研究者詳細 - 西原　広史

論文 - 西原　広史

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Tyr724 phosphorylation of ELMO1 by Sr. is involved in cell spreading and migration via Rac1 activation

Makino Y., Tsuda M., Ohba Y., Nishihara H., Sawa H., Nagashima K., Tanaka S.

Cell Communication and Signaling （Cell Communication and Signaling） 13 （ 1 ） 2015年07月

研究論文（学術雑誌）, 共著, ISSN 1478-811X

© 2015 Makino et al. Background: The complex of Dock180/ELMO1 that functions as a bipartite guanine nucleotide exchange factor for Rac is essential for diverse physiological and pathological processes of cells such as cell migration, phagocytosis, and invasion of cancer cells. Among the Sr. -family tyrosine kinases (SFKs), it has been reported that Hck directly phosphorylates ELMO1, regulating phagocytosis by promoting activation of Rac1; however, the involvement of other SFKs in ELMO1 phosphorylation has remained unknown. Here, we identified novel tyrosine (Y) residues of ELMO1 phosphorylated by SFKs, and examined the effects on Rac1 activity, cell adhesion, spreading, and cell motility on extracellular matrix (ECM). Results: In this study, we unveiled that Sr. and Fyn can induce tyrosine phosphorylation of ELMO1 in in vivo and in vitro phosphorylation assays. Mutational analyses identified both Y720 and Y724 residues of ELMO1 as Sr. -mediated phosphorylation sites, preferentially on Y724. Single substitution of Y724 to Phe abrogated Rac1 activation triggered by Sr. . To elucidate the biological function of pY724, we established NIH3T3 cells stably expressing wild-type ELMO1 or its Y724F mutant together with Dock180. Among them, Y724-deficient cells exhibited a depletion of Rac1 activity with diminished phosphorylation of ELMO1 even upon the ECM-stimulation. It is noteworthy that NIH3T3 cells with ELMO1 Y724F were strikingly defective to promote cell spreading on fibronectin-coated dish, concomitantly exhibiting immature assemblies of actin stress fibers and focal adhesions. Eventually, ELMO1 Y724F significantly impaired cell migration. Conclusion: These results define that Sr. -mediated Y724 phosphorylation in ELMO1 plays a critical role for cell spreading via activation of Rac1, leading to promotion of cell migration. As the overexpression and/or hyperactivation of Sr. have been shown in a wide variety of human cancers, Sr. -mediated phosphorylation of Y724 in ELMO1 may regulate cancer cell adhesion to the ECM, invasion into surrounding tissues, and subsequent distant metastasis.

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Stent thrombosis caused by metal allergy complicated by protein S deficiency and heparin-induced thrombocytopenia: A case report and review of the literature

Konishi T., Yamamoto T., Funayama N., Yamaguchi B., Sakurai S., Nishihara H., Yamazaki K., Kashiwagi Y., Sasa Y., Gima M., Tanaka H., Hotta D., Kikuchi K.

Thrombosis Journal （Thrombosis Journal） 13 （ 1 ） 2015年07月

研究論文（学術雑誌）, 共著, ISSN 1477-9560

© 2015 Konishi et al. A 43-year-old woman recipient of a bare metal coronary stent during an acute anterior myocardial infarction was repeatedly hospitalized with recurrent stent thrombosis (ST) over the following 3 years. Emergent coronary angiography showed a thrombus in the in-stent segment of the proximal left anterior descending artery. We repeatedly aspirated the thrombus, which immediately reformed multiple times. The discontinuation of heparin and administration of thrombolytics and argatroban, followed by repeated balloon dilatations, ended the formation of new thrombi. The patient was found to be allergic to nickel, protein S deficient and carrier of heparin-induced thrombocytopenia antibody. We discuss this case in the context of a) literature pertaining to acute coronary syndromes in the young, and b) the detailed investigations needed to identify thrombotic risk factors. Steroids may be effective to prevent recurrent ST caused by stent allergy.

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Pathological findings of saccular cerebral aneurysms—impact of subintimal fibrin deposition on aneurysm rupture

Hokari M., Nakayama N., Nishihara H., Houkin K.

