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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.
Highlights
Despite advances in the diagnosis, prognosis, and treatment of solid tumors, multiple issues continue to drive morbidity and mortality
The NRPs have garnered the most attention in recent years as vascular endothelial growth factor (VEGF) receptors that function in tumor initiation and progression [19,20,21]. Some of these studies, but not all, have highlighted a key role for the NRPs (NRP1 and NRP2) in mediating this signaling and discounted the contribution of VEGFRs, e.g., [22,23]. This intriguing observation underscores the emphasis of this review on VEGF/NRP signaling in cancer stem cells (CSCs)
One outstanding issue with respect to VEGF/NRP signaling in CSCs is that the expression of both VEGF and the NRPs is not limited to CSCs in many tumors
Summary
Despite advances in the diagnosis, prognosis, and treatment of solid tumors, multiple issues continue to drive morbidity and mortality. One of the most exciting developments is the discovery that autocrine and paracrine VEGF signaling occurs in tumor cells and that this signaling contributes to key aspects of tumorigenesis, especially the function of CSCs, independently of angiogenesis [15] This finding highlighted the importance of VEGF receptors on tumor cells in the context of their role in sustaining CSC function. One study concluded that the ability of NRP1 to mediate PlGF-stimulated growth of medulloblastoma requires its PDZ binding domain and is independent of VEGFR1 activity [22] This motif functions by forming scaffolding complexes that transduce NRP signals, a possibility supported by the finding that GIPC1 mediates the interaction of NRP1 with c-abl, a tyrosine kinase that could mediate NRP1 signaling [14]. The NRP2 cytoplasmic domain contains a motif with partial consensus to an immunoreceptor tyrosine-based activation motif (ITAM) that can mediate signaling in other receptors [59], there is no evidence yet that it is functional
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