Control of systemic progression of pancreatic cancer by blocking VCAM-1: a study of genetically-engineered mouse model
| Project/Area Number |
20K07584
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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 50010:Tumor biology-related
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| Research Institution | Saitama Medical University (2022)
The University of Tokyo (2020-2021) |
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Principal Investigator |
Mizuno Suguru 埼玉医科大学, 医学部, 准教授 (30771050)
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| Co-Investigator(Kenkyū-buntansha) |
伊地知 秀明 東京大学, 医学部附属病院, 講師 (70463841)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 膵癌 / がん微小環境 / がん関連血栓塞栓症 / VCAM-1 / ANP / 癌関連血栓塞栓症 / 癌微小環境 / 予後 |
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| Outline of Research at the Start |
膵癌は依然として最難治癌であり、その予後改善は喫緊の課題である。我々は、ヒトの膵癌組織像の特徴をよく再現できる遺伝子改変膵発癌モデルマウスを樹立しており、接着因子VCAM-1を阻害することで膵癌マウスの生存期間が劇的に延長することを見出した。その機序として、実臨床でも予後不良因子である癌関連血栓塞栓症の制御の関与が示唆されている。本研究では、この膵発癌モデルを用いて、VCAM-1制御による生存延長と血栓塞栓症制御との関連を明らかにし、さらにVCAM-1を膵癌細胞特異的にノックアウトし膵癌の全身病態としての膵癌関連血栓塞栓症を制御し、生命予後改善すなわち膵癌を制御できることを明らかにする。
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| Outline of Final Research Achievements |
Pancreatic cancer is the most lethal cancer. One of the poor prognostic factor is cancer-associated thromboembolism(CAT). We have established a genetically-engineered mouse model of pancreatic cancer that can recapitulate human disease. The model also frequently develops CAT. Treatment of the model with VCAM-1 neutralizing antibody strikingly prolonged the survival, which suggested that inhibition of CAT might have contributed to the prognosis. To clarify the underlying mechanisms, VCAM-1 knockout in the model was planned, however, due to the COVID-19 pandemic, crossing the mice is still ongoing. Instead, we found that VCAM-1 blockade prevented the systemic progression of CAT. In addition, advanced pancreatic cancer patients with CAT showed significantly high level of plasma VCAM-1 and ANP even before the CAT onset, which indicated that these can be promising biomarkers for defining the high risk group of CAT and for the patient selection to be treated with VCAM-1 inhibition therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
最難治癌である膵癌において予後改善効果が期待できるVCAM-1阻害療法の機序として、予後不良因子である癌関連血栓症の進展を抑制することを見出し、血漿VCAM-1、ANP値が癌関連血栓症の高危険群およびVCAM-1阻害療法の対象患者選択のバイオマーカーとなる可能性を示した。実臨床に多い切除不能状態の進行膵癌患者においても予後を大きく改善させる可能性を示している。
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Report
(3 results)
Research Products
(5 results)
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[Journal Article] Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism2020
Author(s)
Sano M, Takahashi R, Ijichi H, Ishigaki K, Yamada T, Miyabayashi K, Kimura G, Mizuno S, Kato H, Fujiwara H, Nakatsuka T, Tanaka Y, Kim J, Masugi Y, Morishita Y, Tanaka M, Uikshiku T, Nakai Y, Tateishi K, Ishii Y, Isayama H, Moses HL, Koike K
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Journal Title
Gut
Volume: 70
Issue: 9
Pages: 1713-1723
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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