VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors

Abstract

We identify a limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, that form rapidly growing, invasive and highly vascularized tumors, as compared with non-stem cancer cells. These ECS cells grow as non-attached spheroids, and display enhanced migration and invasion. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses. In addition, treatment with bevacizumab reduces tumor vascularity and growth. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the neuropilin-1 (NRP-1) co-receptor. Knockdown of NRP-1 inhibits ECS cell spheroid formation, invasion and migration, and attenuates tumor formation. These studies suggest that VEGF-A acts via interaction with NRP-1 to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors.

VEGF-A/Neuropilin 1 Pathway Confers Cancer Stemness via Activating Wnt/β-Catenin Axis in Breast Cancer Cells

“…NRP-1 is an angiogenic co-receptor of VEGF-A, and involved in epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma [4]. Additionally, VEGF-A could enhance epidermal cancer stem cell survival, and the formation of aggressive and highly vascularized tumors via NRP-1 [5, 6]. VEGF-A/NRP-1 axis could facilitate breast cancer progression via facilitating EMT [7].…”

Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation

“…They are also enriched in transcription factors associated with epithelial-mesenchymal transition (EMT) (Snail, Slug, and Twist, HIF-1α) and mesenchymal structural proteins including vimentin, fibronectin and N-cadherin (5). These cells are remarkable in that they form highly aggressive, invasive and vascularized tumors following injection of as few as 100 cells into immune compromised mice (3, 32). As an approach to identify ECS cell-enriched proteins for anti-ECS cell cancer therapy, we identified a number of proteins, including transglutaminase 2 (TG2), that are elevated in ECS cells and are required for ECS cell survival (3, 5, 10, 33).…”

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

“…As noted above, TG2 forms a complex with α6/β4‐integrins to activate YAP1/ΔNp63α signaling in skin cancer cells. Additional studies show that the NRP‐1 angiogenesis mediator and GIPC1, a scaffolding protein, participate in a related complex to drive angiogenic processes in squamous cell carcinoma (Figure B). In this cascade, VEGF‐A forms a complex with NRP‐1, α6/β4‐integrin, GIPC1 and TG2 to trigger signaling events that activate YAP1/ΔNp63α signaling.…”

“…In this cascade, VEGF‐A forms a complex with NRP‐1, α6/β4‐integrin, GIPC1 and TG2 to trigger signaling events that activate YAP1/ΔNp63α signaling. Since GIPC1 can couple to a large number of downstream cascades, this suggests that this TG2 inclusive complex may activate many downstream cancer survival pathways (Figure B). An example is a recent manuscript showing that VEGFA/NRP‐1 activates GIPC1/Syx complex formation to activate RhoA/Rock signaling and p38 MAPK activity to drive epidermal cancer stem cell survival …”