Elucidation of molecular mechanism of cancer stem cell niche at the very early stage aiming at cancer prevention
Project/Area Number |
19K22557
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 50:Oncology and related fields
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Research Institution | Kanazawa University |
Principal Investigator |
Gotoh Noriko 金沢大学, がん進展制御研究所, 教授 (10251448)
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Project Period (FY) |
2019-06-28 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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Keywords | 乳がん / 早期病変 / Ductal carcinoma in situ / 微小環境 / がん予防 / inflammation / precancerous tissues / NFkappaB / breast cancer / FRS2 / 超早期がん / がん幹細胞 / 炎症 |
Outline of Research at the Start |
がんを予防し超早期に治療できれば、がんを根治することが期待されるものの、超早期の乳がん細胞が増殖を開始する分子機構が不明のため、予防法、超早期治療法は未だ存在しない。応募者は最近、前がん状態の乳腺前駆細胞がサイトカインを多く放出して炎症性の微小環境を作り、これが「超早期がん幹細胞ニッチ」としてがん幹細胞の増殖を開始させることをつきとめた。本研究では、応募者の作出した乳がんの独創的マウスモデルと、患者由来検体の培養と移植モデルを解析し、この超早期がん幹細胞ニッチの分子機構を解明する。
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Outline of Final Research Achievements |
We demonstrate that FRS2β an adaptor protein expressed in a small subset of epithelial cells, triggers the pro-inflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β-deficiency in a mouse mammary tumor virus (MMTV)-ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found co-localization of FRS2β and the NEMO subunit of the IκB kinase (IKK) complex in early endosomes led to activation of nuclear factor-κB (NFκB) a master regulator of inflammation. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β-NFκB axis uncovers a hitherto unknown molecular link between the pro-inflammatory changes and the disease onset.
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Academic Significance and Societal Importance of the Research Achievements |
現在,乳がんの早期病変Ductal carcinoma in situ (DCIS)はマンモグラフィで見つけることができる。しかし,その後増殖して悪性の浸潤がんになっていくかどうか見極めがつかないため,手術という侵襲性の高い治療法しか選択肢がなく,実臨床における問題となっている。本研究をさらに発展させることにより,乳がん発症前に整えられている乳腺微小環境を標的とする治療を行うことが可能になると考えられる。ひいては乳がんの発症予防,早期の治療が実現し,従来であれば乳がんにより命を落としていた人々が救われることが期待される。
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Report
(4 results)
Research Products
(47 results)
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[Journal Article] The CD44/COL17A1 Pathway Plays a Vital Role in the Formation of Multilayered, Transformed Epithelia.2021
Author(s)
Kozawa K, ,Sekai M, Ohba K, Ito S, Sako H, Maruyama T, Kakeno M , Kuromiya K, Kamasaki T, Kohashi K, Ishikawa S, Sato N, Asano S, Suzuki H, Tanimura N, Mukai Y, Gotoh N, Tanino M, Tanaka S Natsuga K, Soga T. Nakamura T, Yabuta Y, Saitou M, Ito T, Matsuura K, Tsunoda M,et.al..
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Journal Title
Curr Biol
Volume: 31
Issue: 14
Pages: 3086-3097
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The CD44/COL17A1 pathway plays a vital role in the formation of transformed multi-layered epithelia2021
Author(s)
Kozawa K, Sekai M, Ohba K, Gotoh N, Tanino M, Tanaka S, Natsuga K, Soga T, Nakamura T, Yabuta Y, Saitou M, Itoh T, Matsuura K, Tsunoda M, Kikumori T, Iida T, Mizutani Y, Miyai Y, Enomoto A, Fujita Y.
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Journal Title
Related Report
Peer Reviewed / Open Access
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[Journal Article] Upregulation of S100A10 in metastasized breast cancer stem cells2020
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
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Journal Title
Cancer Science
Volume: 111
Issue: 12
Pages: 4359-4370
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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