Mechanisms for the stromal construction of the scirrhous gastric cancer: role of myeloid cells and cancer stem cells on the formation of tumor stroma

• Project/Area Number: 18H02883
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka City University
• Principal Investigator: Yashiro Masakazu 大阪市立大学, 大学院医学研究科, 准教授 (60305638)
• Co-Investigator(Kenkyū-buntansha): 中前 博久 大阪市立大学, 大学院医学研究科, 准教授 (30364003)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: スキルス胃癌 / CXCL1 / CXCR2 / 線維芽細胞 / 骨髄由来細胞 / 癌間質形成 / 癌間質 / 癌幹細胞 / 骨髄由来間質細胞 / 治療標的 / 癌間質細胞 / 骨髄細胞 / 癌関連線維芽細胞 / CD271 / 予後予測因子 / 間質増生

Outline of Final Research Achievements

Tumor stromal cells play a critical role in the progression of scirrhous gastric cancer (SGC). The aim of this study was to clarify where tumor stromal cells originate from and which factor(s) recruits them into the tumor stroma. The influences of CXCR2 inhibitor on the migration of bone marrow-derived mesenchymal cells (BM-MCs) were examined both in vitro and in vivo. BM-MCs frequently migrated into stroma of DGC in vivo. CXCL1 from DGC cells stimulated the chemoattractant ability of BM-MCs. CXCR2 inhibitor decreased the migration of BM-MCs, stimulated by SGC cells. A CXCR2 inhibitor reduced the recruitment of BM-MCs into the tumor in vivo, decreasing tumor size and lymph node metastasis, and prolonging the survival of gastric tumor-bearing mice. These findings suggested that CXCL1 from SGC cells stimulates the recruitment of BM-MCs into tumor stroma via CXCR2 signaling of BM-MCs. Inhibition of BM-MC recruitment via the CXCL1-CXCR2 axis appears a promising therapy for SGC.

Academic Significance and Societal Importance of the Research Achievements

スキルス胃癌細胞の産生するCXCL1が間葉系幹細胞のCXCR2に作用してCAF増生を招来するメカニズムを世界に先駆けて明らかにした。この成果に基づき、CXCR2阻害あるいはスキルス胃癌細胞産生のCXCL1を阻害してCAF増生を抑制するスキルス胃癌治療法が開発されれば、比較的若年に発症する難治癌であるスキルス胃癌の予後が改善されるため、社会的意義が大きい。

