The role of cancer metastasis in tumor vascular endothelial cells

• Project/Area Number: 26460479
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Itoh Fumiko 東京薬科大学, 生命科学部, 准教授 (70502582)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: TGFβ / 血管新生 / がん転移 / 遺伝子改変マウス / CreER / TGF-β / がん微小環境 / リンパ管新生 / 転移抑制 / 腫瘍循環細胞 / ＴＧＦ－β / 低酸素 / ＴＧＦ－β

Outline of Final Research Achievements

At the late stage of tumorigenesis, cancer cells produce TGF-β which promotes tumor proliferation and metastasis. Although angiogenesis is important for the growth of cancer cells, it remains veiled how abundant TGF-β plays a role in tumor angiogenesis. Hence, we have generated tamoxifen-inducible knockout mice of TGF-β type II receptor； TβRIIfl/fl; Pdgfb-iCreER (TβRIIiECΔ). When Lewis lung carcinoma (LLC) cells were transplanted into　TβRIIiECΔ mice, there was no difference in tumor weight compared to control mice. Tumors formed in TβRIIiECΔ mice had increased angiogenesis, but the blood vessels were fragile and leaky. As blood flow was not secured in tunors, hypoxia could be observed in the tumors from TβRIIiECΔ mouse. When cancer cells invading blood vessels were counted using FACS, we found that circulating tumor cells were increased in TβRIIiECΔ mice. These results suggest that the TGF-β signal in endothelial cells inhibits angiogenesis and metastasis.

Research Products

• [Journal Article] TMED10 Protein Interferes with Transforming Growth Factor (TGF)-β Signaling by Disrupting TGF-β Receptor Complex Formation. (2017)
  • Author(s): Nakano N, Tsuchiya Y, Kako K, Umezaki K, Sano K, Ikeno S, Otsuka E, Shigeta M, Nakagawa A, Sakata N, Itoh F, Nakano Y, Iemura SI, van Dinther M, Natsume T, Ten Dijke P, Itoh S.
  • Journal Title: J Biol Chem Volume: 292(10) Issue: 10 Pages: 4099-4112
  • DOI: 10.1074/jbc.m116.769109
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transforming growth factor-β signaling enhancement by long-term exposure to hypoxia in a tumor microenvironment composed of Lewis lung carcinoma cells. (2015)
  • Author(s): Furuta C, Miyamoto T, Takagi T, Noguchi Y, Kaneko J, Itoh S, Watanabe T, Itoh F.
  • Journal Title: Ｃａｎｃｅｒ Ｓｃｉｅｎｃｅ Volume: 106 Pages: 1524-1533
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy. (2015)
  • Author(s): Ohsawa Y, Takayama K, Nishimatsu S, Okada T, Fujino M, Fukai Y, Murakami T, Hagiwara H, Itoh F, Tsuchida K, Hayashi Y, Sunada Y.
  • Journal Title: ＰｌｏＳ Ｏｎｅ Volume: 10
  • Peer Reviewed / Open Access
• [Journal Article] C18ORF1: A Novel Negative Regulator of TGF-β Signaling. (2014)
  • Author(s): 2. Nakano N, Maeyama K, Ikeno S, Itoh F, Togawa Y, Katsu Y, Thanh Thao, VN, Watanabe Y, Kato M & Itoh, S.
  • Journal Title: J. Biol. Chem., Volume: 289 Issue: 18 Pages: 12680-12680
  • DOI: 10.1074/jbc.m114.558981
  • Peer Reviewed
• [Presentation] Genetic modified analysis of TGF-β type I and Type II receptors in endothelial cells. (2016)
  • Author(s): Saito, Y., Inagawa, T., Miyamoto, T., Itoh, S., Watanabe, T., Itoh, F.
  • Organizer: The 14th Korea-Japan Joint symposium on Vascular Biology.
  • Place of Presentation: Ｎａｇａｓａｋｉ， Ｊａｐａｎ
  • Year and Date: 2016-12-10
  • Int'l Joint Research
• [Presentation] 血管内皮細胞特異的TGF-β ファミリーシグナル欠損による血管構造異常． (2016)
  • Author(s): 宮本樹、斎藤裕紀、高木尊大、伊東進、渡部琢也、伊東史子
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-12-02
• [Presentation] ndothelial TGF-β signaling increases tumor malignancy. (2016)
  • Author(s): Itoh, F., Saito, Y., Inagawa T., Miyamoto, T,, Fruttiger M., Watanabe, T., Itoh, S.
  • Organizer: 19th International Vascular Biology Meeting
  • Place of Presentation: Ｂｏｓｔｏｎ， ＵＳＡ
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] Essential role of Smad4 in endothelial cells. (2016)
  • Author(s): Itoh, F.
  • Organizer: TGF-β meeting。
  • Place of Presentation: Ｌｅｉｄｅｎ， Ｔｈｅ Ｎｅｔｈｅｒｌａｎｄｓ
  • Year and Date: 2016-08-22
  • Int'l Joint Research / Invited
• [Presentation] 血管・リンパ管新生におけるDicerの役割 (2015)
  • Author(s): 伊東 史子、稲川俊彦、羽染聡恵、渡部琢也、伊東進
  • Organizer: 第23回日本血管生物医学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-11
• [Presentation] The role of TGF-β signaling in tumor angiogenesis (2015)
  • Author(s): Ｆｕｍｉｋｏ Ｉｔｏｈ
  • Organizer: Japan-Korea Joint Symposium on Vascular Biology
  • Place of Presentation: MBC Samjoo Art Hall 釜山 韓国
  • Year and Date: 2015-11-16
  • Int'l Joint Research / Invited
• [Presentation] TGF-β regulates lymphangiogenesis. (2015)
  • Author(s): Itoh, F., Takagi, T., Ichikawa, K., Watanabe, T., and Itoh, S.
  • Organizer: JSPS Core-to-core Program on“Cooperative International Framework in TGF-β Family Signaling,”Joint International Symposium on TGF-β Family and Cancer.
  • Place of Presentation: Ｔｓｕｋｕｂａ
  • Year and Date: 2015-01-12 – 2015-01-13
• [Presentation] 腫瘍血管・リンパ管新生におけるTGF-βシグナルの役割． (2014)
  • Author(s): 12.伊東史子、高木尊大、市川圭、Fruttiger M、Oliver G、古田千秋、伊東進、渡部琢也
  • Organizer: 第37回 日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] TGF-β signaling regulates blood- and lymph angiogenesis. (2014)
  • Author(s): Itoh, F., Takagi, T., Ichikawa, K., Fruttiger, M., Oliver, G., Itoh, S., and Watanabe, T.
  • Organizer: 8th International Kloster Seeon Meeting “Angiogenesis.”
  • Place of Presentation: Ｂａｖａｒｉａ， Ｇｅｒｍａｎｙ
  • Year and Date: 2014-09-21 – 2014-09-23
• [Presentation] The role of TGF-β signaling in blood- and lymph angiogenesis. (2014)
  • Author(s): Itoh, F., Takagi, T., Ichikawa, K., Fruttiger, M., Oliver, G., Itoh, S. and Watanabe, T.
  • Organizer: 18th International Vascular Biology Meeting.
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17