Fig. 4.

Genetic blockade of autophagy in endothelial cells (ECs) fosters tumor angiogenesis while systemic treatment with chloroquine (CQ) induces vessel normalization. Left: tumor vasculature is in a state of continuous remodeling due to imbalanced pro- and anti-angiogenic signaling in the tumor microenvironment. CQ treatment induces (right) vessel normalization in tumors, mainly by activating NOTCH1 signaling pathway during its endocytic route. Enhanced NOTCH1 signaling promotes the quiescent EC phenotype. As a result, vessel functionality and structure are improved. Autophagy is heightened in tumor-associated ECs as an adaptive response to overcome metabolic stress and/or as an attempt to reinstate quiescence through reducing oxidative stress. EC-specific genetic impairment of autophagy is associated with a highly angiogenic vascular phenotype. These differential effects on EC function should be taken into consideration when devising interventions aiming to modulate autophagy or the endo-lysososmal system in anticancer therapy