Elucidation of the colon cancer cell cluster formation mechanism and application to novel anti-cancer metastasis treatment

• Project/Area Number: 16K15598
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Juntendo University
• Principal Investigator: Goto Michitoshi 順天堂大学, 医学部, 非常勤講師 (50445532)
• Co-Investigator(Kenkyū-buntansha): 小見山 博光 順天堂大学, 医学部, 非常勤講師 (30348982) ; 折茂 彰 順天堂大学, 医学(系)研究科(研究院), 准教授 (70275866)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 患者大腸癌 / PDX / 癌細胞集合体 / 浸潤・転移 / 大腸癌 / 大腸癌細胞集合体 / PDXモデル / 癌細胞間接着 / 転移のコロニー形成 / E-cadherin / 癌細胞クラスター / EMT（上皮間葉移行） / tumor organoid / EMT(上皮間葉移行) / 癌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Most colorectal cancer cells in patients with colorectal cancer PDX exhibited a strong E-cadherin-positive epithelial phenotype. On the other hand, epithelial / mesenchymal type cancer cells having both epithelial and mesenchymal phenotypes of E-cadherinlow ZEB1 high were also detected. Colon cancer cell aggregates with epithelial / mesenchymal phenotype were detected in the peripheral blood of PDX mice. Suppression of E-cadherin or ZEB1 expression by shRNA significantly suppressed the ability of human colon cancer cell organoids to form metastases in mice. From the above, it was revealed that the colon cancer cell population of patients having epithelial and epithelial / mesenchymal properties are essential for metastatic ability.

Academic Significance and Societal Importance of the Research Achievements

単一癌細胞あるいは癌細胞集団のどちらが浸潤して遠隔臓器に転移を形成するのかは不明である。またそのメカニズムも不明である。申請者は、多くの患者大腸癌はEMTを介することなく、細胞―細胞接着を有した癌細胞集合体を形成し、浸潤し転移形成に寄与していることを明らかにした。申請研究では、現行の普遍的に重要であると認知されているEMTという概念を打ち破り、それに代わる斬新的な着眼点として、癌細胞が集合体を形成することが、細胞死抵抗性を高め、転移巣形成を容易にしていると推測している。
この研究が、今後の癌細胞集合体形成やこれらの浸潤・転移を抑制するような薬剤の開発の助けるなれば幸いである。

