Intracranial microenvironment reveals independent opposing functions of host αVβ3 expression on glioma growth and angiogenesis

alpha V beta 3 integrins are overexpressed in the host-derived vasculature of glioblastoma multiform (GBM) and are believed to contribute to angiogenesis and tumor growth. To directly address the role of host alpha V beta 3 expression in GBM growth and behavior, we intracranially implanted integrin beta 3-expressing GBM cells into beta 3 wild type (WT) or beta 3 knock out ( KO) mice and monitored angiogenesis and growth. GBM in beta 3 WT animals had a vessel density greater than that in beta 3 KO animals, consistent with a pro-angiogenic, pro-tumorigenic view of host integrin function. GBM in beta 3 WT animals, however, were no larger than those in beta 3 KO animals, because GBM in beta 3 WT animals were infiltrated with a higher number of tumor necrosis factor alpha-secreting, apoptosis-inducing macrophages than the tumors in the corresponding beta 3 KO animals. The tumor-suppressive effects of host beta 3 expression could be reversed by macrophage depletion or by transplantation of bone marrow from beta 3 KO animals into beta 3 WT animals, both of which significantly increased tumor growth independently of tumor vessel density. Taken together, these results show that host alpha V beta 3 integrin expression has opposing actions in the intracranial setting, enhancing tumor vascularization and growth while independently enhancing macrophage-mediated tumor elimination. Appropriate management of these functions could lead to enhanced efficacy of anti-integrin based therapies for glioma.