An endogenous VEGF inhibitor, KAI1, is a master switch of angiogenesis

Abstract

Angiogenesis represents new blood-vessel formation controlled by numerous factors. VEGF, the most potent pro-angiogenic factor, is commonly targeted in cancer therapy. However, little is known about endogenous VEGF inhibitors and their control. Here, CD82/KAI1 expressed on pericytes (PCs) acts as an endogenous anti-angiogenic factor. Through transcriptome and functional analysis, I revealed that leukemia inhibitory factor (LIF) is an anti-angiogenic effector molecule of KAI1 through KAI1-Src-p53 axis. Furthermore, KAI1 was shown to bind VEGF and PDGF-BB, preventing VEGFR/PDGFR signalling and tube formation by endothelial cells. In the therapeutic aspect, KAI1-overexpressing pericytes or recombinant KAI1 protein inhibited angiogenesis and cancer cell growth. Taken together, I demonstrated that KAI1 is a key regulator of angiogenesis by interacting with the angiogenic niche, and identified novel molecular mechanisms underlying anti-VEGF/PDGF therapy, which may help develop new anti-cancer strategies.