Research Products

• [Journal Article] Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. (2019)
  • Author(s): Mizukoshi K, Okazawa Y, Haeno H, Koyama Y, Sulidan K, Komiyama H, Saeki H, Ohtsuji N, Ito Y, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: Int J Cancer Volume: 146 Issue: 9 Pages: 2547-2562
  • DOI: 10.1002/ijc.32672
  • Peer Reviewed / Open Access
• [Journal Article] High-sensitivity detection of micrometastases generated by GFP lentivirus-transduced organoids cultured from a patient-derived colon tumor. (2018)
  • Author(s): OkazawaY, Mizukoshi K, KoyamaY, Okubo S, Komiyama H, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: J Vis Exp Volume: 136(e57374) Issue: 136 Pages: 463-473
  • DOI: 10.3791/57374
  • Peer Reviewed / Open Access
• [Journal Article] Survival benefit of lymph node dissection in surgery for colon cancer in elderly patients:multicenter propensity score-matched study in Japan. (2018)
  • Author(s): Takahashi M, Niitsu H, Sakamoto K, Hinoi T, Hattori M, Goto M, Bando H, Hazama S, Maeda K, Okita K, Horie H, Watanabe M; Japan Society of Laparoscopic Colorectal Surgery.
  • Journal Title: Asian J Endosc Surg Volume: 2018 Mar 30 Issue: 4 Pages: 1-9
  • DOI: 10.1111/ases.12474
  • Peer Reviewed
• [Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling. (2018)
  • Author(s): Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
  • Journal Title: Oncogene. Volume: 37 Issue: 9 Pages: 1205-1219
  • DOI: 10.1038/s41388-017-0033-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. (2018)
  • Author(s): Roswall P, Bocci M, Bartoschek M, Li H, Kristiansen G, Jansson S, Lehn S, Sjölund J, Reid S, Larsson C, Eriksson P, Anderberg C, Cortez E, Saal LH, Orsmark-Pietras C, Cordero E, Haller BK, Häkkinen J, Burvenich IJG, Lim E, Orimo A, Höglund M, Rydén L, Moch H, Scott AM, Eriksson U, Pietras K.
  • Journal Title: Nat Med Volume: 24(4) Issue: 4 Pages: 463-473
  • DOI: 10.1038/nm.4494
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pharmacological targeting of neutrophil serine proteases prevents lethality in dextran sulfate sodium (DSS)-induced colitis in mice (2018)
  • Author(s): Ro H, Munakata S, Ueyama T, Komiyama H, Takahashi M, Kojima Y, Tomiki Y, Sakamoto K
  • Journal Title: Journal of Gastrointestinal & Digestive System Volume: 8 Issue: 01 Pages: 551-551
  • DOI: 10.4172/2161-069x.1000551
  • Peer Reviewed / Open Access
• [Journal Article] Salivary chromogranin a as a psychosomatic stress marker is suppressed in laparoscopic surgery compared with open surgery for colon cancer. (2017)
  • Author(s): Ishiyama S, Sakamoto K, Kamiyama H, Niwa K, Sugimoto K, Takahashi M, KojimaY, Goto M, Okuzawa A, Tomiki Y
  • Journal Title: Juntendo Medical Journal Volume: 63 Pages: 88-94
  • NAID: 130006944480
  • Peer Reviewed / Open Access
• [Journal Article] Propensity Score Analysis in the Comparison of Long-Term Outcomes for Locally Advanced Colon Cancer Between Laparoscopic Colectomy and Open Colectomy (2017)
  • Author(s): Sugimoto K, Sakamoto K, Ichikawa R, Kure K, Honjo K, Ro H, Takahashi R, Kawano, Niwa K, Ishiyama S, Kamiyama H, Komiyama H, Takahashi M, Kojima Y, Goto M, Okuzawa A, Ishibiki Y, Tomiki Y
  • Journal Title: Juntendo Medical Journal Volume: 63 Issue: 4 Pages: 264-272
  • DOI: 10.14789/jmj.63.264
  • NAID: 130006106309
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of glycopyrronium and indacaterol inhibits carbachol-induced ERK5 signal in fibrotic processes. (2017)
  • Author(s): Namba Y, Togo S, Tulafu M, Kadoya K, Nagahama KY, Taka H, Kaga N, Orimo A, Liu X, Takahashi K.
  • Journal Title: Respir Res. Volume: 18 Issue: 1 Pages: 46-46
  • DOI: 10.1186/s12931-017-0529-6
  • Peer Reviewed / Open Access
• [Journal Article] Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer. (2016)
  • Author(s): Astrid E-E, Bartoschek M, Gialeli C, Okroj M, Owen S, Jirström K, Orimo A, Jiang W G, Pietras K, Blom A M.
  • Journal Title: Oncotarget Volume: Advance Publication Pages: 1-14
  • Peer Reviewed / Open Access
• [Journal Article] Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer. (2016)
  • Author(s): Chrysostomi Gialeli, Astrid Escudero-Esparza, Michael Bartoschek, Matthias Mörgelin, Petter Storm, Marcin Okroj, Sioned Owen, Karin Jirström, Akira Orimo, Wen G. Jiang, Kristian Pietras, Anna M. Blom
