-κB activity in PC-3M cells also resulted in the downregulation of MMP-9 mRNA and collagenase activity, resulting in decreased invasion through Matrigel. Collectively, these data suggest that blockade of NF-κB activity in PC-3M cells inhibits angiogenesis, invasion, and metastasis.
Sun Jin Kim, Hisanori Uehara, Takashi Karashima, Marya Mccarty, Nancy Shih and Jsaiah J. Fidler : Expression of interleukin-8 correlates with angiogenesis, tumorigenicity, and metastasis of human prostate cancer cells implanted orthotopically in nude mice, Neoplasia, Vol.3, No.1, 33-42, 2001.
(Summary)
We determined whether the expression of interleukin-8 (IL-8) by human prostate cancer cells correlates with induction of angiogenesis, tumorigenicity, and production of metastasis. Low and high IL-8-producing clones were isolated from the heterogeneous PC-3 human prostate cancer cell line. The secretion of IL-8 protein correlated with transcriptional activity and levels of IL-8 mRNA. All PC-3 cells expressed both IL-8 receptors, CXCR1 and CXCR2. The low and high IL-8-producing clones were injected into the prostate of nude mice. Titration studies indicated that PC-3 cells expressing high levels of IL-8 were highly tumorigenic, producing rapidly growing, highly vascularized prostate tumors with and a 100% incidence of lymph node metastasis. Low IL-8-expressing PC-3 cells were less tumorigenic, producing slower growing and less vascularized primary tumors and a significantly lower incidence of metastasis. In situ hybridization (ISH) analysis of the tumors for expression of genes that regulate angiogenesis and metastasis showed that the expression level of IL-8, matrix metalloproteinases, vascular endothelial growth factor (VEGF), and E-cadherin corresponded with microvascular density and biological behavior of the prostate cancers in nude mice. Collectively, the data show that the expression level of IL-8 in human prostate cancer cells is associated with angiogenesis, tumorigenicity, and metastasis.
Yoshimi Bando, Tetsuya Kitagawa, Hisanori Uehara, Nobuya Sano, Nobuo Satake, Y Onose, Takashi Kitaichi, Osamu Miki, Itsuo Katoh and Keisuke Izumi : So-called mesothelial/monocytic incidental cardiac excrescences obtained during valve replacement surgery: report of three cases and literature review., Virchows Archiv, Vol.437, No.3, 331-335, 2000.
(Summary)
We present three cases of so-called mesothelial/monocytic incidental cardiac excrescences (MICE) of the heart and a brief review of related literature. Case 1 was a 51-year-old woman who underwent mitral- and aortic-valve replacement. A tissue sample was submitted as a thrombus attached to the left atrial endocardium. Case 2 was a 69-year-old woman who underwent mitral-valve replacement. The sample was incidentally obtained as whitish clot-like fragments, but its exact origin was not known. Case 3 was a 68-year-old woman who underwent mitral-valve replacement for suspected infective endocarditis. The sample adherent to the pericardium was removed after valvular surgery. Histologically, these lesions were composed of a mixture of plump histiocytoid cells, a papillary arrangement of cuboidal cells, various sized vacuoles, and fibrin. The nests of cuboidal cells resembled cancer cells but showed features of mesothelial cells and no proliferative activity, immunohistochemically or ultrastructurally. In all cases, a suction tube placed in the left atrium was occasionally used to remove overflowing intrapericardial fluid during the surgery. The tip of the suction tube was covered with spiral wire, which is likely to transfer the stripped pericardial mesothelial cells to the left atrium. The significance of MICE is their possibility of being misdiagnosed as metastatic carcinoma by pathologists and a risk of arterial embolization by mesothelial debris clinically.
(Keyword)
Mesothelium / mesothelial/monocytic / incidental cardiac excrescences / cardiac surgery
Hisanori Uehara, Hisashi Otsuka and Keisuke Izumi : Modifying effects of a mixture of acetaminophen, aspirin, dipyrone and ethenzamide on a multiorgan initiation model and its carcinogenicity in male F344 rats, Cancer Letters, Vol.135, No.1, 83-90, 1998.
93.
Akiko Akagi, Nobuya Sano, Hisanori Uehara, Takanori Minami, Hisashi Otsuka and Keisuke Izumi : Non-carcinogenicity of Capsaicinoids in B6C3F1 Mice, Food and chemical toxicology, Vol.36, No.12, 1065-1071, 1998.
94.