Neurosurgical Review （Neurosurgical Review） 38 （ 3 ） 531 - 540 2015年07月

研究論文（学術雑誌）, 共著, ISSN 03445607

© 2015, Springer-Verlag Berlin Heidelberg. Although several studies have suggested that aneurysmal wall inflammation and laminar thrombus are associated with the rupture of saccular aneurysms, the mechanisms leading to the rupture remain obscure. We performed full exposure of aneurysms before clip application and attempted to keep the fibrin cap on the rupture point. Using these specimens in a nearly original state before surgery, we conducted a pathological analysis and studied the differences between ruptured and unruptured aneurysms to clarify the mechanism of aneurysmal wall degeneration. This study included ruptured (n = 28) and unruptured (n = 12) saccular aneurysms resected after clipping. All of the ruptured aneurysms were obtained within 24 h of onset. Immunostainings for markers of inflammatory cells (CD68) and classical histological staining techniques were performed. Clinical variables and pathological findings from ruptured and unruptured aneurysms were compared. Patients with ruptured or unruptured aneurysms did not differ by age, gender, size, location, and risk factors, such as hypertension, smoking, and hyperlipidemia. The absence or fragmentation of the internal elastica lamina, the myointimal hyperplasia, and the thinning of the aneurysmal wall were generally observed in both aneurysms. The existence of subintimal fibrin deposition, organized laminar thrombus, intramural hemorrhage, neovascularization, and monocyte infiltration are more frequently observed in ruptured aneurysms. Multivariate logistic regression analysis showed that ruptured aneurysm was associated with presence of subintimal fibrin deposition and monocyte infiltration. These findings suggest that subintimal fibrin deposition and chronic inflammation have a strong impact on degeneration of the aneurysmal wall leading to their rupture, and this finding may be caused by endothelial dysfunction.

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Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop

Matsumoto R., Tsuda M., Wang L., Maishi N., Abe T., Kimura T., Tanino M., Nishihara H., Hida K., Ohba Y., Shinohara N., Nonomura K., Tanaka S.

Cancer Science （Cancer Science） 106 （ 6 ） 709 - 717 2015年06月

共著, ISSN 13479032

© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.

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Systemic targeting of lymph node metastasis through the blood vascular system by using size-controlled nanocarriers

Cabral H., Makino J., Matsumoto Y., Mi P., Wu H., Nomoto T., Toh K., Yamada N., Higuchi Y., Konishi S., Kano M., Nishihara H., Miura Y., Nishiyama N., Kataoka K.

ACS Nano （ACS Nano） 9 （ 5 ） 4957 - 4967 2015年05月

研究論文（学術雑誌）, 共著, ISSN 19360851

© 2015 American Chemical Society. Occult nodal metastases increase the risk of cancer recurrence, demoting prognosis and quality of life of patients. While targeted drug delivery by using systemically administered nanocarriers can potentially control metastatic disease, lymph node metastases have been mainly dealt by locally injecting nanocarriers, which may not always be applicable. Herein, we demonstrated that sub-50 nm polymeric micelles incorporating platinum anticancer drugs could target lymph node metastases in a syngeneic melanoma model after systemic injection, even after removing the primary tumors, limiting the growth of the metastases. By comparing these micelles with clinically used doxorubicin-loaded liposomes (Doxil) having 80 nm, as well as a 70 nm version of the micelles, we found that the targeting efficiency of the nanocarriers against lymph node metastases was associated with their size-regulated abilities to extravasate from the blood vasculature in metastases and to penetrate within the metastatic mass. These findings indicate the potential of sub-50 nm polymeric micelles for developing effective conservative treatments against lymph node metastasis capable of reducing relapse and improving survival.

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Adult classical glioblastoma with a BRAF V600E mutation

Takahashi Y., Akahane T., Sawada T., Ikeda H., Tempaku A., Yamauchi S., Nishihara H., Tanaka S., Nitta K., Ide W., Hashimoto I., Kamada H.