  • Journal Title: Immunobiology Volume: 221（10） Issue: 10 Pages: 1155-1155
  • DOI: 10.1016/j.imbio.2016.06.072
  • Peer Reviewed
• [Presentation] 患者大腸癌細胞集団の中間型上皮間葉移行を介した浸潤・転移機構 (2019)
  • Author(s): 水越幸輔、岡澤 裕、波江野洋、小山 侑、大久保捷奇、Kaidiliavi Sulidan、 伊藤恭彦、小見山、光、杉本起一、小島 豊、五藤倫敏、垣生園子、樋野興夫、 折茂 彰、坂本一博
  • Organizer: 第30回 日本消化器癌発生学会総会
• [Presentation] 中間型上皮間葉移行による患者大腸癌細胞クラスターの転移への寄与 (2018)
  • Author(s): 岡澤 裕、水越 幸輔、小山 侑、大久保 捷奇、Kaidiliavi Sulidan、伊藤 恭彦、小見山 博光、小島 豊、五藤 倫敏、垣生 園子、樋野 興夫、折茂 彰、坂本 一博
  • Organizer: 第29回 日本消化器癌発生学会総会 東京
• [Presentation] 癌内線維芽細胞と癌悪性化 (2018)
  • Author(s): 折茂彰
  • Organizer: 第836回千葉県がんセンター研究所集談会
  • Invited
• [Presentation] 癌内線維芽細胞の癌悪性化機構の解明および治療標的としての展望 (2018)
  • Author(s): 折茂彰
  • Organizer: 公益財団法人微生物化学研究会セミナー
  • Invited
• [Presentation] Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer. (2017)
  • Author(s): Kawano S, Komiyama H, Goto M, Sakamoto K
  • Organizer: 110th AACR, Washington DC,
  • Int'l Joint Research
• [Presentation] Postoperative adjuvant chemotherapy improves survival in stage II colon cancer ? a propensity score matching analysis. (2017)
  • Author(s): Tsukamoto R, Matsuzawa M, Hagiwara T, Tsuchiya Y, Amemiya K, Motegi S, Makino Y, Kawano S, Honjo K, Kure K, Ichikawa R, Ro H, Ito S, Takahashi R, Niwa K, Ishiyama S, Sugimoto K, Kamiyama H, Takahashi M, Kojima Y, Goto M, Okuzawa A, Tomiki Y, Fukunaga T, Kajiyama Y, Kawasaki S, Sakamoto K:
  • Organizer: 110th AACR, Washington DC
  • Int'l Joint Research
• [Presentation] Identification of a novel diagnostic marker for colon cancer through comprehensive microRNA analysis. (2017)
  • Author(s): Tsukamoto R, Komiyama H, Hosoya M, Kure K, Okazawa Y, Mizukoshi K, Fukaya M, Sugimoto K, Kamiyama H, Tomiki Y, Sakamoto K:
  • Organizer: 第76回日本癌学会学術総会 横浜
• [Presentation] Carcinoma-associated fibroblasts upregulate endoglin expression to mediate their activated myofibroblastic traits. (2017)
  • Author(s): Okubo S, Mezawa Y, Ito Y, Watanabe s, Hino O, Orimo A
  • Organizer: 第76回日本癌学会学術総会v横浜
• [Presentation] CAFs boost mammary cancer invasion and metastasis via formation of the epithelial and mesenchymal tumor cell cluster. (2017)
  • Author(s): Akira Orimo, Yasuhiko Ito, Yoshihiro Mezawa, Kaidiliavi Sulidan, Nadila Wali1, Okio Hino, Kazuyoshi Takeda, Michiaki Hamada, Yuko Matsumura
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Carcinoma-associated fibroblasts attenuate CD26/dipeptidyl peptidase-4 expression via activation of the TGF-β-Smad2/3pathway. (2017)
  • Author(s): Yoshihiro Mezawa, Chikao Morimoto, Okio Hino, and Akira Orimo
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Carcinoma-associated fibroblasts promote metastatic seeding of the highly epithelial human breast carcinoma cell cluster with a quasi-mesenchymal trait. (2017)
  • Author(s): Yasuhiko Ito, Yuko Matsumura, Yoshihiro Mezawa, Kaidiliavi Sulidan, Nadila Wali, Yasuhiko Terao, Satoru Takeda, Ko Okumura, Kazuyoshi Takeda, Okio Hino, Akira Orimo
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Production of monoclonal antibodies against amino acid transporter SLC7A1 to develop novel therapy for colorectal cancer. (2017)
  • Author(s): Fukaya M, Komiyama H, Sugimoto K, Kamiyama H, Sakamoto K:
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Identification of a novel diagnostic marker for colon cancer through comprehensive microRNA analysis. (2017)
  • Author(s): Tsukamoto R, Komiyama H, Hosoya M, Kure K, Okazawa Y, Mizukoshi K, Fukaya M, Sugimoto K, Kamiyama H, Tomiki Y, Sakamoto K:
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] CAFsは細胞接着能を亢進することにより乳がん細胞の転移を促進する (2016)
  • Author(s): 折茂彰・Wali Nadila, 伊藤恭彦，日野興夫，竹田和由，浜田道昭，松村優子
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Multicellular tumor clusters seed metastases in colon patientderived tumor xenografts (2016)
  • Author(s): Okubo S, Mizukoshi K, Okazawa Y, Haeno H, Komiyama H, Saeki H, Ito Y, Gotou M Watanabe S,Hino O, Sakamoto K, Orimo A
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Remarks] 順天堂大学大学院 下部消化管外科学 （消化器外科学講座）
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学大学院 下部消化管外科学
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/