Shuji Ozaki, Koji Ogasahara, Masaaki Kosaka, Toshi Inoshita, Shingo Wakatsuki, Hisanori Uehara and Toshio Matsumoto : Hepatosplenic gamma delta T-cell lymphoma associated with hepatitis B virus infection, The Journal of Medical Investigation : JMI, Vol.44, No.3-4, 215-217, 1998.
(Summary)
Hepatitis B virus (HBV) infection has been implicated in the development of hepatocellular and hematopoietic malignancies. We describe a patient with chronic hepatitis B who developed hepatosplenic gamma delta T-cell lymphoma. A 45-year-old woman presented with marked hepatosplenomegaly and hepatic failure during the course of chronic hepatitis B. Peripheral blood examination revealed 57% abnormal lymphoid cells which expressed the gamma delta T-cell receptor. The cytogenetic analysis of tumor cells showed an abnormal karyotype; 47, XX, -13, +2mar in all 20 metaphases examined. A clonal rearrangement of the T-cell receptor genes was demonstrated by Southern blot analysis, showing monoclonal expansion of tumor cells. A liver biopsy specimen showed fibrosis of the portal areas and sinusoidal infiltration of tumor cells. HBV infection was documented by the presence of IgG anti-HBc and anti-HBs antibodies in serum. Although HBV-DNA was not detected in tumor cells by polymerase chain reaction analysis, there is a possibility that proliferation of gamma delta T cells in response to HBV infection played a role in the pathogenesis of hepatosplenic gamma delta T-cell lymphoma.
(Tokushima University Institutional Repository: 110670, PubMed: 9597812)
95.
Lihong Wang, Naoko Muromoto, Hideki Hayashi, Yasumasa Mitani, Hisanori Uehara, Keisuke Izumi and Yousuke Ebina : Hyperinsulinemia but no diabetes in transgenic mice homozygously expressing the tyrosine kinase-deficient human insulin receptor., Biochemical and Biophysical Research Communications, Vol.240, No.2, 446-451, 1997.
(Summary)
We generated transgenic mice homozygous for the tyrosine kinase-deficient human insulin receptor (hIRK1030M(+/+)) under control of the insulin receptor promoter. Similar growth patterns and results of glucose tolerance tests were observed among normal, heterozygous, and homozygous mice. Insulin tolerance test indicated no significant difference in the hypoglycemic response to insulin among the three genotypes. However, the serum insulin levels of the homozygous mice before and after glucose loading (201.42 +/- 58.15 pg/ml to 578.57 +/- 49.03 pg/ml) were significantly higher than in the control mice (100.92 +/- 19.55 pg/ml to 356.36 +/- 55.08 pg/ml; p < 0.01 and p < 0.01, respectively) and heterozygous mice (74.46 +/- 18.55 pg/ml to 352.33 +/- 52.43 pg/ml; p < 0.005 and p < 0.01, respectively). Immunohistological evidence of pancreatic islets showed no significant difference among the three genotypes. Taken together, these results suggest that the tyrosine kinase-deficient insulin receptor causes hyperinsulinemia but not diabetes in these homozygous transgenic mice.
Nobuya Sano, Hisanori Uehara, Muneo Nakamura and Keisuke Izumi : CYTOMEGALOVIRUS INFECTION OF THE LIVER, The Tokushima Journal of Experimental Medicine, Vol.38, No.1,2, 45-47, 1991.
(Keyword)
Cytomegalovirus / immunohistochemistry / In situ hybridization / Liver
Academic Paper (Unrefereed Paper):
1.
Yosuke Iwakawa, Masaaki Nishi, Yuuma Wada, Kouzou Yoshikawa, Chie Takasu, Mitsuo Shimada, Yasuyo Saijo, Minoru Matsumoto, Takeshi Oya and Hisanori Uehara : Pleomorphic type undifferentiated gastric sarcoma, report of a case., Clinical Journal of Gastroenterology, Vol.16, No.1, 20-25, 2023.
