Analysis on colon cancer malignant progression using novel mouse models
| Project/Area Number |
15H02362
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Kanazawa University |
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Principal Investigator |
Oshima Masanobu 金沢大学, がん進展制御研究所, 教授 (40324610)
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| Research Collaborator |
OSHIMA Hiroko
NAKAYAMA Mizuho
ECHIZEN Kanae
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥32,370,000 (Direct Cost: ¥24,900,000、Indirect Cost: ¥7,470,000)
Fiscal Year 2017: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2016: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2015: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
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| Keywords | 大腸がん / マウスモデル / 悪性化進展 / オルガノイド / 転移 / 微小環境 / 自然転移モデル / 炎症 |
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| Outline of Final Research Achievements |
We have selected five colon cancer driver genes, Apc, Kras, Tgfbr2, Trp53 and Fbxw7, which regulate distinct oncogenic or tumor-suppressor pathways, and generated compound mutant mice by intensive crossing. Phenotype analyses of the mice revealed that suppression of TGF-beta signaling or mutant p53 expression in addition to Wnt activation causes submucosal invasion. Moreover, we found that additional Kras activation mutation induces morphological changes to EMT-like structure and intravasation. These triple mutant tumor-derived organoids acquired metastatic ability rom spleen to the liver. Taken together, the results suggest that Apc, Kras, Tgfbr2 or Apc, Kras, Trp53 is a minimum core for efficient colon cancer metastasis.
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| Academic Significance and Societal Importance of the Research Achievements |
複数の遺伝子変異の積み重ねが大腸がんを発生させるという、「多段階発がん」の概念が確立されているが、それぞれの遺伝子変異の組み合わせにより、がん細胞がどのような悪性化形質を獲得するのかは、未だ不明な点が多く全体像は明らかになっていない。本研究では、ゲノム解析で明らかにされたドライバー遺伝子変異の情報を基にして、マウスモデルを用いた網羅的解析を実施することで、大腸がん細胞の粘膜下浸潤、血管やリンパ管浸潤、遠隔転移などの各悪性化段階に、どのようなドライバー遺伝子変異の組み合わせが関与するのかを初めて明らかにした。得られた知見は、将来の大腸がん転移を標的とした治療薬開発に貢献が期待される。
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Report
(4 results)
Research Products
(60 results)
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[Journal Article] Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer.2018
Author(s)
Sakai E, Nakayama M, Oshima H, Kouyama Y, Niida A, Fujii S, Ochiai A, Nakayama KI, Minori K, Suzuki Y, Hong CP, Ock CY, Kim SJ, Oshima M.
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Journal Title
Cancer Res.
Volume: 78
Issue: 5
Pages: 1334-1346
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation.2017
Author(s)
Nakayama M, Sakai K, Echizen K, Yamada Y, Oshima H, Han TS, Ohki R, Fujii S, Ochiai A, Robine S, Voon DC, Tanaka T, Taketo MM, Oshima M.
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Journal Title
Oncogene
Volume: 36
Issue: 42
Pages: 5885-5896
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Myeloid Differentiation Factor 88 Signaling in Bone Marrow-Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment.2016
Author(s)
Maeda Y, Echizen K, Oshima H, Yu L, Sakulsak N, Hirose O, Yamada Y, Taniguchi T, Jenkins BJ, Saya H, Oshima M.
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Journal Title
Cancer prevention research
Volume: 9
Issue: 3
Pages: 253-263
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells.2016
Author(s)
Naka K, Ishihara K, Jomen Y, Jin CH, Kim DH, Gu YK, Jeong ES, Li S, Krause DS, Kim DW, Bae E, Takihara Y, Hirao A, Oshima H, Oshima M, Ooshima A, Sheen YY, Kim SJ, Kim DK.
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Journal Title
Cancer Sci.
Volume: 107
Issue: 2
Pages: 140-148
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Dipeptide species regulate nutrient signalling essential for the maintenance of chronic myelogenous leukaemia stem cells.2015
Author(s)
Naka K, Jomen Y, Ishihara K, Kim J, Ishimoto T, Bae E, Mohney R, Stirdivant SM, Oshima H, Oshima M, Kim DW, Nakauchi H, Takihara Y, Kato Y, Ooshima A, Kim SJ.
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Journal Title
Nature Communication
Volume: 6
Issue: 1
Pages: 8039-8039
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Book] リンパ学2017
Author(s)
大島浩子，越前佳奈恵，中山瑞穂，大島正伸
Total Pages
5
Publisher
日本リンパ学会
Related Report
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[Book] 特集 胃癌2017
Author(s)
大島浩子，越前佳奈恵，中山瑞穂，大島正伸
Total Pages
6
Publisher
日本臨床社
Related Report
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