Multiple roles for VEGF in non-melanoma skin cancer: angiogenesis and beyond

Vascular endothelial growth factor (VEGF) is known to play a critical role in the development of non-melanoma skin cancers. VEGF is a potent pro-angiogenic factor and it is elevated in mouse and human skin tumors. The use of transgenic and knockout mice has shown that VEGF is essential for tumor development in multiple models of skin carcinogenesis and, until recently, the mechanism of action has been primarily attributed to the induction of angiogenesis. However, additional roles for VEGF have now been discovered. Keratinocytes can respond directly to VEGF, which could influence skin carcinogenesis by altering proliferation, survival, and stemness. In vivo studies have shown that loss of epidermal VEGFR-1 or neuropillin-1 inhibits carcinogenesis, indicating that VEGF can directly affect tumor cells. Additionally, VEGF has been shown to promote tumor growth by recruiting macrophages to skin tumors, which likely occurs through VEGFR-1. Overall, these new studies show that VEGF carries out functions beyond its well-established effects on angiogenesis and highlight the need to consider these alternative activities when developing new treatments for non-melanoma skin cancer.