(Summary)
Reports on pleomorphic type of undifferentiated sarcoma (PUS) originating from the gastrointestinal tract, especially the stomach, are extremely rare. We herein report a case of pleomorphic type undifferentiated gastric sarcoma. The patient was a 67-year-old woman. The chief complaint was upper abdominal pain. Upper gastrointestinal endoscopy, ultrasonography, and contrast-enhanced computed tomography showed two submucosal tumors at the greater curvature of the fundus and the lesser curvature of the gastric angle. Endoscopic ultrasound-guided fine-needle aspiration revealed a c-kit-negative spindle cell tumor at the greater curvature of the fundus. Total gastrectomy, splenectomy, and partial resection of the diaphragm and liver were performed. One lesion had invaded the lateral segment of the liver, left diaphragm and spleen. The postoperative course was uneventful. Histopathological and immunohistochemical examinations of the resected specimen revealed PUS. Peritoneal dissemination was detected at 8 months after surgery. However, no effective therapeutic agents were adopted for chemotherapy. The patient had poor performance status due to disease progression and underwent best supportive care. The patient died 10 months after surgery. This case highlights the imaging, histological diagnosis, and treatment strategy for PUS originating from the stomach. Surgeons should be aware of PUS as a differential diagnosis in cases with submucosal tumor of the stomach.
Yoshimi Bando, Tomoko Kobayashi, Yuko Miyakami, Satoshi Sumida, Takumi Kakimoto, Yasuyo Saijo and Hisanori Uehara : Triple-negative breast cancer and basal-like subtype : Pathology and targeted therapy., The Journal of Medical Investigation : JMI, Vol.68, No.3.4, 213-219, 2021.
(Summary)
Triple-negative breast cancer (TNBC) is a heterogenous disease. For personalized medicine, it is essential to identify and classify tumor subtypes to develop effective therapeutic strategies. Although gene expression profiling has identified several TNBC subtypes, classification of these tumors remains complex. Most TNBCs exhibit an aggressive phenotype, but some rare types have a favorable clinical course. In this review, we summarize the classification and characteristics related to the various TNBC subtypes, including the rare types. Therapeutic methods that are suitable for each subtype are also discussed. Of the intrinsic breast cancer subtypes identified by gene expression analysis, the basal-like subtype specifically displayed decreased expression of an estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) cluster. We also present results that characterize the TNBC and basal-like phenotypes. TNBC may be categorized into four major classes : basal-like, immune-enriched, mesenchymal, and luminal androgen receptor. Therapeutic strategies for each subtype have been proposed along with newly approved targeted therapies for TNBC, such as immune checkpoint inhibitors. Understanding the classification of TNBC based on gene expression profiling in association with clinicopathological factors will facilitate accurate pathological diagnosis and effective treatment selection. J. Med. Invest. 68 : 213-219, August, 2021.
Katsuhiro Kinoshita, Yasuhiko Nishioka, 岸 昌美, 竹﨑 彰夫, Yoshinori Aono, Momoyo Azuma, Jun Kishi, Hisanori Uehara, Keisuke Izumi and Saburo Sone : FAKシグナルの肺線維化における役割-ブレオマイシン肺線維症モデルでの検討, Respiratory Molecular Medicine, Vol.15, No.1, 124-127, 2011.
7.
Hisanori Uehara : Angiogenesis of prostate cancer and antiangiogenic therapy, The Journal of Medical Investigation : JMI, Vol.50, No.3-4, 146-153, Aug. 2003.
(Summary)
Tumor-associated angiogenesis refers to the growth of new vessels toward and within the tumor. Several studies have revealed that increasing intratumoral microvessel density, a major of tumor-associated angiogenesis, correlates with greater aggressiveness of prostate cancer. Angiogenesis consists of multiple, sequential, and interdependent steps dependent on the local balance of proangiogenic and antiangiogenic molecules Many proangiogenic and antiangiogenic molecules have been demonstrated to regulate growth and metastasis of prostate cancer. As tumor-associated angiogenesis is a crucial step in the process of prostate cancer development, inhibition of tumor neovascularization, and/or destruction of tumor vasculature (antiangiogenic therapy) may maintain the tumors in a dormant state or, perhaps in combination with cytotoxic therapies, potentiate shrinkage of tumors. Recently, therapeutic agents targeting the receptors of proangiogenic molecules and their signal transduction cascade have been developed. In this article, the role of angiogenic molecules in prostate cancer biology, and the application of angiogenesis inhibition to therapeutics for prostate cancer are reviewed.
(Keyword)
Angiogenic Proteins / Drug Design / Endostatins / Humans / Interferons / Male / Neovascularization, Pathologic / Prostatic Neoplasms / Signal Transduction
(Tokushima University Institutional Repository: 110690, PubMed: 13678383)
Proceeding of International Conference:
1.