World Journal of Surgical Oncology （World Journal of Surgical Oncology） 13 （ 1 ） 2015年03月

研究論文（学術雑誌）, 共著, ISSN 1477-7819

© Takahashi et al. The B-Raf proto-oncogene serine/threonine kinase (B-Raf) is a member of the Raf kinase family. The BRAF V600E mutation occurs frequently in certain brain tumors such as pleomorphic xanthoastrocytoma, ganglioglioma, and pilocytic astrocytoma, and less frequently in epithelioid and giant cell glioblastoma. BRAF V600E mutation in these cases has been canonically detected using Sanger sequencing or immunohistochemistry but not with next-generation sequencing (NGS). Moreover, to our knowledge, there is no detailed report of the BRAF V600E mutation in an adult glioblastoma with classical histologic features (c-GBM). Therefore, we performed NGS analysis to determine the mutational status of BRAF of 13 glioblastomas (GBMs) (11 primary and 2 secondary cases) and detected one tumor harboring the BRAF V600E mutation. We report here the detection of the BRAF V600E mutation in a patient with c-GBM and describe the patient's clinical course as well as the results of histopathological analysis.

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In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line

Nanjo S., Nakagawa T., Takeuchi S., Kita K., Fukuda K., Nakada M., Uehara H., Nishihara H., Hara E., Uramoto H., Tanaka F., Yano S.

Cancer Science （Cancer Science） 106 （ 3 ） 244 - 252 2015年03月

共著, ISSN 13479032

© 2015 The Authors. EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

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肺高血圧症における血管病変の形態学的・免疫組織学的変化

谷野美智枝, 辻野一三, 石田雄介, 加藤容崇, 王磊, 木村太一, 西原広史, 田中伸哉

日本病理学会会誌（(一社)日本病理学会） 104 （ 1 ） 311 - 311 2015年03月

ISSN 0300-9181

Gastritis cystica profundaを背景にした重複胃癌の免疫組織学的検討

志藤茜, 杢里花, 湯澤明夏, 石川麻倫, 加藤容崇, 石田雄介, 木村太一, 谷野美智枝, 西原広史, 田中伸哉

日本病理学会会誌（(一社)日本病理学会） 104 （ 1 ） 513 - 513 2015年03月

ISSN 0300-9181

Importance of luminal membrane mesothelin expression in intraductal papillary mucinous neoplasms

Einama T., Kamachi H., Nishihara H., Homma S., Kanno H., Ishikawa M., Kawamata F., Konishi Y., Sato M., Tahara M., Okada K., Muraoka S., Kamiyama T., Taketomi A., Matsun Y., Furukawa H., Todo S.

Oncology Letters （Oncology Letters） 9 （ 4 ） 1583 - 1589 2015年

研究論文（学術雑誌）, 共著, ISSN 17921074

© 2014, Spandidos Publications. All rights reserved. The present study demonstrated that luminal membrane mesothelin expression is a reliable prognostic factor in gastric cancer. Intraductal papillary mucinous neoplasms (IPMNs) often exhibit a spectrum of dysplasia, ranging between adenoma and carcinoma. Therefore, an immunohistochemical analysis of mesothelin expression in IPMN was performed in the present study, focusing on the localization of mesothelin. IPMNs were classified into two groups, IPMNs associated with invasive carcinoma and low-high (L-H) grade dysplasias. The tumors were classified as mesothelin-positive or -negative and in the mesothelin-positive cases, the localization of mesothelin was evaluated as luminal membrane- or cytoplasmic-positive. Among the 37 IPMNs, mesothelin expression was observed in 21 samples (56.8%), including 46.2% (12 out of 26) of the L-H dysplasia and 81.8% (9 out of 11) of the invasive carcinoma samples (P=0.071). Luminal membrane localization was observed in 10 samples (27%), including 15.4% (4/26) of the L-H dysplasia samples and 54.5% (6 out of 11) of the invasive carcinoma samples (P=0.022). Six patients experienced post-operative recurrence, with five of the recurrent tumors exhibiting mesothelin expression and all six exhibiting luminal membrane localization. It was concluded that immunohistochemical examinations for mesothelin expression and localization are clinically useful for prognostic assessments and decision making regarding further treatment subsequent to surgical procedures in patients with IPMN.

