Identification of the novel niche factor implicated in cancer stem cell maintenance in tumor stroma.

• Project/Area Number: 16H06257
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: ISHIMOTO Takatsugu 熊本大学, 医学部附属病院, 特任准教授 (00594889)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2017: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2016: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 胃癌 / 癌関連線維芽細胞 / 腫瘍間質 / 慢性炎症 / 癌幹細胞 / CAFs

Outline of Final Research Achievements

Cancer stem cell (CSC) have been implicated in chemo-resistance and tumor relapse, and the stem cell-like properties are regulated by CSC niche. However, the CSC niche in solid tumor is totally unknown. In the current study, we identified RHBDF2 as a gene overexpressed in cancer associated fibroblasts (CAFs), and showed that this molecule enhances gastric cancer (GC) cell invasion through oncogenic and non-canonical TGFB1 signaling. Further analysis using specific inhibitor of RHBDF2 may lead to the inhibition of GC invasion and metastasis.

Academic Significance and Societal Importance of the Research Achievements

これまで癌細胞の性質に依ると考えられていた浸潤・転移が、腫瘍微小環境に存在する線維芽細胞（CAFs）の働きによって引き起こされることを明らかにした。さらにはCAFsを用いた網羅的な遺伝子発現解析によって、胃がん細胞とCAFsの相互作用を介した浸潤・転移機構に重要な新規遺伝子（RHBDF2）を見出しており、胃癌浸潤の新たな分子メカニズムの解明に繋がった。

