Angiogenesis in glioblastoma: Molecular and cellular mechanisms and clinical applications

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and carries poor prognosis. Despite advances in therapy, no significant increase in survival has been achieved for GBM patients. These tumors inevitably recur in the majority of patients, and the therapeutic options for recurrent tumors are limited. GBMs are aggressive, fast-growing, and highly infiltrative tumors, with exuberant angiogenesis (microvascular proliferation) and necrosis. However, the newly formed tumor vessels are structurally and functionally abnormal, creating areas of hypoxia and ultimately necrosis, contributing to tumor progression and aggressiveness. Since GBMs are hypervascular in nature, targeting tumor angiogenesis emerged as a promising therapeutic strategy. In this review, we summarized the molecular and cellular mechanisms governing GBM angiogenesis, the other modes of tumor vascularization, and the key mediators of these processes. We also discussed the importance of tumor hypoxia in promoting angiogenic and vasculogenic processes, the contributions of GBM stem cells to tumor vasculature, the anti-angiogenic therapy for GBM, and the resistance to such therapy. A better understanding of the molecular and cellular basis of GBM neovascularization, the mechanisms of resistance to therapy, and the contributions of GBM stem cells to tumor vasculature will lead to the development of more effective treatment strategies.