Kei Daizumoto, Naoka Osafune, Kohei Torii, Ryota Nishimura, Hisanori Uehara, Mitsuki Nishiyama, Saki Kobayashi, Yutaro Sasaki, Ryotaro Tomida, Yoshito Kusuhara, Tomoya Fukawa, Kunihisa Yamaguchi and Masayuki Takahashi : Deep learning-based depth prediction system for upper tract urothelial carcinoma, the 111th Annual Meeting of the Japanese Urological Association (JUA), PDA-36-05, Yokohama, Apr. 2024.
(Keyword)
medical image / deep learning
2.
Kei Daizumoto, Naoka Osafune, Kohei Torii, Ryota Nishimura, Hisanori Uehara, Mitsuki Nishiyama, Saki Kobayashi, Yutaro Sasaki, Ryotaro Tomida, Yoshiteru Ueno, Yoshito Kusuhara, Tomoya Fukawa, Kunihisa Yamaguchi, Yasuyo Yamamoto, Masayuki Takahashi and Junya Furukawa : Development of pT classification prediction system in UTUC using deep-learning, 39th Annual European Association of Urology Congress, A0130, Paris, Apr. 2024.
3.
Koyama Kazuya, Kagawa Kozo, Nishimura Haruka, Hiroshi Kawano, Yuko Toyoda, Hisatsugu Goto, Hirohisa Ogawa, Hisanori Uehara and Yasuhiko Nishioka : Novel Multi-tyrosine Kinase Inhibitor TAS-115 Attenuates Bleomycin-induced Pulmonary Fibrosis In Mice., ATS 2018 International Conference, San Diego, May 2018.
4.
Yuko Toyoda, Morizumi Shun, Seidai Satou, Okazaki Hiroyasu, Chen Yanjuan, Hisatsugu Goto, Hirohisa Ogawa, Nishimura Haruka, Koyama Kazuya, Hiroshi Kawano, Yoshinori Aono, Hisanori Uehara and Yasuhiko Nishioka : Role of Fibroblast Growth Factor/Fibroblast Growth Factor Receptor Signal in Bleomycin-Induced Pulmonary Fibrosis in Mice., ATS 2017 International Conference, Washington, D.C., May 2017.
5.
S Morizumi, S Sato, Shinji Abe, H Okazaki, C Yanjuan, Hisatsugu Goto, Masaki Hanibuchi, Yoshinori Aono, Hirohisa Ogawa, Masaki Hanibuchi, Hisanori Uehara and Yasuhiko Nishioka : Anti-fibrotic efficacy of nintedanib on pulmonary fibrosis via suppression of fibrocyte activity., ERS2016 International Conference, Sep. 2016.
6.
Hisatsugu Goto, Atsushi Mitsuhashi, Atsuro Saijo, Takuya Kuramoto, Sho Tabata, Yoshinori Aono, Hisanori Uehara, Masaki Hanibuchi and Yasuhiko Nishioka : Fibrocytes mediate acquired resistance to anti-angiogenic therapy with bevacizumab in thoracic tumors, ATS 2016 International Conference, May 2016.
7.
Koichi Tsuneyama, Ryosuke Bessho, Masahiro Miki, Hayato Baba, Tetsuyuki Takahashi, Hirohisa Ogawa and Hisanori Uehara : Hyperinsulinemia, not hyperglycemia accelerates the progression of hepatocellular carcinoma in neonatal streptozotocin induced mouse model, Annual meeting, American Association for the study of the Liver, Nov. 2015.
8.
Hirokazu Ogino, Mitsuhashi Atsushi, Hisatsugu Goto, Atsuro Saijo, Kuramoto Takuya, Tabata Sho, Hisanori Uehara, Souji Kakiuchi, Masaki Hanibuchi and Yasuhiko Nishioka : Characterization of sphere-forming stem-like population of lung cancer cell line in multi-organ metastasis model, ATS 2015 International Conference, Denver, May 2015.
9.
Hisatsugu Goto, Mitsuhashi Atsushi, Atsuro Saijo, Kuramoto Takuya, Tabata Sho, Yoshinori Aono, Hisanori Uehara, Souji Kakiuchi, Masaki Hanibuchi and Yasuhiko Nishioka : The role of fibrocytes in the acquired resistance to anti-angiogenic therapy with bevacizumab in malignant pleural mesothelioma, ATS 2015 International Conference, Denver, May 2015.
10.
Mitsuhashi Atsushi, Hisatsugu Goto, Kuramoto Takuya, Tabata Sho, Yukishige Sawaka, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, Ledford G Julie, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses progression of human lung adenocarcinoma in nude mice via modulating host immune response., 18th Congress of the Asian Pacific Society of Respirology, Yokohama, Nov. 2013.
