The function of cancer associated fibroblasts-derived exosomes on the energy metabolism of scirrhous type gastric cancer

• Project/Area Number: 15K21646
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics; Experimental pathology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Naito Yutaka 国立研究開発法人国立がん研究センター, 研究所, 外来研究員 (70738210)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: Exosome / microRNA / スキルス胃癌 / 癌関連線維芽細胞 / 代謝 / 癌微小環境 / メタボローム

Outline of Final Research Achievements

In the present study, we use co-culture system of fibroblasts with high-metastatic scirrhous gastric cancer (SGC) cells or low-metastatic SGC cells as a model to understand how to create favorable microenvironments for cancer metastasis. By comparing transcriptome profiles of fibroblasts co-cultured with high- or low-metastatic SGC cells, it revealed that glucose metabolism in fibroblasts was reprogrammed by co-culture with high-metastatic SGC cells. We also found that high-metastatic DGC-derived extracellular vesicles (EVs) dominantly induced inflammatory cytokines through TGF-β independent manner. Under co-culture condition also strongly induced the expressions of glycolysis-related genes and decreased the expression of oxidative phosphorylation-related genes in high-metastatic SGC cells. Thus, our finding suggests the cellular crosstalk between cancer cells and fibroblasts via EVs in SGC microenvironment.

