Dissection of molecular mechanisms of the metastatic niche dormancy and application to the ant-metastatic therapy

• Project/Area Number: 16K15625
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Juntendo University
• Principal Investigator: kojima yutaka 順天堂大学, 医学部, 准教授 (00327800)
• 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 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• 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: metastatic dormancy / CAFs / tumor microenvironment / CAFｓ / 大腸癌 / niche / Metastatic dormancy / Niche / 癌微小環境 / 癌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Our previous findings demonstrated that CAFs promote tumor malignancy of nearby carcinoma cells. We here aimed to determine whether CAFs also regulate the niche for metastatic dormancy to boost metastasis. To do so, we checked roles of CAFs on metastatic ability of tumor organoids generated from human colon carcinomas. We found that CAFs boost tumor metastasis of colon tumor organoids in the liver and lungs significantly more than did control fibroblasts did, when orthotopically injected into immunodeficient mice. These findings indicate that CAFs may play roles for niches to activate metastatic dormancy, however, more clear evidences await future study.

Academic Significance and Societal Importance of the Research Achievements

癌死亡の９０％は転移再発に起因している。癌診断時に臨床的に転移が認められないが、原発巣治療後数年以内に転移再発で命を落とす患者数は少なくない。転移再発は、遠隔臓器の新しい環境に適応できず細胞増殖を停止している(dormant)癌細胞の再増殖に依存している。もし癌細胞のdormancyを制御機構を解明し臨床に応用することができれば、転移癌細胞との共存が可能になるかもしれない。

Research Products

• [Journal Article] Endoscopic Submucosal Dissection Decreases Additional Colorectal Resection for T1 Colorectal Cancer. (2018)
  • Author(s): Tomiki Y, Kawai M, Kawano S, Ishiyama S, Sugimoto K, Takahashi M, Kojima Y, Murakami T, Ritsuno H, Shibuya T, Sakamoto N, Sakamoto K.
  • Journal Title: Medical Science Monitor Volume: 24 Pages: 6910-6917
  • DOI: 10.12659/msm.909380
  • Peer Reviewed
• [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] Case report of perineal hernia after laparoscopic abdominoperineal resection. (2018)
  • Author(s): Honjo K, Sakamoto K, Motegi S, Tsukamoto R, Munakata S, Sugimoto K, Kamiyama H, Takahashi M, Kojima Y, Fukunaga T, Kajiyama Y, Kawasaki S
  • Journal Title: Asian journal of endoscopic surgery Volume: 11 Issue: 2 Pages: 173-176
  • DOI: 10.1111/ases.12420
  • 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] 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] Superior mesenteric artery syndrome improved by enteral nutritional therapy according to the ｃontrolling nuritional status score. (2017)
  • Author(s): Takehara K, Sakamoto K, Takahashi R, Kawai M, Kawano S, Munakata S, Sugimoto K, Takahashi M, Kojima Y, Fukunaga T, Kajiyama Y, Kawasaki S:
  • Journal Title: Case Reports in Gastroenterology Volume: 11(3) Issue: 3 Pages: 721-727
  • DOI: 10.1159/000484129
  • Peer Reviewed / Open Access
• [Journal Article] Minimally Invasive Surgery for Colorectal Cancer (2017)
  • Author(s): Sakamoto K, Tsukamoto R, Kawano S, Kawai M, Niwa K, Ishiyama S, Sugimoto K, Kamiyama H, Komiyama H, Takahashi M, Kojima Y, Goto M, Okuzawa A, Tomiki Y:
  • Journal Title: Juntendo Medical Journal Volume: 63 Issue: 5 Pages: 384-392
  • DOI: 10.14789/jmj.63.384
  • NAID: 130006219695
  • ISSN: 2187-9737, 2188-2126
  • 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 Issue: 2 Pages: 88-94
  • DOI: 10.14789/jmj.63.88
  • NAID: 130006944480
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Journal Article] LSD1/KDM1 isoform LSD1+8a contributes to neural differentiation in small cell lung cancer (2017)
  • Author(s): Jotatsu, T., Yagishita, S., Tajima, K., Takahashi, F., Mogushi, K., Hidayat, M., Wirawan, A., Ko, R., Kanemaru, R., Shimada, N., Mitani, K., Saito, T., Takamochi, K., Suzuki, K., Kohsaka, S., Kojima, S., Mukae, H., Yatera, K., and Takahashi, K.
  • Journal Title: Biochemistry and Biophysics Reports Volume: ９ Pages: 86-94
  • DOI: 10.1016/j.bbrep.2016.11.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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, advanced publication Volume: 2016 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] 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] Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer. (2017)
  • Author(s): Kawano S, Komiyama H, Kojima Y, Sakamoto K et al.
  • 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] 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] 水越幸輔, 岡澤 裕, 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: (2017)
  • Author(s): 患者大腸癌由来PDXおよびオルガノイドを使用した転移モデルの樹立.
  • Organizer: 第28回日本消化器癌発生学会総会, 熊本
• [Presentation] 大腸癌術後の再発に対して複合的免疫細胞療法(全身化学療法/免疫細胞療法併用)を施行した2例. (2017)
  • Author(s): 杉本起一, 土谷祐樹, 松澤宏和, 本庄薫平, 河合雅也, 宗像慎也, 丹羽浩一郎, 石山 隼, 神山博彦, 高橋 玄, 小島 豊, 後藤重則, 瀧本理修, 神垣 隆, 坂本 一博.
  • Organizer: 第55回日本癌治療学会学術集会
• [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] 癌内線維芽細胞と癌悪性化 (2017)
  • 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 (2017)
  • 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] 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
• [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
• [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/