Research Products

• [Journal Article] Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts (2019)
  • Author(s): N. Ishii, K. Araki, T. Yokobori, K. Hagiwara, G. Dolgormaa, T. Yamanaka, T. Handa, M. Tsukagoshi, T. Igarashi, A. Watanabe, N. Kubo, N. Harimoto, A. Masamune, K. Umezawa, H. Kuwano, K. Shirabe
  • Journal Title: Cancer Science Volume: 10 Issue: 1 Pages: 334-434
  • DOI: 10.1111/cas.13874
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas (2018)
  • Author(s): Arima Kota、Ohmuraya Masaki、Miyake Keisuke、Koiwa Mayu、Uchihara Tomoyuki、Izumi Daisuke、Gao Feng、Yonemura Atsuko、Bu Luke、Okabe Hirohisa、Imai Katsunori、Hashimoto Daisuke、Baba Yoshifumi、Chikamoto Akira、Yamashita Yo-ichi、Furukawa Toru、Araki Kimi、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Oncogene Volume: 38 Issue: 8 Pages: 1211-1224
  • DOI: 10.1038/s41388-018-0510-y
  • Peer Reviewed
• [Journal Article] Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression (2018)
  • Author(s): Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H, Ishimoto T
  • Journal Title: The Journal of Pathology Volume: 245 Issue: 4 Pages: 445-455
  • DOI: 10.1002/path.5098
  • Peer Reviewed
• [Journal Article] Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer. (2018)
  • Author(s): Arima K, Komohara Y, Bu L, Tsukamoto M, Itoyama R, Miyake K, Uchihara T, Ogata Y, Nakagawa S, Okabe H, Imai K, Hashimoto D, Chikamoto A, Yamashita YI, Baba H, Ishimoto T
  • Journal Title: Cancer Sci Volume: 109(2) Issue: 2 Pages: 462-470
  • DOI: 10.1111/cas.13467
  • Peer Reviewed / Open Access
• [Journal Article] Nrf2 promotes oesophageal cancer cell proliferation via metabolic reprogramming and detoxification of reactive oxygen species. (2018)
  • Author(s): Kitano Y, Baba Y, Nakagawa S, Miyake K, Iwatsuki M, Ishimoto T, Yamashita YI, Yoshida N, Watanabe M, Nakao M, Baba H.
  • Journal Title: J Pathol. Volume: 244(3) Issue: 3 Pages: 346-357
  • DOI: 10.1002/path.5021
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. (2017)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang KK, Joyce LN, Kalpana R, Tay ST, Suzuki Y, Cho BC, Kuroda D, Arima K, Izumi D, Iwatsuki M, Baba Y, Oki E, Watanabe M, Saya H, Hirakawa K, Baba H, Tan P.
  • Journal Title: Gastroenterology Volume: in press Issue: 1 Pages: 191-204
  • DOI: 10.1053/j.gastro.2017.03.046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Colorectal Cancer Stem Cells Acquire Chemoresistance Through the Upregulation of F-Box/WD Repeat-Containing Protein 7 and the Consequent Degradation of c-Myc. (2017)
  • Author(s): Izumi D, Ishimoto T, Miyake K, Eto T, Arima K, Kiyozumi Y, Uchihara T, Kurashige J, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Goel A, Tan P, Baba H.
  • Journal Title: Stem Cells. Volume: 35(9) Issue: 9 Pages: 2027-2036
  • DOI: 10.1002/stem.2668
  • Peer Reviewed
• [Journal Article] PD-L1 Expression, Tumor-infiltrating Lymphocytes, and Clinical Outcome in Patients With Surgically Resected Esophageal Cancer. (2017)
  • Author(s): Yagi T, Baba Y, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Ann Surg. Volume: Dec 4 Issue: 3 Pages: 471-478
  • DOI: 10.1097/sla.0000000000002616
  • Peer Reviewed / Open Access
• [Journal Article] Clinical usefulness of postoperative C-reactive protein/albumin ratio in pancreatic ductal adenocarcinoma. (2017)
  • Author(s): Arima K, Yamashita YI, Hashimoto D, Nakagawa S, Umezaki N, Yamao T, Tsukamoto M, Kitano Y, Yamamura K, Miyata T, Okabe H, Ishimoto T, Imai K, Chikamoto A, Baba H.
  • Journal Title: Am J Surg. Volume: Aug 26 Issue: 1 Pages: 111-115
  • DOI: 10.1016/j.amjsurg.2017.08.016
  • Peer Reviewed
• [Journal Article] The microbiome and hepatobiliary-pancreatic cancers. (2017)
  • Author(s): Mima K, Nakagawa S, Sawayama H, Ishimoto T, Imai K, Iwatsuki M, Hashimoto D, Baba Y, Yamashita YI, Yoshida N, Chikamoto A, Baba H
  • Journal Title: Cancer Lett. Volume: 402 Pages: 9-15
  • DOI: 10.1016/j.canlet.2017.05.001
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. (2016)
  • Author(s): Tokunaga R, Imamura Y, Nakamura K, Ishimoto T, Nakagawa S, Miyake K, Nakaji Y, Tsuda Y, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Saeki H, Yoshida N, Oki E, Watanabe M, Oda Y, Bass AJ, Maehara Y, Baba H.
  • Journal Title: Oncotarget Volume: in press Issue: 15 Pages: 19748-61
  • DOI: 10.18632/oncotarget.7782
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer. (2016)
