Glioblastoma angiogenesis and tumor cell invasiveness are differentially regulated by β8 integrin.

Abstract

Glioblastoma multiforme (GBM) is a highly invasive brain tumor that develops florid microvascular proliferation and hemorrhage. However, mechanisms that favor invasion versus angiogenesis in this setting remain largely uncharacterized. Here, we show that integrin β8 is an essential regulator of both GBM-induced angiogenesis and tumor cell invasiveness. Highly angiogenic and poorly invasive tumors expressed low levels of β8 integrin, whereas highly invasive tumors with limited neovascularization expressed high levels of β8 integrin. Manipulating β8 integrin protein levels altered the angiogenic and invasive growth properties of GBMs, in part, reflected by a diminished activation of latent TGFβs, which are extracellular matrix protein ligands for β8 integrin. Taken together, these results establish a role for β8 integrin in differential control of angiogenesis versus tumor cell invasion in GBM. Our findings suggest that inhibiting β8 integrin or TGFβ signaling may diminish tumor cell invasiveness during malignant progression and following antivascular therapies.