Functional regulation of high endothelial venules by the AM-RAMP2 system and its application to the development of methods to suppress cancer metastasis

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15524
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Shinshu University
• Principal Investigator: Tanaka Megumu 信州大学, 医学部, 日本学術振興会特別研究員RPD (90786401)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: アドレノメデュリン / RAMP2 / リンパ節転移 / 高内皮細静脈 / 血管恒常性

Outline of Final Research Achievements

Adrenomedullin (AM) is a vasoactive peptide. We have reported that knockout mice of AM and its receptor-modulating protein RAMP2 are embryonic lethal with vascular abnormalities. Therefore, we established drug-inducible endothelial cell (EC)-specific RAMP2 knockout mice (DI-E-RAMP2-/-).
In this study, transplantation of Lewis lung carcinoma cells into footpads resulted in that spontaneous metastasis to the lymph node (LN) being enhanced in DI-E-RAMP2-/-. DI-E-RAMP2-/- contained fewer high endothelial venules (HEVs) than controls, and the HEVs that were present exhibited abnormal structures. In DI-E-RAMP2-/-, a significant decrease in T cells was observed, which may suppress the immune system and allow metastasis. Next, we generated mice overexpressing RAMP2 in the EC (E-RAMP2Tg), and contrary to DI-E-RAMP2-/-, LN metastasis was suppressed and survival was improved.
These findings indicate that disruption of vascular endothelial homeostasis is a promoting factor of tumor metastasis.

Free Research Field

腫瘍医学

Academic Significance and Societal Importance of the Research Achievements

アドレノメデュリン（AM）は血管拡張ペプチドとして同定されたが、それ以外にも多彩な作用を有する。様々な病態において、血中AM濃度が上昇することから、AMの臨床応用が期待されているが、AMの血中半減期は短く、慢性疾患への適応には制限がある。我々はAMの受容体活性調節タンパク：RAMPの研究を行っている。今までの検討から、AM-RAMP2系は血管発生だけでなく、血管恒常性維持に必須であり、それらの破綻が癌の血行性転移・リンパ節転移・臓器間転移を促進させる結果を見出した。現在、RAMPに結合する低分子化合物のスクリーニングを進めており、RAMP2の選択的活性化による癌転移抑制薬の開発が期待される。