VEGF/Neuropilin Signaling in Cancer Stem Cells

Abstract

The function of vascular endothelial growth factor (VEGF) in cancer extends beyond angiogenesis and vascular permeability. Specifically, VEGF-mediated signaling occurs in tumor cells and this signaling contributes to key aspects of tumorigenesis including the self-renewal and survival of cancer stem cells (CSCs). In addition to VEGF receptor tyrosine kinases, the neuropilins (NRPs) are critical for mediating the effects of VEGF on CSCs, primarily because of their ability to impact the function of growth factor receptors and integrins. VEGF/NRP signaling can regulate the expression and function of key molecules that have been implicated in CSC function including Rho family guanosine triphosphatases (GTPases) and transcription factors. The VEGF/NRP signaling axis is a prime target for therapy because it can confer resistance to standard chemotherapy, which is ineffective against most CSCs. Indeed, several studies have shown that targeting either NRP1 or NRP2 can inhibit tumor initiation and decrease resistance to other therapies.

Keywords: VEGF; cancer stem cell; neuropilin.

Figure 1

One proposed mechanism for how vascular endothelial growth factor/neuropilin (VEGF/NRP) signaling impacts cancer stem cell (CSC) function independently of VEGFRs. Oncogenic transformation and conditions in the tumor microenvironment result in the establishment of autocrine VEGF/NRP2 signaling in tumor cells that contributes to the genesis of a CSC phenotype. VEGF/NRP2 signaling facilitates α6β1 integrin engagement with laminins such as laminin 511 in a CSC niche. Signaling through this integrin activates a focal adhesion kinase/Ras pathway that promotes the Gli1-mediated expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI-1), a stem cell factor. VEGF/NRP2 signaling also promotes the repression of LATS by Rac1 and the consequent activation of the stem cell factor and Hippo effector TAZ. The convergence of these signaling pathways contributes to the acquisition of stem cell properties including self-renewal, survival, and chemoresistance.