A Mosaic Mouse Model of Astrocytoma Identifies αvβ8 Integrin as an Essential Regulator of Tumor-Induced Angiogenesis

Abstract

The process of angiogenesis involves a complex set of cell-cell and cell-extracellular matrix (ECM) interactions that coordinately regulate new blood vessel growth and maturation. Although many factors that promote angiogenesis have been characterized, the identities and mechanisms of action of many endogenous inhibitors of angiogenesis remain unclear. Furthermore, little is known about how tumor cells selectively circumvent the actions of these inhibitors to drive pathological angiogenesis, a requisite event for tumor progression. Using mosaic mouse models of the malignant brain cancer, astrocytoma, we report that tumor cells induce pathological angiogenesis by suppressing expression of the ECM protein receptor αvβ8 integrin. Diminished integrin expression in astrocytomas cells leads to reduced activation of latent TGFβs, resulting in impaired TGFβ receptor signaling events in tumor-associated endothelial cells. These data reveal that astrocytoma cells manipulate their angiogenic balance by selectively suppressing αvβ8 integrin expression/function, and also demonstrate that an adhesion and signaling axis normally involved in developmental brain angiogenesis is pathologically exploited in adult brain tumors.