  • Author(s): Izumi D, Ishimoto T, Miyake K, Sugihara H, Eto K, Sawayama H, Yasuda T, Kiyozumi Y, Kaida T, Kurashige J, Imamura Y, Hiyoshi Y, Iwatsuki M, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Takamori H, Araki N, Tan P, Baba H.
  • Journal Title: Int J Cancer Volume: 1;138(5) Issue: 5 Pages: 1207-19
  • DOI: 10.1002/ijc.29864
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Extracellular vesicles from cancer associated fibroblasts induce drug resistance via integrinβ1/FAK signaling in gastric cancer cells (2019)
  • Author(s): 1.Takatsugu Ishimoto、Tomoyuki Uchihara, Keisuke Miyake, Atsuko Yonemura, Tadahito Yasuda, Rumi Itoyama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Hideo Baba
  • Organizer: 11th AACR-JCA Joint Conference
  • Int'l Joint Research
• [Presentation] 腫瘍間質に依存するdiffuse-type胃がん浸潤性増殖機構の解明 (2018)
  • Author(s): 2.石本崇胤、三宅慧輔、伊東山瑠美、内原智幸、吉田直矢、馬場秀夫
  • Organizer: 第29回日本消化器癌発生学会総会
• [Presentation] Expansion of pancreatic cancer stem-like cells through PGE2 accumulation in inflammatory environment (2018)
  • Author(s): 3.Takatsugu Ishimoto, Kota Arima,Luke Bu,Tomoyuki Uchihara,Keisuke Miyake,Tsugio Eto,Rumi Itoyama,Hideo Baba
  • Organizer: AACR annual meeting 2018
  • Int'l Joint Research
• [Presentation] 腫瘍炎症環境において間質に依存する胃癌進展の分子メカニズム (2018)
  • Author(s): 4.石本崇胤、三宅慧輔、八代正和、内原智幸、有馬浩太、泉大輔、岩槻政晃、馬場祥史、渡邊雅之、Patrick Tan、馬場秀夫
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk. (2017)
  • Author(s): Ishimoto T, Miyake K, Yashiro M, Eto T, Izumi D, Arima K, Baba Y, Watanabe M, Hirakawa K, Baba H.
  • Organizer: American Association for Cancer Research Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Identification of a new molecule mediating gastric cancer invasion based on genomic analysis of cancer-associated fibroblasts. (2017)
  • Author(s): Ishimoto T, Miyake K, Yashiro M, Eto T, Arima K, Izumi D, Baba Y, Hirakawa K, Tan P, Baba H.
  • Organizer: 12th International gastric cancer congress.
  • Int'l Joint Research
• [Presentation] 腫瘍炎症環境における間質とのクロストークを介したdiffuse-type胃癌進展機構 (2017)
  • Author(s): 石本 崇胤、Patrick Tan、馬場秀夫
  • Organizer: JDDW 2017
• [Presentation] Identification of molecular mechanism underlying diffuse-type gastric cancer invasion depending on tumor stroma. (2017)
  • Author(s): Ishimoto T, Miyake K, Yashiro M, Eto T, Arima K, Izumi D, Baba Y, Hirakawa K, Tan P, Baba H.
  • Organizer: The 76th Annual Meeting of the Japan Cancer Association.
• [Presentation] 腫瘍間質に依存するびまん性胃癌浸潤分子メカニズムの同定 (2017)
  • Author(s): 石本 崇胤、Patrick Tan、馬場秀夫
  • Organizer: 第28回日本消化器癌発生学会
• [Presentation] 腫瘍間質に依存する diffuse type 胃癌浸潤の新しい分子機構の解明 (2017)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、江藤二男、有馬浩太、泉大輔、岩槻政晃、馬場祥史、吉田直矢、渡邊雅之、Patrick Tan、馬場秀夫
  • Organizer: 第50回制癌剤適応研究会
  • Place of Presentation: ホテルクレメント徳島（徳島県）
• [Presentation] 腫瘍間質ゲノム解析に基づいた胃癌浸潤を制御する新規分子機構の解明 (2017)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、江藤二男、有馬浩太、泉大輔、岩槻政晃、馬場祥史、渡邊雅之、平川弘聖、Patrick Tan、馬場秀夫
  • Organizer: 第89回日本胃癌学会総会
  • Place of Presentation: 広島国際会議場（広島県）
• [Presentation] RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk. (2016)
  • Author(s): Ishimoto T, Miyake K, Yashiro M, Eto T, Izumi D, Arima K, Baba Y, Watanabe M, Hirakawa K, Baba H
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: ワシントン（米国）
  • Int'l Joint Research
• [Presentation] Identification of the novel molecules mediating gastric cancer invasion based on genomic analysis of cancer-associated fibroblasts. (2016)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Huang K, Arima K, Izumi D, Baba Y, Baba H, Tan P
  • Organizer: ESMO-ASIA 2016
  • Place of Presentation: シンガポール
  • Int'l Joint Research
• [Presentation] Cancer Associated Fibroblasts (CAFs)ゲノム解析に基づいた胃癌浸潤を制御する新規遺伝子の同定 (2016)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、有馬浩太、泉大輔、澤山浩、岩槻政晃、馬場祥史、坂本快郎、吉田直矢、平川弘聖、馬場秀夫、Patrick Tan
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Cancer Associated Fibroblastsゲノム解析に基づいたdiffuse type胃癌浸潤を制御する新規遺伝子の同定 (2016)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、泉大輔、有馬浩太、馬場祥史、渡邊雅之、平川弘聖、Patrick Tan、馬場秀夫
  • Organizer: 第71回日本消化器外科学会総会
  • Place of Presentation: アスティとくしま（徳島県）
• [Presentation] 網羅的ゲノム解析に基づいた胃癌Cancer Associated Fibroblasts (CAFs) の特性解明 (2016)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、泉大輔、志垣博信、藏重淳二、岩槻政晃、馬場祥史、坂本快郎、宮本裕士、吉田直矢、平川弘聖、 Patrick Tan、馬場秀夫
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪府）