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Inhibition of Eph receptor A4 by 2,5-dimethylpyrrolyl benzoic acid suppresses human pancreatic cancer growing orthotopically in nude mice

Takano H., Nakamura T., Tsuchikawa T., Kushibiki T., Hontani K., Inoko K., Takahashi M., Sato S., Abe H., Takeuchi S., Sato N., Hiraoka K., Nishihara H., Shichinohe T., Hirano S.

Oncotarget （Oncotarget） 6 （ 38 ） 41063 - 41076 2015年

研究論文（学術雑誌）, 共著, ISSN 1949-2553

Ephrin receptor A4 (EphA4) is overexpressed in human pancreatic adenocarcinoma (PDAC) and activate cell growth. Recent studies have identified small molecules that block EphA4. In this study, we investigated the correlation between EphA4 expression and the prognosis of patients with PDAC. We also examined the cytostatic efficacy of 2,5-dimethylpyrrolyl benzoic acid (compound 1), a small molecule that blocks EphA4, in PDAC cells. Overall survival of patients with EphA4 positivity was significantly shorter than that of patients with EphA4 negativity (P = 0.029). In addition, multivariate analysis revealed that EphA4 expression was an independent prognostic factor in PDAC patients (P = 0.039). Compound 1 showed a cytostatic efficacy in PDAC cells expressing EphA4 in vitro and in vivo. Our study indicated that compound 1 suppressed both EphA4 and Akt phosphorylations, and induced apoptosis in PDAC cells expressing EphA4. In conclusion,compound 1 has a high potential as a therapeutic agent for patients with PDAC.

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Polymeric micelles loaded with platinum anticancer drugs target preangiogenic micrometastatic niches associated with inflammation

Wu H., Cabral H., Toh K., Mi P., Chen Y., Matsumoto Y., Yamada N., Liu X., Kinoh H., Miura Y., Kano M., Nishihara H., Nishiyama N., Kataoka K.

Journal of Controlled Release （Journal of Controlled Release） 189 1 - 10 2014年09月

研究論文（学術雑誌）, 共著, ISSN 01683659

Nanocarriers have been used for specific delivery of therapeutic agents to solid tumors based on the enhanced permeability and retention in cancerous tissues. Despite metastasis is the main reason of cancer-related death and a priority for nanocarrier-based therapies, the targeting ability of nanocarriers to the metastatic disease is poorly understood, especially for preangiogenic micrometastases as nanocarriers usually use the malignant neovasculature for enhancing their accumulation. Thus, herein, we studied the ability of micellar nanocarriers incorporating (1,2-diaminocyclohexane)platinum(II) (DACHPt) for treating liver metastases of bioluminescent murine colon adenocarcinoma C-26, during overt and preangiogenic metastatic stages. After intravenous injection, DACHPt-loaded micelles (DACHPt/m) effectively inhibited the tumor growth in both metastatic tumor models. While the anticancer activity of the micelles against overt metastases was associated with their selective accumulation in cancerous tissues having neovasculature, the ability of DACHPt/m to target preangiogenic metastases was correlated with the inflammatory microenvironment of the niche. This targeting capability of polymeric micelles to preangiogenic metastasis may provide a novel approach for early diagnosis and treatment of metastases. © 2014 Elsevier B.V.

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SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1.

Minami Y., Kohsaka S., Tsuda M., Yachi K., Hatori N., Tanino M., Kimura T., Nishihara H., Minami A., Iwasaki N., Tanaka S.

Cancer science （Cancer science） 105 （ 9 ） 1152 - 1159 2014年09月

研究論文（学術雑誌）, 共著, ISSN 1347-9032

MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3'-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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Human pathological basis of blood vessels and stromal tissue for nanotechnology

Nishihara H.

Advanced Drug Delivery Reviews （Advanced Drug Delivery Reviews） 74 19 - 27 2014年07月

単著, ISSN 0169409X

The recent development of nanotechnology has already produced clinically applicable "nanodrugs," which are largely dependent on a novel concept for the drug delivery system. Thus the elucidation of local pharmacokinetics of nanodrugs is indispensable for the further development of nanomedicine; however, the detailed pathophysiology associated with nano-sized materials especially in pathologic lesions has not been well-described. In this review article, the microscopic appearance of vascular pericytes in addition to endothelial cells is discussed in the normal state and also in several pathological conditions which could be the major targets for nanomedicine. Moreover, the role of stromal tissue including myofibroblasts is also focused on, as well as inflammatory cells. Finally, the significance of disease-specific tissue structure in the establishment of personalized nanomedicine is discussed. © 2014 Elsevier B.V.

