| Project/Area Number |
21K06958
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49030:Experimental pathology-related
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| Research Institution | National Defense Medical College |
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Principal Investigator |
Mochizuki Satsuki 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 外科学, 講師 (80365428)
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| Co-Investigator(Kenkyū-buntansha) |
上野 秀樹 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 外科学, 教授 (90597535)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | ADAM / ECM / 癌微小環境 / 癌関連線維芽細胞 / 線維性癌間質反応 / 大腸癌 / がん関連線維芽細胞 / CAF / TIMP / DR / PDC / 低分化胞巣 / オルガノイド / ADAM12 / Desmoplastic reaction / ADAM9s / ADAM9 / 細胞外マトリックス |
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| Outline of Research at the Start |
当教室では、大腸癌症例を癌細胞浸潤先端部の間質構造の違いから、類粘液性間質と不規則な膠原線維を特徴とするImmature型、類粘液性間質を認めずケロイドで出現するヒアリン化膠原線維が存在するIntermediate 型、繊細な膠原線維が配列した線維性構造からなるMature型に分類 (Desmoplastic reaction: DR分類) し、予後との関係性を検討した結果、手術後の予後はMature型、Intermediate型、Immature型の順に不良となることが明らとなっている。本研究では、DR分類が予後因子となる理由を調べるため、大腸癌手術検体からCAFや大腸癌オルガノイド培養を行い、ADAM分子の網羅的発現と機能解析について検討を行う。
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| Outline of Final Research Achievements |
Desmoplastic reaction (DR), which is morphologically classified to Mature, Intermediate and Immature types, is correlated with patient prognosis. Conditioned media of CAFs from tumor with Immature type DR (CAFsImmature) significantly increased proliferation and migration of CRC cells compared to those of CAFs from Mature-type DR (CAFsMature). Subcutaneous implantation of CRC cells together with CAFsImmature in mice significantly promoted tumor growth and peritoneal dissemination compared to those with CAFsMature. Systematic examination indicated that ADAM9s expression is significantly higher in CAFsImmature than in CAFsMature. Knockdown of ADAM9s in CAFsImmature suppressed the promoting effects on CRC cell proliferation and migration. ADAM9s overproduced by CAFsImmature has been suggested to promote CRC cell proliferation and migration, suggesting an impact on poor prognosis of patients with Immature-type DR.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究による研究成果は、「 Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness」のタイトルでInt J Cancer 15: 1706-1721, 2022 誌に責任著者として発表し、本論文は2022年度日本結合組織学会大高賞を受賞した。
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