Intracranial Microenvironment Reveals Independent Opposing Functions of Host αVβ3 Expression on Glioma Growth and Angiogenesis

Abstract

alphaVbeta3 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 alphaVbeta3 expression in GBM growth and behavior, we intracranially implanted integrin beta3-expressing GBM cells into beta3 wild type (WT) or beta3 knock out (KO) mice and monitored angiogenesis and growth. GBM in beta3 WT animals had a vessel density greater than that in beta3 KO animals, consistent with a pro-angiogenic, pro-tumorigenic view of host integrin function. GBM in beta3 WT animals, however, were no larger than those in beta3 KO animals, because GBM in beta3WT animals were infiltrated with a higher number of tumor necrosis factor alpha-secreting, apoptosis-inducing macrophages than the tumors in the corresponding beta3 KO animals. The tumor-suppressive effects of host beta3 expression could be reversed by macrophage depletion or by transplantation of bone marrow from beta3 KO animals into beta3 WT animals, both of which significantly increased tumor growth independently of tumor vessel density. Taken together, these results show that host alphaVbeta3 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.