Antiangiogenic Therapy and Mechanisms of Tumor Resistance in Malignant Glioma
Mechanisms of glioma resistance to anti-angiogenic therapeutic modalities. (Top) Adaptive (evasive) resistance. After an initial transitory response phase, the tumor switches to mechanisms that induce neovascularization and renewed tumor growth and progression, thereby evading therapeutic blockade. These consist of pro-angiogenic factor substitution (typically dependence on FGF and angiopoietin signalling in cases of VEGF blockade), recruitment of endothelial cells and pericytes from the bon-marrow, protection of existing tumor blood vessels via increased pericyte coverage and increased tumor cell invasiveness whereby tumor cells invade adjacent normal tissue to achieve vascular sufficiency. (Bottom) Intrinsic (cellular) resistance. From the outset, some gliomas are nonresponsive to angiogenesis blockade. This may be accounted for by the preexistence of multiple redundant pro-angiogenic signals, which would allow for continued angiogenesis during anti-angiogenic insults. In addition, glioma stem cells (GSCs) (green circles) have been identified as key mediators of glioma angiogenesis and may share intrinsic cell survival and lifespan prolonging characteristics with normal tissue stem cells. Specifically, GSCs may reside in a noncycling quiescent state, thus blocking entry of drugs through the tumor cell membrane and may express relatively high levels of ABC-drug transporters, enabling a multi-drug resistance phenotype via efflux of drugs from the tumor cell. Red lines, tumor blood vessels.