11.
Katsuhiro Kinoshita, Yoshinori Aono, Hisatsugu Goto, Momoyo Azuma, Takezaki Akio, Yoshijima Terumi, Kishi Masami, Jun Kishi, Yuko Toyoda, Hiroshi Kawano, Abe Shuichi, Toshifumi Tezuka, Hisanori Uehara, Keisuke Izumi and Yasuhiko Nishioka : Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice., 18th Congress of the Asian Pacific Society of Respirology, Yokohama, Nov. 2013.
12.
Hisatsugu Goto, Mitsuhashi Atsushi, Kuramoto Takuya, Tabata Sho, Yukishige Sawaka, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, Ledford G. Julie, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses lung cancer progression by regulating tumor-associated macrophage polarization., ATS 2013 Conference, Philadelphia, May 2013.
13.
Keisuke Izumi, Chie Takasu, Tetsuyuki Takahashi and Hisanori Uehara : Serum biochemistry and microarray analysis of liver and colonic mucosa in LETO and OLETF rats treated with 20% caloric restriction and high-fat diet, American Association for Cancer Research 104th Annual Meeting, Apr. 2013.
14.
Tetsuyuki Takahashi, Hisanori Uehara and Keisuke Izumi : Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and usefulness of TMPRSS4 as a molecular target for synergistic efficacy, American Association for Cancer Research 104st Annual Meeting, Apr. 2013.
15.
Atsushi Mitsuhashi, Hisatsugu Goto, Trung The Van, Takuya Kuramoto, Sho Tabata, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, Saburo Sone and Yasuhiko Nishioka : Acquired resistance to anti-VEGF therapy via angiogenic switch in orthotopically implanted human malignant pleural mesothelioma in SCID mice., Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research, Maui, Feb. 2013.
16.
Sawaka Yukishige, Hisatsugu Goto, Atsushi Mitsuhashi, Takuya Kuramoto, Sho Tabata, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, Julie G. Ledford, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses lung cancer progression by regulating tumor-associated macrophage polarization., Ninth AACR-Japanese Cancer Association Joint Conference: Breakthroughs in Basic and Translational Cancer Research, Maui, Feb. 2013.
17.
Atsushi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Sho Tabata, Sawaka Yukishige, Shinji Abe, Masaki Hanibuchi, Souji Kakiuchi, Atsuro Saijo, Yoshinori Aono, Hisanori Uehara, Seiji Yano, Julie G Ledford, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses progression of human lung adenocarcinoma in nude mice via modulating host immune response, Joint Meeting to Seoul National University, Seoul, Dec. 2012.
18.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Atsuro Saijo, Souji Kakiuchi, Masaki Hanibuchi, Yoichi Maekawa, Koji Yasutomo, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, 14th International Biennial Congress of the Metastasis Research Society, Brisbane, Sep. 2012.
19.
Takuya Kuramoto, Hisatsugu Goto, Atsushi Mitsuhashi, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Seidai Sato, Souji Kakiuchi, Masaki Hanibuchi, Yoichi Maekawa, Koji Yasutomo, Shin-ichi Akiyama, Saburo Sone and Yasuhiko Nishioka : Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through down-regulation of NF-kappa-B activity, AACR Annual Meeting 2012, Chicago, Apr. 2012.
20.
Tomoya Fukawa, Ono Masaya, Hisanori Uehara, Taisuke Matsuo, Nakamura Yusuke, Hiro-omi Kanayama and Toyomasa Katagiri : Identification and characterization of RCCDH as a novel molecular target for clear renal cell carcinoma., 70th Annual Meeting of the Japanese Cancer Association, Oct. 2011.
21.
Katsuhiro Kinoshita, Yasuhiko Nishioka, Masami Kishi, Momoyo Azuma, Yoshinori Aono, Hisanori Uehara, Akio Takezaki, S. Hatakeyama, E. Kawahara and Saburo Sone : Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice., ATS 2011 International Conference, Denver, May 2011.
22.
Momoyo Azuma, Yasuhiko Nishioka, El-morshedy Mohammed Reham, Jun Kishi, Masami Kishi, Katsuhiro Kinoshita, Hisanori Uehara, Keisuke Izumi and Saburo Sone : The role of sphingosine 1-phospate (SIP) signaling in pulmonary fibrosis., ATS 2011 International Conference, Denver, May 2011.
