Prediction of cancer metastasis by tumor endothelial secreting proteins

• Project/Area Number: 26462390
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Hokkaido University
• Principal Investigator: Shinohara Nobuo 北海道大学, 医学研究科, 教授 (90250422)
• Co-Investigator(Kenkyū-buntansha): 間石 奈湖 北海道大学, 遺伝子病制御研究所, 助教 (00632423) ; 土屋 邦彦 北海道大学, 大学病院, 助教 (50374442)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 腫瘍血管新生 / biglycan / 転移 / 腫瘍血管内皮 / biglycan, / LOX / biglycan, LOX

Outline of Final Research Achievements

In this study, we addressed the involvement of tumor endothelial secreting molecule in cancer metastasis. Among these molecules, we focused on biglycan and analyzed the role of biglycan in cancer metastatic potential. We observed that biglycan-secreted from tumor endothelial cells activate NF-B and ERK in cancer cells and attract cancer cells towards tumor blood vessels, resulting in increase of lung metastasis. Furthermore, blood level of biglycan in cancer patients correlated with vascular invasion of cancer. These suggested that tumor endothelial secreting factor may be biomarker in cancer metastasis.

Research Products

• [Journal Article] Outcome of metastatic urothelial carcinoma treated by systemic chemotherapy: Prognostic factors based on real-world clinical practice in Japan. (2017)
  • Author(s): Abe T, Ishizaki J, Kikuchi H, Minami K, Matsumoto R, Harabayashi T, Sazawa A, Mochizuki T, Chiba S, Akino T, Murakumo M, Miyajima N, Tsuchiya K, Maruyama S, Murai S, Shinohara N.
  • Journal Title: Urol Oncol. Volume: 35
  • DOI: 10.1016/j.urolonc.2016.08.016
  • Peer Reviewed / Open Access
• [Journal Article] Vasohibin-1 as a Novel Prognostic Factor for Head and Neck Squamous Cell Carcinoma (2017)
  • Author(s): Torii C., Hida Y., Shindoh M., Akiyama K., Ohga N., Maishi N., Ohiro Y., Ono M., Totsuka Y., Kitagawa Y., Tei K., Sato Y., Hida K.
  • Journal Title: Anticancer Res Volume: 37 Pages: 1219-1225
  • DOI: 10.21873/anticanres.11437
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aneuploidy of murine immortalized endothelial cell line, MS1 (2017)
  • Author(s): Hida K., Maishi N., Dorcas Akuba-Muhyia Annan, Kondoh M., Hojo T., Umma Habiba, Ohga N., Ishikawa K, Sato M., Torii C., Yanagiya M., Morimoto M., Hida Y., Shindoh M.
  • Journal Title: Journal of Oral Biosciences Volume: 59 Pages: 50-54
  • DOI: 10.1016/j.job.2016.10.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Aldo-keto reductase 1C1 induced by interleukin-1β mediates the invasive potential and drug resistance of metastatic bladder cancer cells (2016)
  • Author(s): Matsumoto R, Tsuda M, Yoshida K, Tanino M, Kimura T, Nishihara H, Abe T, Shinohara N, Nonomura K, Tanaka S
  • Journal Title: Sci Rep. Volume: 4 Pages: 34625-34625
  • DOI: 10.1038/srep34625
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor endothelial cells express high pentraxin 3 levels. (2016)
  • Author(s): Hida K., Maishi N., Kawamoto T., Akiyama K., Ohga N., Hida Y., Yamada K., Hojo T., Kikuchi H., Sato M., Torii C., Shinohara N., Shindoh M
  • Journal Title: Pathology International Volume: 66 Pages: 687-694
  • DOI: 10.1111/pin.12474
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of characteristics of mouse immortalized normal endothelial cells, MS1 and primary cultured endothelial cells. (2016)
  • Author(s): Hida K., Maishi N., Torii C., Yanagiya M., Annan Akuba-Muhyia Dorcas., Morimoto M., Alam Mohammad Towfik
  • Journal Title: Hokkaido J. Dent. Sci. Volume: 37 Pages: 40-48
  • NAID: 120005855959
  • Peer Reviewed
• [Journal Article] Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan (2016)
  • Author(s): N. Maishi, Y. Ohba, K. Akiyama, N. Ohga, J.I. Hamada, H. Nagao-Kitamoto, M. Alam, K. Yamamoto, T. Kawamoto, N. Inoue, A. Taketomi, M. Shindoh, Y. Hida and K. Hida.
