| Project/Area Number |
21K08645
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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 55010:General surgery and pediatric surgery-related
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| Research Institution | The University of Tokushima |
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Principal Investigator |
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 肥満細胞 / 大腸癌 / 放射線化学療法 / 腫瘍微小環境 / 癌関連線維芽細胞 / Osteopontin |
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| Outline of Research at the Start |
これまでにmast cellを制御し、mast cell-CAF interactionを介したTME制御を試みた報告はなく、活性化肥満細胞（TAMC）から放出されたOsteopontin（OPN）により、Activated CAFが誘導され、TMEが完成すると考えられる（TME based on mast cell-CAF interaction with OPN cycle）。このmast cell-CAF interactionにおけるクロストークの詳細な解明が難治性癌治療のブレークスルーとなり得ると考え、本研究ではTMEにおけるmast cell-CAF interactionの機序解明とともに、その解除を目的とした治療戦略について検討する。
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| Outline of Final Research Achievements |
We aimed to examine the correlation between mast cell (MC) infiltration and neoadjuvant chemoradiotherapy (nCRT) response for locally advanced rectal cancer (LARC). Protein levels of the MC marker tryptase and tumor-associated macrophages (TAMs) marker CD206 were evaluated with immunohistochemistry (IHC). The effects of MCs on the malignant potential were examined using in vitro assays with a colorectal cancer (CRC) cell line. By tryptase IHC analysis. MC infiltration was significantly correlated with nCRT response. The 5-year DFS rate was significantly lower in the MC-positive group. MC infiltration was the independent prognostic indicator. MC infiltration was significantly correlated with CD206 expression. In vitro experiments suggested that tumor activated mast cells could promote CRC malignant behavior via production of macrophage inhibitory factor. MC infiltration in LARC patients was positively correlated with TAM infiltration and resistance to nCRT.
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| Academic Significance and Societal Importance of the Research Achievements |
下部直腸癌症例における肥満細胞（Mast cell：MC）浸潤は術前化学放射線療法CRTの治療抵抗性、Tumor associated macrophage(TAM)TAMの浸潤と正の相関を示し、DFSにおいて独立予後不良因子であった。MCはCRT抵抗性直腸癌の新たな治療のtargetになりうる。腫瘍微環境構築の根幹となる肥満細胞をtargetとした難治性癌の治療戦略確立を目指すことは社会的にも意義のあることであり、癌人口が増加の一途をたどる現状を考慮すると、腫瘍微小環境攻略の糸口となる治療法開発による学術的、臨床的、経済的恩恵は計り知れないと考えられる。
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