Functions and Clinical Implications of Autocrine VEGF Signaling in Colorectal Cancer

Vascular endothelial growth factor (VEGF) signaling is linked to invasiveness and aggressive disease in colorectal cancer (CRC), and two VEGF-directed agents, bevacizumab and aflibercept, are currently approved for treatment of metastatic disease. CRC cells are a major source of VEGF that is secreted into the tumor environment where it can associate with VEGF receptors on neighboring endothelial cells thereby promoting tumor angiogenesis. In addition, the CRC cells express functional VEGF receptors giving rise to autocrine VEGF signaling. So far, the biological and clinical implications of autocrine VEGF signaling have attracted less attention than the classical paracrine VEGF signaling pathways. In this review we focus on the effect of autocrine VEGF signaling on the survival, invasion, and drug-resistance of CRC cells and on the prognostic value of expression of VEGF ligands and receptors in CRC patients. We then discuss the different factors associated with a therapeutic response to VEGF blockage and summarize future challenges.