  • Journal Title: Scientific Reports Volume: 6 Pages: 1-1
  • DOI: 10.1038/srep28039
  • NAID: 120005819304
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Five-point Likert scaling on MRI predicts clinically significant prostate carcinoma. (2015)
  • Author(s): Harada T, Abe T, Kato F, Matsumoto R, Fujita H, Murai S, Miyajima N, Tsuchiya K, Maruyama S, Kudo K, Shinohara N
  • Journal Title: BMC urol Volume: 91
  • Peer Reviewed
• [Journal Article] Clinical significance and therapeutic potential of prostate cancer antigen-1/ALKBH3 in human renal cell carcinoma. (2015)
  • Author(s): Hotta K, Sho M, Fujimoto K, Shimada K, Yamato I, Anai S, Harada H, Tsujikawa K, Konishi N, Shinohara N, Nakajima Y
  • Journal Title: Oncol reports Volume: 34 Pages: 648-654
  • Peer Reviewed
• [Journal Article] Identification of a subgroup with worse prognosis among patients with poor-risk testicular germ cell tumor. (2015)
  • Author(s): Kojima T, Kawai K, Tsuchiya K, Abe T, Shinohara N, Tanaka T, Masumori N, Yamada S, Arai Y, Narita S, Tsuchiya N, Habuchi T, Nishiyama H
  • Journal Title: Int J Urol Volume: 22 Pages: 923-927
  • DOI: 10.1111/iju.12844
  • Peer Reviewed
• [Journal Article] Prospective mapping of lymph node metastasis in Japanese patients undergoing radical cystectomy for bladder cancer: characteristics of micrometastasis. (2015)
  • Author(s): Matsumoto R, Takada N, Abe T, Minami K, Harabayashi T, Nagamori S, Hatanaka KC, Miyajima N, Tsuchiya K, Maruyama S, Murai S, Shinohara N
  • Journal Title: Jpn. J. Clin. Oncol Volume: 45 Pages: 874-880
  • Peer Reviewed
• [Journal Article] CRK adaptor protein induces epithelial-mesenchymal transition and metastasis of bladder cancer cells via HGF/c-Met feedback loop. (2015)
  • Author(s): 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
  • Journal Title: Cancer Sci Volume: 106 Pages: 709-717
  • Peer Reviewed
• [Journal Article] Diagnostic outcome of ureteroscopy in urothelial carcinoma of the upper urinary tract: Incidence of later cancer detection and its risk factors after the first examination. (2015)
  • Author(s): Murahashi N, Abe T, Shinohara N, Murai S, Harabayashi T, Sazawa A, Maruyama S, Tsuchiya K, Miyajima N, Hatanaka K, Nonomura K
  • Journal Title: BMC Urol Volume: 92
  • DOI: 10.1186/s12894-015-0086-6
  • Peer Reviewed
• [Journal Article] Phase 1/2 study of S-1 in combination with sorafenib for metastatic renal cell carcinoma. (2015)
  • Author(s): Naito S, Sakai H, Hashine K, Tomita T, Shinohara N, Fujisawa M, Eto M, Ozono S, Akaza H
  • Journal Title: Ann Oncol Volume: 26 Pages: 1871-1876
  • Peer Reviewed
• [Journal Article] Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular-targeted therapy. (2015)
  • Author(s): Shinohara N, Obara W, Tatsugami K, Naito S, Kamba T, Takahashi M, Murai S, Abe T, Oba K, Naito S
  • Journal Title: Cancer Sci Volume: 106 Pages: 618-626
  • NAID: 120005822783
  • Peer Reviewed
• [Journal Article] Japanese Society of Renal Cancer: Role of cytoreductive nephrectomy for Japanese patients with primary renal cell carcinoma in the cytokine and targeted therapy era. (2015)
  • Author(s): Tatsugami K, Shinohara N, Kondo T, Yamasaki T, Eto M, Tsushima T, Terachi T, Naito S
  • Journal Title: Int J Urol Volume: 22 Pages: 736-740
  • Peer Reviewed
• [Journal Article] CXCL 12-CXCR7 axis is important for tumor endothelial cell angiogenic property (2015)
  • Author(s): Yamada K., Maishi N., Akiyama K., Alam Mohammad Towfik, Ohga N., Kawamoto T., Shindoh M. Takahashi N., Kamiyama T., Hida Y., Taketomi A. and Hida K.
