Interaction of protumor stromal cells accelerates cancer progression

• Project/Area Number: 16H04691
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Akita University
• Principal Investigator: Tanaka Masamitsu 秋田大学, 医学系研究科, 教授 (20291396)
• Research Collaborator: KURIYAMA SEI ; ITOH GO
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: がん間質 / 癌関連線維芽細胞 / 腫瘍随伴マクロファージ / 中皮細胞 / 細胞外小胞 / 情報伝達 / 間質細胞 / マクロファージ / 線維芽細胞 / 内皮細胞 / スキルス胃癌 / 癌間質細胞 / 癌

Outline of Final Research Achievements

It is not well understood how Tumor-derived extracellular vesicles (TEVs) are delivered and effect on stromal cells in a tumor microenvironment. We identified a novel function of macrophages in delivery and transmission of TEVs. TEV incorporated macrophages (TEV-MΦ) increased invasion and widely disseminated. Upon contact with host stromal cells including mesothelial cells (MC), fibroblasts and endothelial cells, TEV-MΦs released membrane blebs containing TEVs. Then, scattered blebs were incorporated in these stromal cells, which transferred tumor-derived proteins and RNAs. Macrophage mediated transfer of TEVs caused myofibroblastic change in the recipient cells. In TEV-MΦ injected mice stomach, TEVs were delivered by MΦs to MCs covering the stomach, and MCs entered the gastric wall to create a niche that favored invasion of gastric cancer cells. These findings suggest a novel function of TAMs that transfer TEVs to surrounding stromal cells and increase CAF-like cells.

Academic Significance and Societal Importance of the Research Achievements

癌をサポートする様々な間質細胞の形質転換が広範囲に起きる事は、やがて癌細胞の浸潤を招く場を形成する。MΦが癌の情報を周辺のヘテロな間質細胞に伝搬していくメカニズムの一端を明らかにした事で、癌細胞とサポーター的な間質細胞間のネットワークを遮断し、癌の広がりを未然に防ぐ治療方針の基盤となる。今後特に化療後の再燃、憎悪の経過をとる症例で治療標的や予測分子が見出される事が期待される。