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Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma

Kohsaka S., Hinohara K., Wang L., Nishimura T., Urushido M., Yachi K., Tsuda M., Tanino M., Kimura T., Nishihara H., Gotoh N., Tanaka S.

Neuro-Oncology （Neuro-Oncology） 16 （ 7 ） 960 - 970 2014年07月

研究論文（学術雑誌）, 共著, ISSN 15228517

Background Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target. Methods Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples. Results Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG. Conclusion These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients. © 2014 The Author(s).

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Immunohistochemical evaluation of O <sup>6</sup> -methylguanine DNA methyltransferase (MGMT) expression in 117 cases of glioblastoma

Miyazaki M., Nishihara H., Terasaka S., Kobayashi H., Yamaguchi S., Ito T., Kamoshima Y., Fujimoto S., Kaneko S., Katoh M., Ishii N., Mohri H., Tanino M., Kimura T., Tanaka S.

Neuropathology （Neuropathology） 34 （ 3 ） 268 - 276 2014年06月

研究論文（学術雑誌）, 共著, ISSN 09196544

Temozolomide (TMZ) is an oral alkylating agent which is widely used in the treatment of glioblastoma (GBM) and is composed of astrocytic and/or oligodendroglial tumors, and the evaluation of O 6 -methylguanine DNA methyltransferase (MGMT) expression is important to predict the response to TMZ therapy. In this study, we conducted immunohistochemical analysis of 117 cases of Japanese GBM including 19 cases of GBM with oligodendroglioma component (GBMO), using a scoring system for quantitative evaluation of staining intensity and proportion of MGMT, and performed survival analysis of these patients. Immunohistochemically, 55 cases (47%) were positive for MGMT with various intensities and proportions (total score (TS)≥2), while 62 cases (53%) were negative (TS=0). The distribution of MGMT expression pattern was not affected by any clinicopathological parameters such as the histological subtype (GBM vs. GBMO), age and gender. The survival analysis of these patients revealed that the minimal expression of MGMT (TS≥2) was a significant unfavorable prognostic factor (P<0.001) as well as resectability (P=0.004). Moreover, multivariate analysis showed that minimal MGMT expression in GBM was the most potent independent predictor for progression free survival (P<0.001) and also overall patient survival (P<0.001). This is the first report employing the scoring system for both staining intensity and proportion to evaluate immunohistochemical MGMT expression in GBM. In addition, our results emphases the clinicopathological values of the immunohistochemical approach for MGMT expression in glioma patients as a routine laboratory examination. © 2014 Japanese Society of Neuropathology.

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Prognostic factors for survival in patients with high-grade meningioma and recurrence-risk stratification for application of radiotherapy

Yamaguchi S., Terasaka S., Kobayashi H., Asaoka K., Motegi H., Nishihara H., Kanno H., Onimaru R., Ito Y., Shirato H., Houkin K.

PLoS ONE （PLoS ONE） 9 （ 5 ） 2014年05月

研究論文（学術雑誌）, 共著, ISSN 1932-6203

Background: Radiotherapy for high-grade meningioma (HGM) is one of the essential treatment options for disease control. However, appropriate irradiation timing remains under debate. The object of this study is to discern which prognostic factors impact recurrence in HGM patients and to propose a risk-stratification system for the application of postoperative radiotherapy. Methods: We retrospectively reviewed 55 adult patients who were diagnosed with Grade II and III intracranial meningioma. Cox regression models were applied to the analysis for impact on early recurrence in HGM patients without postoperative radiotherapy. Results: Grade III malignancy (P = 0.0073) and transformed histology (P = 0.047) proved to be significantly poor prognostic factors of early recurrence by multivariate analysis. The other candidates for recurrence factors were Simpson Grade 3-5 resection, preoperative Karnofsky Performance status < = 70%, and MIB-1 labeling index > = 15%. According to these prognostic factors, postoperative HGM patients could be stratified into three recurrence-risk groups. The prognoses were significantly different between each group, as the 3-year actual recurrence-free rates were 90% in low-risk group, 31% in intermediate-risk group, and 15% in high-risk group. Conclusion: We propose recurrence-risk stratification for postoperative HGM patients using clinically available factors. Our results suggest that the prognosis for patients with high-risk HGMs is dismal, whereas HGM patients belonging to the lowrisk group could have favorable prognoses. This stratification provides us with the criteria necessary to determine whether to apply adjuvant radiotherapy to postoperative HGM patients, and to also help identify potentially curable HGMs without adjuvant radiotherapy. © 2014 Yamaguchi et al.