Research Products

• [Int'l Joint Research] University of Helsinki/Department of Pathology Helsinki/Department of Surgery, Helsinki(フィンランド)
• [Journal Article] Crosstalk Between Cancer Associated Fibroblasts and Cancer Cells in Scirrhous Type Gastric Cancer (2020)
  • Author(s): Miki Yuichiro、Yashiro Masakazu、Moyano-Galceran Lidia、Sugimoto Atsushi、Ohira Masaichi、Lehti Kaisa
  • Journal Title: Frontiers in Oncology Volume: 10 Pages: 568557-568557
  • DOI: 10.3389/fonc.2020.568557
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance (2020)
  • Author(s): Uchihara T, Miyake K, Yonemura A, Komohara Y, Itoyama R, Koiwa M, Yasuda T, Arima K, Harada K, Eto K, Hayashi H, Iwatsuki M, Iwagami S, Baba Y, Yoshida N, Yashiro M, Masuda M, Ajani Jaffer A, Tan Patrick, Baba H, Ishimoto T
  • Journal Title: Cancer Research Volume: 80 Issue: 16 Pages: 3222-3235
  • DOI: 10.1158/0008-5472.can-19-3803
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serine threonine kinase 11/liver kinase B1 mutation in sporadic scirrhous-type gastric cancer cells. (2020)
  • Author(s): Nishimura S, Yashiro M, Sera T, Yamamoto Y, Kushitani Y, Sugimoto A, Kushiyama S, Togano S, Kuroda K, Okuno T, Murakami Y, Ohira M.
  • Journal Title: Carcinogenesis. Volume: 41 Issue: 11 Pages: 1616-1623
  • DOI: 10.1093/carcin/bgaa031
  • NAID: 120007007731
  • Peer Reviewed / Open Access
• [Journal Article] Cancer Extracellular Vesicles Contribute to Stromal Heterogeneity by Inducing Chemokines in Cancer-Associated Fibroblasts (2019)
  • Author(s): Naito Y, Yamamoto Y, Sakamoto N, Shimomura I, Kogure A, Kumazaki M, Yokoi A, Yashiro M, Kiyono T, Yanagihara K, Takahashi RU, Hirakawa K, Yasui W, Ochiya T.
  • Journal Title: Oncogene Volume: 38 Issue: 28 Pages: 5566-5579
  • DOI: 10.1038/s41388-019-0832-4
  • Peer Reviewed / Open Access
• [Journal Article] Identification of candidates for driver oncogenes in scirrhous‐type gastric cancer cell lines (2019)
  • Author(s): Sai Eirin、Miwa Yoshiyuki、Takeyama Reina、Kojima Shinya、Ueno Toshihide、Yashiro Masakazu、Seto Yasuyuki、Mano Hiroyuki
  • Journal Title: Cancer Science Volume: 110 Issue: 8 Pages: 2643-2651
  • DOI: 10.1111/cas.14111
  • Peer Reviewed / Open Access
• [Journal Article] High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1 (2019)
  • Author(s): Kasurinen Aaro、Gramolelli Silvia、Hagstrm Jaana、Laitinen Alli、Kokkola Arto、Miki Yuichiro、Lehti Kaisa、Yashiro Masakazu、Ojala P?ivi M.、B?ckelman Camilla、Haglund Caj
  • Journal Title: Cancer Medicine Volume: 8 Issue: 16 Pages: 6995-7005
  • DOI: 10.1002/cam4.2576
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer (2019)
  • Author(s): Kuroda Kenji、Yashiro Masakazu、Sera Tomohiro、Yamamoto Yurie、Kushitani Yukako、Sugimoto Atsushi、Kushiyama Syuhei、Nishimura Sadaaki、Togano Shingo、Okuno Tomohisa、Tamura Tatsuro、Toyokawa Takahiro、Tanaka Hiroaki、Muguruma Kazuya、Ohira Masaichi
  • Journal Title: PLOS ONE Volume: 14 Issue: 11 Pages: 0224727-0224727
  • DOI: 10.1371/journal.pone.0224727
  • Peer Reviewed / Open Access
• [Journal Article] The Clinicopathological Significance of the CXCR2 Ligands, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8 in Gastric Cancer (2019)
  • Author(s): YAMAMOTO YURIE、KURODA KENJI、SERA TOMOHIRO、SUGIMOTO ATSUSHI、KUSHIYAMA SHUHEI、NISHIMURA SADAAKI、TOGANO SHINGO、OKUNO TOMOHISA、YOSHII MAMI、TAMURA TATSURO、TOYOKAWA TAKAHIRO、TANAKA HIROAKI、MUGURUMA KAZUYA、OHIRA MASAICHI、YASHIRO MASAKAZU
  • Journal Title: Anticancer Research Volume: 39 Issue: 12 Pages: 6645-6652
  • DOI: 10.21873/anticanres.13879
  • Peer Reviewed
• [Journal Article] 231.A Pretreatment-Free, Polymer-Based Platform Prepared by Molecular Imprinting and Post-Imprinting Modifications for Sensing Intact Exosomes (2019)
  • Author(s): K Mori, M Hirase, T Morishige, E Takano, H Sunayama, Y Kitayama, S Inubushi, R Sasaki, M Yashiro, and T Takeuchi
  • Journal Title: Angew Chem Int Ed Engl. Volume: 58 Issue: 6 Pages: 1612-1615
  • DOI: 10.1002/anie.201811142
  • Peer Reviewed
• [Journal Article] Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment (2019)
  • Author(s): Umakoshi M, Takahashi S, Itoh G, Kuriyama S, Sasaki Y, Yanagihara K, Yashiro M, Maeda D, Goto A, Tanaka M.
  • Journal Title: Oncogene Volume: 38(12): Issue: 12 Pages: 2162-2176
  • DOI: 10.1038/s41388-018-0564-x
  • Peer Reviewed
• [Journal Article] Significance of the Lysyl Oxidase Members Lysyl Oxidase Like 1, 3, and 4 in Gastric Cancer (2018)
  • Author(s): Kasashima Hiroaki、Yashiro Masakazu、Okuno Tomohisa、Miki Yuichiro、Kitayama Kisyu、Masuda Go、Kinoshita Haruhito、Morisaki Tamami、Fukuoka Tatsunari、Hasegawa Tsuyoshi、Sakurai Katsunobu、Toyokawa Takahiro、Kubo Naoshi、Tanaka Hiroaki、Muguruma Kazuya、Hirakawa Kosei、Ohira Masaichi
  • Journal Title: Digestion Volume: 98 Issue: 4 Pages: 238-248
  • DOI: 10.1159/000489558
  • Peer Reviewed
• [Journal Article] 222.Clinico-pathological significance of exosome marker CD63 expression on cancer cells and stromal cells in gastric cancer (2018)
  • Author(s): Miki Y, Yashiro M, Okuno T, K Kuroda, S Togano, Hirakawa K, Ohira M.
  • Journal Title: PLoS One Volume: 13 Issue: 9 Pages: 1-9
  • DOI: 10.1371/journal.pone.0202956
  • Peer Reviewed
• [Presentation] Bone marrow-derived stromal cells in the tumor microenvironment might be associated with the progression of gastric cancer. (2019)
  • Author(s): Yashiro M.
  • Organizer: American Association for Cancer Research 109th Annual Meeting
  • Int'l Joint Research
• [Presentation] CD9-positive exosomes from cancer-associate fibroblasts (CAFs) stimulate the migration ability of diffuse-type of gastric cancer cells. (2019)
  • Author(s): Yashiro M.
  • Organizer: 11th AACR-JCA Joint Conference
  • Int'l Joint Research
• [Presentation] CD9-positive exosomes from cancer-associate fibroblasts (CAFs) stimulate the migration ability of diffuse-type of gastric cancer cells (2019)
  • Author(s): Yashiro M.
  • Organizer: 11th JCA-AACR Meeting 2019
  • Int'l Joint Research
• [Presentation] Pyruvate Kinase Isozymes M2 and Glutaminase Might Be Promising Molecular Targets for the Treatment of Gastric Cancer (2018)
  • Author(s): Yashiro M.
  • Organizer: American Association for Cancer Research 108th Annual Meeting
  • Int'l Joint Research
• [Presentation] 6.Targeting tumor microenvironment in gastric cancer treatment. (2018)
  • Author(s): Yashiro M.
  • Organizer: KNGCA week 2018 (Seoul ,Korea)
  • Invited
• [Remarks] 大阪公立大学大学院医学研究科 癌分子病態制御学講座 ホームページ
  • URL: https://ganbunshi.com/
• [Remarks] www.med.osaka-cu.ac.jp/ocum-surgery/research
• [Remarks] 癌分子病態制御学
  • URL: http://www.med.osaka-cu.ac.jp/surgical-oncology/cancer/research_expense.html#geriatric04