Figure 1. Mechanisms of evasion of antiangiogenic therapy in glioblastoma.

A subset of GBM patients treated with antiangiogenic agents exhibit intrinsic resistance and fail to show any response. By contrast, many GBM do benefit from angiogenesis inhibitors; however, the response phase is transitory and followed by the induction of evasive resistance pathways, in which tumors adapt to bypass angiogenic blockade. Two main patterns of evasive recurrence following initial antiangiogenic response in GBM have been observed. In the proangiogenic pattern, relapsing tumors display contrast enhancement on MRI and activate alternate proangiogenic factors or recruit various BMDCs to reinitiate neovascularization, even while VEGF signaling remains inhibited. In the proinvasive evasion pattern, relapsing tumors are not contrast enhancing but rather show increasing FLAIR-bright volumes indicative of more infiltrating growth. Proinvasive evasion mechanisms directly affect tumor cell behavior in response to antiangiogenic treatment to facilitate tumor cell invasion. GBM stem-like cells may also survive or be enriched by antiangiogenic therapy, eventually leading to tumor regrowth or invasion.

BMDC: Bone marrow-derived cell; EPC: Endothelial progenitor cell; FLAIR: Fluid-attenuated inversion recovery; GBM: Glioblastoma; GSC: Glioblastoma stem cell; MMP: Matrix metalloproteinase; PPC: Pericyte progenitor cell; SDF-1α: Stromal-derived factor-1α.