Genetic deletion of Vegfr2 in endothelial cells leads to immediate disruption of tumor vessels and aggravation of hypoxia

Am J Pathol. 2021 Nov 30:S0002-9440(21)00511-3. doi: 10.1016/j.ajpath.2021.11.003. Online ahead of print.ABSTRACTVascular endothelial growth factor (VEGF) blockers are used widely in clinics to target various types of human cancer. Although VEGF blockers exert marked tumor suppressive effects, the therapeutic effects can be limited. Moreover, accumulating evidence shows that VEGF acts not just on endothelial cells but also on various non-endothelial cells, including tumor and immune cells, suggesting a need to revisit the bona fide action of VEGF on endothelial cells using specific genetic mouse models. Here, tamoxifen-inducible endothelial-specific knockout mice lacking Vegfr2, the major signal transducer for VEGF, were used. The initial event resulting from cessation of endothelial Vegfr2 signaling was vascular truncation and fragmentation, rather than maturation of abnormalized vessels. Although deletion of endothelial Vegfr2 suppressed intra-tumor hemorrhage, it enhanced hypoxia in tumor cells and reduced the number of infiltrating cytotoxic T cells, suggesting a profound reduction in intra-tumor blood flow. In various tissues, deletion of endothelial Vegfr2 induced regression of healthy capillaries in intestinal villi substantiating intestinal perforation, which is one of the most common side effects of VEGF blockade in humans. Overall, the data suggest that some of the known effects of VEGF blockers on tumor vessels are caused by partial cessation of VEGF signaling, or ...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research