  • Journal Title: Int J Cancer Volume: 137 Pages: 2825-2836
  • Peer Reviewed
• [Journal Article] Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel (2015)
  • Author(s): Akiyama K., Maishi N., Ohga N., Hida Y., Ohba Y., Alam Mohammad Towfik, Kawamoto T., Ohmura H., Yamada K., Torii C., Shindoh M. and *Hida K.
  • Journal Title: Am J Pathol Volume: 185 Pages: 572-580
  • Peer Reviewed
• [Journal Article] CRK adaptor protein induces epithelial-mesenchymal transition and metastasis of bladder cancer cells via HGF/c-Met feedback loop (2015)
  • Author(s): Matsumoto R, Tsuda M, Wang L, et al
  • Journal Title: Cancer science Volume: in press
• [Journal Article] Prognosis of Japanese patients with previously untreated metastatic renal cell carcinoma in the era of molecular-targeted therapy (2015)
  • Author(s): Shinohara N, Obara W, Tatsugami K et al
  • Journal Title: Cancer science Volume: in press
  • NAID: 120005822783
• [Journal Article] Outcome of metastasectomy for urothelial carcinoma: a multi-institutional retrospective study in Japan (2014)
  • Author(s): Abe T, Kitamura H, Obara W, Matsumura N, Tsukamoto T, Fujioka T, Hara I, Murai S, Shinohara N, Nonomura K
  • Journal Title: The Journal of urology Volume: 191 Pages: 932-936
  • NAID: 120005438267
  • Peer Reviewed
• [Journal Article] Comparison of 90-day complications between ileal conduit and neobladder reconstruction after radical cystectomy： A retrospective multi-institutional study in Japan (2014)
  • Author(s): Abe T, Takada N, Shinohara N, Matsumoto R, Murai S, Sazawa A, Maruyama S, Tsuchiya K, Kanzaki S, Nonomura K
  • Journal Title: International journal of urology Volume: 21 Pages: 554-559
  • Peer Reviewed
• [Journal Article] Successful penile reconstruction after multimodal therapy in patients with primitive neuroectodermal tumor originating from the penis (2014)
  • Author(s): Akino T, Shinohara N, Hatanaka K, Kobayashi N, Yamamoto Y, Nonomura K
  • Journal Title: International journal of urology Volume: 21 Pages: 619-621
  • Peer Reviewed
• [Journal Article] Identification and expression of troponin T, a new marker on the surface of cultured tumor endothelial cells by aptamer ligand (2014)
  • Author(s): Ara MN, Hyodo M, Ohga N, Akiyama K, Hida K, Hida Y, Shinohara N, Harashima H
  • Journal Title: Cancer medicine Volume: 3 Pages: 825-834
  • Peer Reviewed
• [Journal Article] RENAL nephrometry score is a predictive factor for the annual growth rate of renal mass (2014)
  • Author(s): Matsumoto R, Abe T, Shinohara N, Murai S, Maruyama S, Tsuchiya K, Nonomura K
  • Journal Title: International journal of urology Volume: 21 Pages: 549-552
  • Peer Reviewed
• [Journal Article] Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells (2014)
  • Author(s): Otsubo T, Hida Y, Ohga N, Sato H, Kai T, Matsuki Y, Takasu H, Akiyama K, Maishi N, Kawamoto T, Shinohara N, Nonomura K, Hida K
  • Journal Title: Cancer science Volume: 105 Pages: 560-567