23.
Atsushi Mitsuhashi, Hisatsugu Goto, Hirokazu Ogino, Takuya Kuramoto, Seidai Sato, Makoto Tobiume, Masaki Hanibuchi, Souji Kakiuchi, Seiji Yano, Hisanori Uehara, Yasuhiko Nishioka and Saburo Sone : Novel therapeutic strategy with E7080, an orally active inhibitor of multiple recepter tyrosine kinase, for controllong experomental metastasis by lung cancer in immunodeficient mice., 第9回アジア臨床腫瘍学会学術集会, Gifu, Aug. 2010.
24.
Kenji Matsuzaki, Mayumi Takeuchi, Hisanori Uehara and Hiromu Nishitani : Ovarian teratomas: Usual, unusual imaging manifestations and pitfalls, ECR 2006, Wien, Mar. 2006.
25.
Kenji Matsuzaki, Mayumi Takeuchi, Hiromu Nishitani and Hisanori Uehara : Pathologies of the uterine myometrium: Usual and unusual manifestations and pitfalls on magnetic resonance imaging, ECR 2006, Wien, Mar. 2006.
26.
M. Azuma, Yasuhiko Nishioka, Yoshinori Aono, M. Inayama, H. Makino, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Inhibition of bleomycin-induced pulmonary fibrosis in mice by imatinib (Gleevec) and erythromycin-a role of aipha-1-acid glycoprotein, 100th American thoracic society (ATS), San Diego, May 2005.
27.
Yasuhiko Nishioka, M. Inayama, H. Makino, M. Ugai, Yoshinori Aono, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Anti-fibrotic effect of IKKB inhibitor IMD-0354 in bleomycin-induced pulmonary fibrosis, 100th American thoracic society (ATS), San Diego, May 2005.
28.
Mami Inayama, Yasuhiko Nishioka, Masahiko Azuma, Yoshinori Aono, Hideki Makino, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Anti-fibrotic effect of IKKB inhibitor IMD-0354 in bleomycin-induced pulmonary fibrosis, 100th American Thoracic Society Annual Meeting, San Diego, May 2005.
29.
Zhi-Rong Qian, Toshiaki Sano, Katsuhiko Yoshimoto, Asa L. Sylvia, Mitsuyoshi Hirokawa and Hisanori Uehara : DNA methyltransferase 1 (DNMT1) protein overexpression correlates with tumor invasion and DNA hypermethylation of multiple tumor suppressor genes in human pituitary adenomas., 96th Annual Meeting of American Association of Cancer Research, Anaheim, Apr. 2005.
30.
Kenji Matsuzaki, Mayumi Takeuchi, Hisanori Uehara and Hiromu Nishitani : Differential diagnosis of multiple hyperintense lesions of the liver on T1W1 of MRI with pathologic correlation, ECR 2005, Wien, Mar. 2005.
31.
Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara and Hiromu Nishitani : Ancient schwannoma of the female pelvis;Radiologic-pathologic correlation, ECR 2005, Wien, Mar. 2005.
Yoshinori Aono, Yasuhiko Nishioka, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Anti-fibrotic effect of STI571(Gleevec) in bleomycin-induced pulmonary fibrosis, 99th American thoracic society (ATS), Orlando, May 2004.
34.
Yasuhiko Nishioka, Yoshinori Aono, M. Inayama, M. Ugai, J. Kishi, Hisanori Uehara, Keisuke Izumi and Saburo Sone : Imatinib as a novel PDGF receptor-targeted drug to prevent bleomycin-induced lung fibrosis, 第44回日本呼吸器学会総会 International progam 3, Tokyo, Apr. 2004.
35.
Mayumi Takeuchi, Kenji Matsuzaki, Hisanori Uehara and Hiromu Nishitani : Clear Cell Carcinoma of the Ovary: Radiologic-Pathologic Correlation, RSNA 2004, Chicago, Apr. 2004.
36.
Kenji Matsuzaki, Mayumi Takeuchi, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Differential diagnosis of the fluid collection in the female pelvis: Radiologic-pathophysiologic correlation, ECR 2004, Wien, Mar. 2004.
37.
Mayumi Takeuchi, Kenji Matsuzaki, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Radiologic findings of pseudomyxoma peritonei with pathologic correlation: Usual and unusual manifestations, and pitfalls, ECR 2004, Wien, Mar. 2004.
38.
