Molecular mechanisms of cancer development and progression in obesity.

• Project/Area Number: 18K07231
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fujita Health University
• Principal Investigator: Shimono Yohei 藤田医科大学, 医学部, 教授 (90594630)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: がん幹細胞 / 脂肪細胞 / 乳がん / 卵巣がん / アディプシン / アディポカイン

Outline of Final Research Achievements

Based on the observation linking obesity to the risk of various types of cancers, tumor promoting effects of adipocytes were investigated. Adipose tissue-derived stem cells (ADSCs) established from the surgical specimens of breast cancer patients enhanced the cancer stem cell properties of breast cancer cells. Similarly, ADSCs promoted the cancer stem cell properties of ovarian cancer cells. We then identified the compounds that suppressed the ability of ADSCs to promote cancer stem cell properties. These findings indicate that adipocytes are novel therapeutic targets in various cancers.

Academic Significance and Societal Importance of the Research Achievements

がんの発症および進展にはがん細胞の周囲にある細胞（がん間質細胞）の働きが重要である。本研究は、がん間質細胞の新たな一員としての脂肪細胞の重要性を明らかにするとともに、それが乳がんや卵巣がんにおいて、がん形成の根源にあるがん幹細胞の性質を増強することを示した。さらに、脂肪細胞を標的として効果的にがん幹細胞性を抑制する化合物を同定した。本研究の知見から、がん間質を標的とすることで抗がん作用を発揮する全く新機構の抗がん剤を開発できる可能性が明らかになった。