Research Products

• [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] PLEKHN1 promotes apoptosis by enhancing Bax-Bak hetero-oligomerization through interaction with Bid in human colon cancer (2018)
  • Author(s): Kuriyama S, Tsuji T, Sakuma T, Yamamoto T, Tanaka M
  • Journal Title: Cell Death Discovery Volume: 4 Issue: 1 Pages: 11-11
  • DOI: 10.1038/s41420-017-0006-5
  • Peer Reviewed / Open Access
• [Journal Article] Lateral attachment of kinetochores to microtubles is enriched in prometaphase rosette and facilitates chromosome alignment and bi-orientation establishment (2018)
  • Author(s): Itoh G, Ikeda M, Iemura K, Amin MA, Kuriyama S, Tanaka M, Mizuno N, Osakada H, Haraguchi T, Tanaka K
  • Journal Title: Sci Rep Volume: 8(1) Issue: 1 Pages: 3888-3888
  • DOI: 10.1038/s41598-018-22164-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A study of wound repair in Dictyostelium cells by using novel laserporation (2018)
  • Author(s): Mst Shaela Pervin, Go Itoh, Md Shahabe Uddin Talukder, Koushiro Fujimoto, Yusuke V Morimoto, Masamitsu Tanaka, Masahiro Ueda, Shigehiko Yumura
  • Journal Title: Scientific reports Volume: 8 Issue: 1 Pages: 7969-7969
  • DOI: 10.1038/s41598-018-26337-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Curucumin analog, GO-Y078, overcomes resistance to tumor angiogenesis inhibitors (2018)
  • Author(s): Shimazu K, Inoue M, Sugiyama S, Fukuda K, Yoshida T, Taguchi D, Uehara Y, Kuriyama S, Tanaka M, Miura M, Nanjo H, Iwabuchi Y, Shibata H.
  • Journal Title: Cancer Sci. Volume: 109(10) Issue: 10 Pages: 3285-3293
  • DOI: 10.1111/cas.13741
  • Peer Reviewed
• [Journal Article] Mesothelial cells create a novel tissue niche that facilitates gastric cancer invasion (2017)
  • Author(s): Tanaka M., Kuriyama S., Itoh G., Maeda D., Goto A., Tamiya Y., Yanagihara K., Yashiro M., Aiba N.
  • Journal Title: Cancer Research Volume: ７７ Issue: 3 Pages: 684-695
  • DOI: 10.1158/0008-5472.can-16-0964
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer-associated fibroblasts induce cancer cell apoptosis that regulates invasion mode of tumors. (2017)
  • Author(s): Itoh G., Chida S., Yanagihara K., Yashiro M., Aiba N., Tanaka M.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 31 Pages: 4434-4444
  • DOI: 10.1038/onc.2017.49
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spatiotemporal expression of UPK3B and its promoter activity during embryogenesis and spermatogenesis (2017)
  • Author(s): Kuriyama S, Tamiya Y, Tanaka M
  • Journal Title: Histochem Cell Biol Volume: １４７ Issue: 1 Pages: 17-26
  • DOI: 10.1007/s00418-016-1486-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The low expression of miR-451 predicts a worse prognosis in non-small cell lung cancer cases. (2017)
  • Author(s): Goto A, Tanaka M, Yoshida M, Umakoshi M, Nanjo H, Shiraishi K, Saito M, Kohno T, Kuriyama S, Konno H, Imai K, Saito H, Minamiya Y, Maeda D.
  • Journal Title: PLoS One. Volume: 12 Issue: 7 Pages: 1-6
  • DOI: 10.1371/journal.pone.0181270
  • NAID: 120007089063
  • Peer Reviewed / Open Access
• [Presentation] Macrophages transmit tumor-derived extracellular vesicles to stromal cells and create pro-tumor microenvironment. (2018)
  • Author(s): 田中正光
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Macrophages transfer cancer cell derived EVs to stromal cells that promotes gastric cancer invasion. (2018)
  • Author(s): 田中正光
  • Organizer: 第107回日本病理学会総会
• [Presentation] Gene expression profiling of organ tropism related upregulation in osteosarcoma derived sub-cell lines. (2018)
  • Author(s): 栗山 正、田中正光
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Cancer invasion geometry of giant cancer cells cooperating with stromal cells. (2018)
  • Author(s): 伊藤 剛、田中正光
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Cancer cell-derived extracellular vesicles educate macrophages to facilitate tumor invasion. (2017)
  • Author(s): 田中正光
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] PLEKHN1 promotes apoptosis by enhancing Bax oligomerization through interaction with Bid in human colon cancer. (2017)
  • Author(s): 栗山 正、田中正光
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] CAF (cancer-associated fibroblasts) induce cancer cell apoptosis that regulates invasion mode of tumors. (2017)
  • Author(s): 伊藤 剛、田中正光
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 癌関連線維芽細胞による癌細胞死誘導は腫瘍の浸潤モードを制御する (2017)
  • Author(s): 田中正光
  • Organizer: 第106回日本病理学会総会
• [Presentation] Collective durotaxis of cranial neural crest cells in Xenopus (2017)
  • Author(s): 栗山 正、田中正光
  • Organizer: The 50th JSDB meeting
• [Presentation] 癌細胞のデス小胞が促進する CAF リード型の癌浸潤プロセスの解明 (2017)
  • Author(s): 伊藤 剛、田中正光
  • Organizer: 日本生化学会東北支部第83回例会・シンポジウム（招待講演）
  • Invited
• [Presentation] Collective durotaxis of cranial neural crest cells in Xenopus. (2017)
  • Author(s): 栗山 正、田中正光
  • Organizer: The 50th JSDB meeting
• [Presentation] 癌細胞のデス小胞が促進する CAF リード型の癌浸潤プロセスの解明 (2017)
  • Author(s): 伊藤 剛、田中正光
  • Organizer: 日本生化学会東北支部第83回例会・シンポジウム
  • Invited
• [Remarks] 秋田大学大学院医学系研究科 分子生化学講座HP
  • URL: http://www.med.akita-u.ac.jp/~seika2/Akita_Univ._Dept._Molecular_Biochemistry/youkoso.html
• [Remarks] 秋田大学大学院医学系研究科 分子生化学講座ＨＰ
  • URL: http://www.med.akita-u.ac.jp/~seika2/Akita_Univ._Dept._Molecular_Biochemistry/youkoso.html