Mayumi Takeuchi, Kenji Matsuzaki, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Pathologies of the uterine endometrial cavity: Usual and unusual manifestations and pitfalls on magnetic resonance imaging, ECR 2004, Wien, Mar. 2004.
39.
Kenji Matsuzaki, Mayumi Takeuchi, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Teratomatous tumors in the female pelvis: imaging-pathologic correlation, RSNA 2003, Chicago, Nov. 2003.
40.
Kenji Matsuzaki, Mayumi Takeuchi, Shusaku Yoshida, Hiromu Nishitani and Hisanori Uehara : Neurogenic tumors in the female pelvis simulating gynecologic tumors: imaging-pathologic correlation, RSNA 2003, Chicago, Nov. 2003.
Yuko Miyakami, Sumida Satoshi, Takayama Yoshimasa, Yoshimi Bando, Hisanori Uehara and Michiko Yamashita : A case of classic Hodgkin lymphoma nodular sclerosis, relapsing in the skin with T-cell receptor gene rearrangement, The journal of the Japanese Society of Lymphoreticular Tissue, Jun. 2024.
蔭山 武史, 紀本 彩佳, 厚美 憲吾, Takumi Kakimoto, Tomoko Kobayashi, Michiko Yamashita, Yoshimi Bando, Hisanori Uehara and 竹内 賢吾 : Four cases of blastic plasmacytoid dendritic cell tumors with skin lesions, 第113回日本病理学会総会, Mar. 2024.
6.
Takumi Kakimoto, 笠井 孝彦, 紀本 彩佳, 蔭山 武史, 厚美 憲吾, Tomoko Kobayashi, Yoshimi Bando and Hisanori Uehara : Solitary fibrous tumor of the skin: case report and literature review, 第113回日本病理学会総会, Mar. 2024.
7.
紀本 彩佳, Tomoko Kobayashi, 蔭山 武史, 厚美 憲吾, Takumi Kakimoto, Yoshimi Bando and Hisanori Uehara : A case of adenocarcinoma, mullerian type, possibly associated with hormone therapy, 第113回日本病理学会総会, Mar. 2024.
Tomoko Kobayashi, Hisanori Uehara, Minoru Matsumoto and Yoshimi Bando : An autopsy caseacute fibrinous and organizing pneumonia with progressing respiratory failure, 第108回日本病理学会総会, May 2019.
27.
Minoru Matsumoto, Tomoko Kobayashi, Yoshimi Bando and Hisanori Uehara : Involvement of adipocyte-derived factors on bladder cancer progression, 第108回日本病理学会総会, May 2019.
Kei Daizumoto, Tetsuro Yoshimaru, Yosuke Matsushita, Tomoya Fukawa, Hisanori Uehara, 尾野 雅哉, Masato Komatsu, Hiro-omi Kanayama and Toyomasa Katagiri : Crucial roles of DDX31 as related to the status of TP53 in bladder cancer progression, 第77回日本癌学会学術総会, Sep. 2018.
Koichi Tsuneyama, Hirohisa Ogawa, Takaaki Tsunematsu and Hisanori Uehara : 新生児期ストレプトゾトシン投与4CS系マウスは通常食飼育によって持続高血糖なしに肝腫瘍を発症する, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 384, Apr. 2016.
37.
Hirohisa Ogawa, Takaaki Tsunematsu, Hisanori Uehara and Koichi Tsuneyama : ダニ抗原経鼻感作はIL-17/好中球を増加させ平滑筋肥厚を伴う気道リモデリングを誘導する, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 386, Apr. 2016.
38.
Hisanori Uehara, Hirohisa Ogawa, Takaaki Tsunematsu and Koichi Tsuneyama : 前立腺癌細胞の骨内増殖におけるlipolysis stimulated lipoprotein receptorの役割, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 466, Apr. 2016.
39.
Takaaki Tsunematsu, Yasusei Kudo, Akiko Yamada, Rieko Arakaki, Hirohisa Ogawa, Hisanori Uehara, Naozumi Ishimaru and Koichi Tsuneyama : 染色体パッセンジャー複合体タンパク質Borealinのユビキチン分解の意義とその癌化への関与, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 548, Apr. 2016.
40.
良祐 別所, Takaaki Tsunematsu, Hirohisa Ogawa, Hisanori Uehara and Koichi Tsuneyama : 自然発症2型糖尿病モデルマウスにおける膵島の外分泌腺組織への変化がβ細胞の機能不全に果たす役割, Proceedings of the Japanese Society of Pathology, Vol.105, No.1, 595, Apr. 2016.