Research Products

• [Int'l Joint Research] コロンビア大学(米国)
• [Int'l Joint Research] モンペリエ大学(フランス)
• [Int'l Joint Research] コロンビア大学(米国)
• [Int'l Joint Research] モンペリエ大学(フランス)
• [Journal Article] Upregulation of S100A10 in metastasized breast cancer stem cells (2020)
  • Author(s): Yanagi Hisano、Watanabe Takashi、Nishimura Tatsunori、Hayashi Takanori、Kono Seishi、Tsuchida Hitomi、Hirata Munetsugu、Kijima Yuko、Takao Shintaro、Okada Seiji、Suzuki Motoshi、Imaizumi Kazuyoshi、Kawada Kenji、Minami Hironobu、Gotoh Noriko、Shimono Yohei
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4359-4370
  • DOI: 10.1111/cas.14659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Upregulation of CIP2A in estrogen depletion‐resistant breast cancer cells treated with low‐dose everolimus (2020)
  • Author(s): Nishio Eiji、Hayashi Takanori、Akaza Mao、Hisatomi Yukiko、Hikichi Masahiro、Fujii Takuma、Utsumi Toshiaki、Harada Nobuhiro、Shimono Yohei
  • Journal Title: FEBS Open Bio Volume: 10 Issue: 10 Pages: 2072-2080
  • DOI: 10.1002/2211-5463.12956
  • Peer Reviewed / Open Access
• [Journal Article] miR-93 targets WASF3 and functions as a metastasis suppressor in breast cancer. (2020)
  • Author(s): Shibuya N, Kakeji Y, Shimono Y.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 6 Pages: 2093-2103
  • DOI: 10.1111/cas.14423
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-9-5p-CDX2 Axis: A Useful Prognostic Biomarker for Patients with Stage II/III Colorectal Cancer. (2019)
  • Author(s): Nishiuchi A, Hisamori S, Sakaguchi M, Fukuyama K, Hoshino N, Itatani Y, Honma S, Maekawa H, Nishigori T, Tsunoda S, Obama K, Miyoshi H, Shimono Y, Taketo MM, Sakai Y.
  • Journal Title: Cancers (Basel) Volume: 11 Issue: 12 Pages: 1891-1891
  • DOI: 10.3390/cancers11121891
  • NAID: 120006846477
  • Peer Reviewed / Open Access
• [Journal Article] Lack of association of ovariectomy-induced obesity with overeating and the reduction of physical activities. (2019)
  • Author(s): Nishio E, Hayashi T, Nakatani M, Aida N, Suda R, Fujii T, Wakatsuki T, Honda S, Harada N, Shimono Y.
  • Journal Title: Biochemistry and Biophysics Reports Volume: 20 Pages: 100671-100671
  • DOI: 10.1016/j.bbrep.2019.100671
  • Peer Reviewed / Open Access
• [Journal Article] miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells. (2019)
  • Author(s): Mukohyama J, Isobe T, Hu Q, Hayashi T, Watanabe T, Maeda M, Yanagi H, Qian X, Yamashita K, Minami H, Mimori K, Sahoo D, Kakeji Y, Suzuki A, Dalerba P, Shimono Y.
  • Journal Title: Cancer Research Volume: 79 Issue: 20 Pages: 5151-5158
  • DOI: 10.1158/0008-5472.can-18-3544
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells. (2019)
  • Author(s): Honma S, Hisamori S, Nishiuchi A, Itatani Y, Obama K, Shimono Y, Sakai Y.
  • Journal Title: Cancers Volume: 11 Issue: 5 Pages: 635-635
  • DOI: 10.3390/cancers11050635
  • NAID: 120006644046
  • Peer Reviewed / Open Access
• [Journal Article] Adipose-derived stem cells enhance human breast cancer growth and cancer stem cell-like properties through adipsin. (2019)
  • Author(s): Goto H, Shimono Y, Funakoshi Y, Imamura Y, Toyoda M, Kiyota N, Kono S, Takao S, Mukohara T, Minami H.
  • Journal Title: Oncogene Volume: 38 Issue: 6 Pages: 767-779
  • DOI: 10.1038/s41388-018-0477-8
  • Peer Reviewed
• [Journal Article] 3D Culture Represents Apoptosis Induced by Trastuzumab Better than 2D Monolayer Culture. (2018)
  • Author(s): Tatara T, Mukohara T, Tanaka R, Shimono Y, Funakoshi Y, Imamura Y, Toyoda M, Kiyota N, Hirai M, Kakeji Y, Minami H.
  • Journal Title: Anticancer research Volume: 38 Pages: 2831-2839
  • Peer Reviewed
• [Presentation] 脂肪細胞によるがん幹細胞性制御能の解析. (2021)
  • Author(s): Shimono Y, Gotoh N.
  • Organizer: 令和2年度金沢大学がん進展制御研究所共同利用・共同研究拠点研究成果報告会
• [Presentation] MicroRNA profiling of latently metastasized human breast cancer stem cells. (2020)
  • Author(s): Shimono Y, Shibuya N, Nishimura T, Gotoh N, Kakeji Y.
  • Organizer: 第79回日本癌学会学術総会 (International Session)
  • Invited
• [Presentation] Peritoneal adipose tissue-derived stem cells enhance clonogenicity of ovarian cancer cells. (2020)
  • Author(s): Maeda M, Hayashi T, Nishio E, Asai N, Fujii T, Shimono Y.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Upregulation of S100A10 in metastasized breast cancer stem cells. (2020)
  • Author(s): Yanagi H, Watanabe T, Nishimura T, Hayashi T, Okada S, Suzuki M, Minami H, Suzuki A, Kawada K, Gotoh N, Shimono Y.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Gamma-glutamylcyclotransferase as a novel regulator of cancer stem cell properties in breast cancers. (2020)
  • Author(s): Hayashi T, Maeda M, Okada S, Suzuki M, ShimonoY.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Downregulation of miR-93 in micrometastatic cancer stem cells of human breast cancer xenograft. (2019)
  • Author(s): Shibuya N, Shimono Y, Minami H, Kakeji Y, Suzuki A.
  • Organizer: 第78回 日本癌学会学術総会
• [Presentation] miR-221 targets an RNA-binding protein QKI-5 and enhances the tumorigenic capacity of human colorectal cancer stem cells. (2019)
  • Author(s): Shimono Y, Mukohyama J, Hayashi T, Watanabe T, Isobe T, Hu Q, Sahoo D, Minami H, Mimori K, Dalerba P, Kakeji Y, Suzuki A.
  • Organizer: 第17回 幹細胞シンポジウム
• [Presentation] Adipsin is an adipokine that promotes cancer stem cell-like properties of breast cancer patient-derived xenograft cells. (2019)
  • Author(s): Shimono Y, Goto H, Funakoshi Y, Imamura Y, Toyoda M, Kiyota N, Kono S, Takao S, Mukohara T, Minami H.
  • Organizer: 第3回 三次元培養研究会
• [Remarks] 藤田医科大学医学部生化学講座
  • URL: http://www.fujita-hu.ac.jp/~biochem1/index.html
• [Remarks] 藤田医科大学がん医療研究センター
  • URL: https://fcc.fujita-hu.ac.jp/research/
• [Patent(Industrial Property Rights)] 抗がん剤 (2019)
  • Inventor(s): 下野洋平、後藤秀彰、南博信
  • Industrial Property Rights Holder: 下野洋平、後藤秀彰、南博信
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2020