Research Products

• [Journal Article] How cancer cells dictate their microenvironment: present roles of extracellular vesicles. (2017)
  • Author(s): Naito Y, Yoshioka Y, Yamamoto Y, Ochiya T.
  • Journal Title: Cellular and Molecular Life Sciences Volume: 74 Issue: 4 Pages: 697-713
  • DOI: 10.1007/s00018-016-2346-3
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Transmission of HBV-DNA mediated by ceramide-triggered extracellular vesicles (2016)
  • Author(s): Takahiro Sanada, Yuichi Hirata, Yutaka Naito, Naoki Yamamoto, Yoshiaki Kikkawa, Yuji Ishida, Chihiro Yamasaki, Chise Tateno, Takahiro Ochiya, and *Michinori Kohara
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 3 Issue: 2 Pages: 272-283
  • DOI: 10.1016/j.jcmgh.2016.10.003
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-B non-C hepatocellular carcinoma. (2016)
  • Author(s): Nojima M, Matsui T, Tamori A, Kubo S, Shirabe K, Kimura K, Shimada M, Utsunomiya T, Kondo Y, Iio E, Naito Y, Ochiya T, Tanaka Y.
  • Journal Title: Molecular Cancer Volume: 15 Issue: 1 Pages: 31-31
  • DOI: 10.1186/s12943-016-0514-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fukutin, identified by the Escherichia coli ampicillin secretion trap (CAST) method, participates in tumor progression in gastric cancer. (2016)
  • Author(s): Oo HZ, Sentani K, Mukai S, Hattori T, Shinmei S, Goto K, Sakamoto N, Naito Y, Anami K, Trang PT, Yanagihara K, Oue N, Yasui W.
  • Journal Title: Gastric Cancer Volume: 19 Issue: 2 Pages: 443-452
  • DOI: 10.1007/s10120-015-0511-2
  • NAID: 40020835493
  • Peer Reviewed / Open Access
• [Journal Article] Significance of miR-148a in Colorectal Neoplasia: Downregulation of miR-148a Contributes to the Carcinogenesis and Cell Invasion of Colorectal Cancer. (2015)
  • Author(s): Hibino Y, Sakamoto N, Naito Y, Goto K, Oo HZ, Sentani K, Hinoi T, Ohdan H, Oue N, Yasui W.
  • Journal Title: Pathobiology Volume: 82 Issue: 5 Pages: 233-241
  • DOI: 10.1159/000438826
  • Peer Reviewed
• [Journal Article] Characteristic miR-24 Expression in Gastric Cancers among Atomic Bomb Survivors. (2015)
  • Author(s): Naito Y, Oue N, Pham TT, Yamamoto M, Fujihara M, Ishida T, Mukai S, Sentani K, Sakamoto N, Hida E, Sasaki H, Yasui W.
  • Journal Title: Pathobiology Volume: 82 Issue: 2 Pages: 68-75
  • DOI: 10.1159/000398809
  • Peer Reviewed
• [Journal Article] がんの新規診断・治療標的としてのエクソソームの応用と展開 (2015)
  • Author(s): 内藤 寛、吉岡 祐亮、落谷 孝広
  • Journal Title: 癌と化学療法 Volume: 42 Pages: 647-655
• [Journal Article] microRNAs and Hepatitis B. (2015)
  • Author(s): Naito Y, Tanaka Y, Ochiya T.
  • Journal Title: microRNA: Medical Evidence, Advances in Experimental Medicine and Biology Volume: 888 Pages: 389-399
  • DOI: 10.1007/978-3-319-22671-2_19
  • ISBN: 9783319226705, 9783319226712
• [Presentation] スキルス胃癌微小環境における癌関連線維芽細胞由来細胞外小胞の機能解析 (2016)
  • Author(s): 内藤 寛、八代 正和、清野 透、平川 弘聖、安井 弥、勝田 毅、落谷 孝広
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜 (神奈川県、横浜市)
  • Year and Date: 2016-10-06
• [Presentation] スキルス胃癌癌関連線維芽細胞に由来する分泌型microRNAの機能解析 (2016)
  • Author(s): 内藤 寛、吉岡 祐亮、山本 雄介、八代 正和、清野 透、平川 弘聖、安井 弥、落谷 孝広
  • Organizer: 第8回日本RNAi研究会・第3回日本細胞外小胞学会
  • Place of Presentation: グランドプリンスホテル広島 (広島県、広島市)
  • Year and Date: 2016-08-31
• [Presentation] Functional roles of CaF-derived extracellular vesicles in scirrhous type gastric cancer (2016)
  • Author(s): Yutaka Naito, Takahiro Ochiya
  • Organizer: Keystone symposia, Exosomes/Microvesicles: Novel Mechanisms of Cell-Cell Communication (E4)
  • Place of Presentation: Keystone Resort, Keystone, Colorado, USA
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Functional analysis of extracellular vesicles in scirrhous type gastric cancer microenvironment. (2016)
  • Author(s): Yutaka Naito, Masakazu Yashiro, Kosei Hirakawa, Toru Kiyono, Wataru Yasui and Takahiro Ochiya.
  • Organizer: International Society For Extracellular Vesicles (ISEV)2016. The Fifth International Meeting of ISEV.
  • Place of Presentation: The Netherlands, Rotterdam
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] Functional role of microRNA in scirrhous type gastric cancer microenvironment. (2016)
  • Author(s): Yutaka Naito
  • Organizer: 4th international Postgraduate Conference on Pharmaceutical Sciences 2016
  • Place of Presentation: 千葉、東京理科大学
  • Year and Date: 2016-02-27
  • Int'l Joint Research / Invited
• [Presentation] スキルス胃癌微小環境における細胞外小胞の機能 (2015)
  • Author(s): 内藤 寛、八代 正和、平川 弘聖、安井 弥、落谷 孝広
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] スキルス胃癌微小環境における細胞外小胞の網羅的解析 (2015)
  • Author(s): 内藤 寛、八代 正和、平川 弘聖、安井 弥、落谷 孝広
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] スキルス胃癌微小環境における分泌型microRNAの機能解析 (2015)
  • Author(s): 内藤 寛、八代 正和、平川 弘聖、安井 弥、落谷 孝広
  • Organizer: 第7回日本RNAi研究会・第2回日本細胞外小胞学
  • Place of Presentation: 広島
  • Year and Date: 2015-08-26
• [Presentation] Functional analysis of extracellular vesicles as a novel regulatory agent of scirrhous type gastric cancer microenvironment. (2015)
  • Author(s): Yutaka Naito, Masakazu Yashiro, Kosei Hirakawa, Wataru Yasui, Takahiro Ochiya.
  • Organizer: International Society For Extracellular Vesicles (ISEV) 2015
  • Place of Presentation: America, Washington, D.C.
  • Year and Date: 2015-04-23
  • Int'l Joint Research