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Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma

Mahabir R., Tanino M., Elmansuri A., Wang L., Kimura T., Itoh T., Ohba Y., Nishihara H., Shirato H., Tsuda M., Tanaka S.

Neuro-Oncology （Neuro-Oncology） 16 （ 5 ） 671 - 685 2014年05月

研究論文（学術雑誌）, 共著, ISSN 15228517

BackgroundIonizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown.MethodsTo investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines.ResultsIn 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3β were increased after irradiation in a Snail-dependent manner, and TGF-β was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role. © 2013 © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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MicroRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway

Mitamura T., Watari H., Wang L., Kanno H., Kitagawa M., Hassan M., Kimura T., Tanino M., Nishihara H., Tanaka S., Sakuragi N.

Molecular Cancer （Molecular Cancer） 13 （ 1 ） 2014年04月

研究論文（学術雑誌）, 共著, ISSN 1476-4598

Background: We aimed to investigate whether MIR31 is an oncogene in human endometrial cancer and identify the target molecules associated with the malignant phenotype.Methods: We investigated the growth potentials of MIR31-overexpressing HEC-50B cells in vitro and in vivo. In order to identify the target molecule of MIR31, a luciferase reporter assay was performed, and the corresponding downstream signaling pathway was examined using immunohistochemistry of human endometrial cancer tissues. We also investigated the MIR31 expression in 34 patients according to the postoperative risk of recurrence.Results: The overexpression of MIR31 significantly promoted anchorage-independent growth in vitro and significantly increased the tumor forming potential in vivo. MIR31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3'-UTR and consequently promoted the translocation of YAP1, a key molecule in the Hippo pathway, into the nucleus. Meanwhile, the nuclear localization of YAP1 increased the transcription of CCND1. Furthermore, the expression levels of MIR31 were significantly increased (10.7-fold) in the patients (n = 27) with a high risk of recurrence compared to that observed in the low-risk patients (n = 7), and this higher expression correlated with a poor survival.Conclusions: MIR31 functions as an oncogene in endometrial cancer by repressing the Hippo pathway. MIR31 is a potential new molecular marker for predicting the risk of recurrence and prognosis of endometrial cancer. © 2014 Mitamura et al.; licensee BioMed Central Ltd.

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Differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma: A case report of an elderly man

Takahashi K., Tsuda M., Kanno H., Murata J., Mahabir R., Ishida Y., Kimura T., Tanino M., Nishihara H., Nagashima K., Tanaka S.

Brain Tumor Pathology （Brain Tumor Pathology） 31 （ 2 ） 118 - 123 2014年04月

研究論文（学術雑誌）, 共著, ISSN 14337398

Small cell glioblastoma is a histological subtype of glioblastoma with characteristic features of highly proliferative, monotonous small glial cells with high nuclear cytoplasm ratio. Morphologically, malignant lymphoma or small cell metastatic carcinoma should be carefully discriminated. Some cases are difficult to differentiate from anaplastic oligodendroglioma. In this report, we present a case of small cell glioblastoma of an elderly man. The lack of IDH1/2 mutation was confirmed by immunohistochemistry and direct sequencing. Fluorescence in situ hybridization revealed the lower rates of chromosome 1p and 19q deletion. Microsatellite analysis disclosed partial 10q alteration near the PTEN locus. Not only morphological and immunohistochemical examinations, but also cytogenetical investigations for IDH1/2 mutation, 1p/19q loss, and PTEN alteration, are strongly supportive methods for the differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma. © 2013 The Japan Society of Brain Tumor Pathology.

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