  • Peer Reviewed
• [Journal Article] Suprabasin as a novel tumor endothelial cell marker (2014)
  • Author(s): Alam MT, Nagao-Kitamoto H, Ohga N, Akiyama K, Maishi N, Kawamoto T, Shinohara N, Taketomi A, Shindoh M, Hida Y et al
  • Journal Title: Cancer science Volume: 105 Pages: 1533-1540
  • NAID: 120005539218
  • Peer Reviewed
• [Journal Article] Overall survival and final efficacy and safety results from a Japanese phase Ⅱstudy of axitinib in cytokine-refractory metastatic cell carcinoma (2014)
  • Author(s): Eto M, Uemura H, Tomita Y, Hanayama H, Shinohara N, Kamei Y, Fujii Y, Umeyama Y, Ozono S, Naito S et al
  • Journal Title: Cancer science Volume: 105 Pages: 1576-1583
  • Peer Reviewed
• [Journal Article] Suprabasin as a novel tumor endothelial cell marker (2014)
  • Author(s): Alam Mohammed Towfik, Nagao-Kitamoto H, Ohga N, Akiyama K, Maishi N, Kawamoto T, Shinohara N, Taketomi A, Shindoh M, Hida Y, Hida K
  • Journal Title: Cancer Science Volume: 105 Pages: 1533-1540
  • NAID: 120005539218
  • Peer Reviewed
• [Presentation] 腫瘍血管内皮細胞によるBiglycanの分泌を介したがんの転移促進 (2017)
  • Author(s): 間石奈湖
  • Organizer: 第２回口腔医科学フロンティア研究会
  • Place of Presentation: ＺＡＯセンタープラザ(山形市)
• [Presentation] Correlation between CXCR7 expression of blood vessels and clinicopathological features in oral squamous cell carcinoma， (2016)
  • Author(s): 柳谷美沙，間石奈湖，鳥居ちさほ，樋田泰浩，大賀則孝，鄭 漢忠，進藤正信，北川善政，樋田京子
  • Organizer: 第24回日本血管生物医学会学術集会
  • Place of Presentation: 長崎ブリックホール（長崎市）
• [Presentation] Tumor endothelial cells acquire drug resistance by exosomal-miR derived from high metastatic tumor. (2016)
  • Author(s): Hida K., Torii C., Maishi N., Morimoto M., Akiyama K., Kawamoto T., Minami T., Yoshioka Y., Mohammad Towfik Alam, Shindoh M., Hida Y., Ochiya T
  • Organizer: The 19th International Vascular Biology Meeting, 2016
  • Place of Presentation: Sheraton Boston Hotel(Boston, US)
  • Int'l Joint Research
• [Presentation] Tumor endothelial cells in high metastatic tumors promote metastasis via biglycan (2016)
  • Author(s): Maishi N., Ohba Y., Akiyama K., Ohga N., Hamada J., Nagao-Kitamoto H., Mohammad Towfik Alam, Shindoh M., Hida Y. Hida K.
  • Organizer: The 19th International Vascular Biology Meeting
  • Place of Presentation: Sheraton Boston Hotel(Boston,US)
  • Int'l Joint Research
• [Presentation] 「癌研究における女性研究者」，“腫瘍血管内皮細胞によるがん転移促進” (2016)
  • Author(s): 間石奈湖，樋田京子
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Invited
• [Presentation] 「酸化ストレスと発がん～最新の知見～」，“活性酸素が腫瘍血管内皮細胞に及ぼす影響” (2016)
  • Author(s): 間石 奈湖、樋田 京子
  • Organizer: 第 69 回日本酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際センター（仙台市）
  • Invited
• [Presentation] 腫瘍血管内皮細胞によるbiglycanの分泌を介したがんの転移促進 (2016)
  • Author(s): 間石奈湖，秋山廣輔，大賀則孝，浜田淳一，樋田京子
  • Organizer: 第25回日本がん転移学会学術集会・総会
  • Place of Presentation: 米子コンベンションセンター（米子市）
• [Presentation] 腫瘍血管内皮細胞によるがん転移促進 (2016)
  • Author(s): 間石奈湖
  • Organizer: 第12回北海道癌免疫制御研究会
  • Place of Presentation: メルキュールホテル札幌（札幌市）