41.
徹行 高橋, Hisanori Uehara, Koichi Tsuneyama and 貴雄 土方 : プロスタグランジンE2受容体シグナリング阻害は膵臓がんにおけるIGF-1受容体シグナリングを介した増殖刺激を消失させる, 日本薬学会年会要旨集, No.4, 202, Mar. 2016.
Tetsuyuki Takahashi, Hisanori Uehara and Keisuke Izumi : Inhibition of EP-mediated signaling influences growth stimulation by HB-EGF and IGF in pancreas cancer cells, 日本癌学会第72回総会, Oct. 2013.
The Trung VAN, Hisatsugu Goto, 倉本 卓哉, Souji Kakiuchi, Seidai Satou, The Trung VAN, Atsuro Saijo, 田畑 祥, Hirohisa Ogawa, Hisanori Uehara, Shin-ichi Akiyama, Yasuhiko Nishioka, Rae Jo WRIGHT and Saburo Sone : 肺サーファクタント蛋白SP-Aの肺がん進展における機能解析, Journal of Japanese Medical Society for Lung Surfactant and Biological Interface, Vol.43, 32, Oct. 2012.
Tomoya Fukawa, Ono Masaya, Taisuke Matsuo, Hisanori Uehara, Nakamura Yusuke, Hiro-omi Kanayama and Toyomasa Katagiri : RCCDH Regulates p53 Tumor suppressor activity in renal cell carcinomas., The 71th Annual Meeting of the Japanese Cancer Association, Sep. 2012.
56.
Atsuhi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Sho Tabata, Hirohisa Ogawa, Hisanori Uehara, Shin-ichi Akiyama, Wright Jo Rae, Saburo Sone and Yasuhiko Nishioka : 肺surfactant protein A(SP-A)の肺癌進展における機能解析, 第21回日本がん転移学会学術集会・総会, Jul. 2012.
Atsushi Mitsuhashi, Hisatsugu Goto, Takuya Kuramoto, Syo Tabata, Hirohisa Ogawa, Hisanori Uehara, Shin-ichi Akiyama, Jo Rae Wright, Saburo Sone and Yasuhiko Nishioka : Surfactant protein A suppresses progression of human lung adenocarcinoma in nude mice via modulating host immune response., 第52回日本呼吸器学会学術講演会, Apr. 2012.
61.
Chie Takasu, Tetsuyuki Takahashi, Hisanori Uehara and Keisuke Izumi : Effect of caloric restriction and high fat diet on azoxymethane-induced carcinogenesis in LETO and OLETF rats, 日本癌学会第70回総会, Oct. 2011.
62.
Tetsuyuki Takahashi, Hisanori Uehara and Keisuke Izumi : 15-PGDH influences cell growth and susceptibility to apoptotic induction in pancreatic cancer cells, 日本癌学会第70回総会, Oct. 2011.
63.
Hisanori Uehara, Tetsuyuki Takahashi, 渡邉 俊介 and Keisuke Izumi : Effect of FABP4 on motility and invasiveness of prostate cancer, 日本癌学会第70回総会, Oct. 2011.
Ryoga Yuasa, Kohta Hata, Sarina Takeuchi, Michiko Yamashita, Ryohei Sumitani, Hisanori Uehara, Yoshimi Bando and Koichi Tsuneyama : 同種骨髄移植後の造血微小環境についての病理学的研究, THE TOKUSHIMA JOURNAL OF MEDICAL TECHNOLOGY, 27, Dec. 2021.
Mutant p53 - Cancer Immunology Research from the DDX31 axis (Project/Area Number: 23K08758 )
RCC Precision Medicine Project using PDX models (Project/Area Number: 23K08736 )
Development of Next Generation "Light" Fertility Treatment Using LEDs (Project/Area Number: 21K19573 )
Development of a next-generation patient-derived cancer model using chicken eggs and establishment of a drug screening method (Project/Area Number: 19K22689 )
Role of fatty acid binding protein 4 (FABP4) as an exogenous ligand, on growth of prostate cancer cells (Project/Area Number: 15K08403 )
A novel signaling crosstalk between prostaglandin E2 receptors and IGF-1 receptor as a possible molecular target for antitumor therapy (Project/Area Number: 15K06873 )
Trial of inhibition of prostate cancer cell growth in the bone using bone marrow-derived stem cells (Project/Area Number: 18590373 )