癌幹細胞によるミエロイド細胞活性を介した発癌促進機構

• Project Area: Development of Novel Treatment Strategies Targeting Cancer Stem Cells
• Project/Area Number: 23130501
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: 地主 将久 北海道大学, 遺伝子病制御研究所, 准教授 (40318085)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2012: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
• Keywords: がん幹細胞 / ミエロイド細胞 / MFG-E8 / IL-6 / 抗がん剤耐性 / M-CSF / IRF5 / 抗がん剤 / 乳がん / 転写因子

Research Abstract

がん幹細胞制御による腫瘍内ミエロイド細胞の発がん制御に係わる責任因子の解析を行うことにより、腫瘍微小環境制御に係わるあらたな発癌活性メカニズムの解析を遂行し、現時点で以下の2点を明らかにした。第一に、がん幹細胞より産生される特異的な液性因子を介して、腫瘍マクロファージを介した発癌活性に重要な増殖因子であるMFG-E8、IL-6の産生が誘導された。さらに、MFG-E8とIL-6はがん幹細胞のStat3とsonic-Hedgehog経路の活性を誘導することで、その自己複製能、抗癌剤抵抗性を増幅させるのに寄与していた。第二に、がん幹細胞による発癌促進マクロファージ分化に必須の因子の同定、およびその産生メカニズムについて解析を遂行したところ、抗がん剤耐性を獲得した乳がん細胞や大腸がん細胞から得られたがん幹細胞で高度のM-CSF産生が誘導し、免疫抑制や発癌活性に寄与するM2型マクロファージの腫瘍内浸潤、活性を惹起するという特性を有することが判明した。さらに網羅的遺伝子解析により、抗がん剤耐性株由来の乳がん幹細胞のSF産生を特異的に制御する転写因子IRF5の同定に成功した。このIRF5を干渉RNAで阻害することにより、がん幹細胞のM-CSF産生抑制、およびMFG-E8やArginase-IやIL-10などM2 subsetに特徴的な因子発現を有意に抑制すること同定した。さらにIRF5を阻害することで、癌幹細胞によるM2マクロファージ誘導および腫瘍増殖の抑制が達成された。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Colonization of an acid resistant Kingella denitrificans in the stomach may contribute to gastric dysbiosis by Helicobacter pylori. (2014)
  • Author(s): Nishikawa J, Nakazawa T, Iizasa H, Jinushi M, Sakaida I, Yoshiyama H.
  • Journal Title: Journal of Infection and Chemotherapy Volume: 20 Issue: 3 Pages: 169-174
  • DOI: 10.1016/j.jiac.2013.09.007
  • Peer Reviewed
• [Journal Article] Clinical significance of macrophage heterogeneity in human malignant tumors. (2014)
  • Author(s): Komohara Y, Jinushi M, Takeya M
  • Journal Title: Cancer Science Volume: 105 Issue: 1 Pages: 1-8
  • DOI: 10.1111/cas.12314
  • Peer Reviewed
• [Journal Article] Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas (2013)
  • Author(s): Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M
  • Journal Title: Cancer Immunol Immunother Volume: 62 Issue: 4 Pages: 629-637
  • DOI: 10.1007/s00262-012-1371-9
  • Peer Reviewed
• [Journal Article] TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance. (2013)
  • Author(s): Baghdadi M, Yoneda A, Yamashina T, Nagao H, Komohara Y, Nagai S, Akiba H, Foretz M, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Takeya M, Viollet B, Yagita H, Jinushi M
  • Journal Title: Immunity Volume: 39 Issue: 6 Pages: 1070-1081
  • DOI: 10.1016/j.immuni.2013.09.014
  • Peer Reviewed
• [Journal Article] Putting the brakes on anticancer therapies: suppression of innate immune pathways by tumor-associated myeloid cells. (2013)
  • Author(s): Jinushi M, Yagita H, Yoshiyama H, Tahara H
  • Journal Title: Trends in Molecular Medicine Volume: 19 Issue: 9 Pages: 536-545
  • DOI: 10.1016/j.molmed.2013.06.001
  • Peer Reviewed
• [Journal Article] ATM-mediated DNA damage signals mediate immune escape through integrin αvβ3-dependent mechanisms. (2012)
  • Author(s): Jinushi M
  • Journal Title: Cancer Res Volume: 72 Issue: 1 Pages: 56-65
  • DOI: 10.1158/0008-5472.can-11-2028
  • Peer Reviewed
• [Journal Article] The role of innate immune signals in the regulation of antitumor immunity (2012)
  • Author(s): Jinushi M
  • Journal Title: Onco Immunology Volume: 1(2) Pages: 1-6
• [Journal Article] Chronic activation of DNA damage signals causes tumor immune evasion in the chemoresistant niche (2012)
  • Author(s): Jinushi M
  • Journal Title: Onco Immunology Volume: 1(3) Pages: 1-3
• [Journal Article] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells (2011)
  • Author(s): Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, Yagita H, Takaoka A, Tahara H.
  • Journal Title: Proc Natl Acad Sci USA Volume: 108巻 Issue: 30 Pages: 12425-30
  • DOI: 10.1073/pnas.1106645108
  • NAID: 10030575946
  • Peer Reviewed
• [Presentation] Tumor-associated dendritic cells suppress nucleic acids-mediated innate immune recognition by TIM-3-dependent mechanisms (2011)
  • Author(s): Jinushi M
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉市)
  • Year and Date: 2011-11-27
• [Presentation] Dendritic cell-derived TIM-3 is a universal repressor of nucleic acid-mediated antitumor innate immune responses (2011)
  • Author(s): Jinushi M
  • Organizer: Cold Spring Harbor Laboratory Meetings "Harnessing Immunity to Prevent and Treat Disease"
  • Place of Presentation: Cold Spring Harbor Laboratory, NY, (USA)
  • Year and Date: 2011-11-18
• [Presentation] ATM mediated DNA damage signals suppress antitumor immunity by integrin-αvβ3-dependent mechanisms (2011)
  • Author(s): Jinushi M
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場(名古屋市)
  • Year and Date: 2011-10-04
• [Presentation] Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses in MFG-E8-dependent manner (2011)
  • Author(s): Jinushi M
  • Organizer: 第9回日本臨床腫瘍学会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2011-07-21
• [Remarks] 研究室URL
  • URL: http://www.igm.hokudai.ac.jp/vec/