Elucidation of the mechanism of hematogenous organ-specific metastasis formation focusing on the heterogeneity of angiogenesis mechanism of hematogenous organ-specific metastasis formation

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17657
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyushu University
• Principal Investigator: NAKAYAMA Hiromichi 九州大学, 医学研究院, 共同研究員 (80866773)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 血管新生 / 膵癌 / 血行性転移 / ADM / M2 / マクロファージ / MMP9 / IL12A

Outline of Final Research Achievements

The purpose of this study was to elucidate the mechanism of hematogenous metastasis, a major cause of death in pancreatic cancer. We initially planned to compare and investigate angiogenesis types, but when we observed mouse-derived pancreatic tumor tissues by IHC, we found that the distribution of CD31-positive cells was biased toward areas showing an acinar-to-ductal metaplasia (ADM)-like lesion. Immunostaining analysis using resected human pancreatic tumor tissues revealed higher microvessel density and significantly higher expression of CD68, CD163, and IL12A in ADM-like lesions. Furthermore, MMP9 expression was found consistent with M2 macrophages in the tumor, and endothelial cells attached to the supernatant of M2 macrophages promoted angiogenesis. These results suggest that angiogenesis may be promoted via MMP9 produced by M2 macrophages in ADM like lesions.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

膵癌の遠隔転移を制御する新規治療法の開発は膵癌患者の予後改善に直接的に寄与し、社会的要請度・貢献度・緊急性が高い。
本研究では、膵癌組織中のADM like lesionにおいて血管新生が促進しており、その要因として、IL12Aによって動員された骨髄由来マクロファージが腫瘍内で免疫抑制性機能を持つM2マクロファージへと変化し、マクロファージが産生するMMP9によって血管新生が促進している可能性が示された。
膵癌における主要な死因の一つである血行性転移のメカニズムにおける重要な知見であり、血管新生を標的とした膵癌患者の予後を改善する新規治療の開発に繋がると考えられる。