| Project/Area Number |
16K09312
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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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| Research Field |
Gastroenterology
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| Research Institution | Prefectural University of Hiroshima |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 腫瘍微小環境 / 転移 / 大腸癌 / 癌間質相互作用 / 微小環境 / 大腸がん転移モデル / 分子標的治療 / 大腸癌転移モデル / 大腸癌自然発症モデル |
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| Outline of Final Research Achievements |
Hinoi et al. succeeded in creating a mouse model that spontaneously develops large intestine tumor by inactivating APC gene. Based on this model, CDX2P-Cre; Apc knock-out + mutant KRAS knock-in mice model and CDX2P-Cre; Apc knock-out +TGFBRII knock-out mice were generated by adding KRAS and TGFBRII mutation, respectively. The pathological features of these models were analyzed. The tumor acquired invasiveness when KRAS mutation and TGFBRII mutation were added to the APC mutation. Extracellular matrix volume, and expression of alpha-smooth muscle actin (α-SMA), which is a marker for cancer-associated fibroblast (CAF), were increased in the mice to which KRAS mutation or TGFBRII mutation was added. Higher values in micro vessel density and lymph vessel density were observed in mice with KRAS or TGFBRII mutation. The tumor developed in these spontaneous tumorigenesis models with multiple mutations, closely resembled human colorectal cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では共同研究者の檜井らが開発した3種類のマウス浸潤性大腸癌自然発症モデルを用いて、分子病理学的特徴を検討した。遺伝子異常の蓄積により、腫瘍が浸潤能を獲得し、癌細胞のみならず、周囲の間質に大きな変化を示すことを証明した。これまで我々は同所移植モデルを用いて、治療実験に用いていたが、腫瘍の分化度や間質反応などにおいて、ヒト大腸癌組織との相違点があった。複数の遺伝子変異を大腸粘膜特異的に発現させる自然発症モデルでは、よりヒト大腸癌に類似した、間質反応豊富で浸潤性の強い腫瘍が得られ、実験モデルとして有用であると考えられた。
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