VEGF signaling: Role in angiogenesis and beyond

Abstract

Angiogenesis is a crucial process for tissue development, repair, and tumor survival. Vascular endothelial growth factor (VEGF) is a key driver secreted by cancer cells, promoting neovascularization. While VEGF's role in angiogenesis is well-documented, its influence on the other aspects in tumor microenvironemt is less discussed. This review elaborates on VEGF's impact on intercellular interactions within the tumor microenvironment, including how VEGF affects pericyte proliferation and migration and mediates interactions between tumor-associated macrophages and cancer cells, resulting in PDL-1-mediated immunosuppression and Nrf2-mediated epithelial-mesenchymal transition. The review discusses VEGF's involvement in intra-organelle crosstalk, tumor metabolism, stemness, and epithelial-mesenchymal transition. It also provides insights into current anti-VEGF therapies and their limitations in cancer treatment. Overall, this review aims to provide a thorough overview of the current state of knowledge concerning VEGF signaling and its impact, not only on angiogenesis but also on various other oncogenic processes.

Keywords: Angiogenesis; Anti-VEGF therapies; Intercellular crosstalk; Intra-organelle crosstalk; Tumor microenvironment; VEGF-VEGFR.

Fig. 1.

Diagrammatic representation of different VEGFs, their respective receptor kinases and function. The interaction of VEGFR-1 and VEGFR-2 with their respective ligands viz. VEGF A, VEGF B, VEGF C, VEGF D or PIGF play important roles in vasculogenesis and angiogenesis. Activation of VEGFR-3 by VEGF C or VEGF D is crucial in lymphangiogenesis. Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) act as co-receptors for VEGF to enhance signal transduction.

Fig. 2.

Diagram showing the mechanism of VEGF-induced angiogenesis. Hypoxia in the TME can stimulate the expression of VEGF, primarily through the action of a transcription factor called hypoxia-inducible factor-1 (HIF-1) that binds to hypoxia response elements (HRE) in the promoter regions of various genes, including the VEGF gene. VEGF expressed by tumor cells induces signaling cascades in ECs that involve MAPK and PI3K pathways, cumulatively promoting EC survival, proliferation, and migration.

Fig. 3.

Diagrammatic representation showing the interaction between tip cells and stalk cells resulting in sprouting angiogenesis. In sprouting angiogenesis, tip cells and stalk cells interact through a combination of paracrine and juxtacrine signaling mechanisms. Tip cells, in response to VEGF-A, express DLL4 which activates Notch receptor on stalk cells to modulate the expression of VEGFR1, VEGFR2 and VEGFR3. This maintains their ‘stalk cell’ fate and promotes proliferation. In tip cells, the VEGF-A/VEGF-R2 signaling leads to the expression of PDGFB, VEGFR3 and VEGFR2 that causes lamellipodia/filopodia formation.

Fig. 4.

Role of VEGF in the tumor microenvironment. The TME consists of CCs along with several other cell types including ECs, pericytes, TAMs, and CAFs among others. Pericytes communicate with ECs through both juxtacrine and paracrine signaling. VEGF in the TME induces proliferation and migration of pericytes either directly or indirectly through NO produced by ECs. ECs secrete PDGF-B, which binds to PDGFRs on pericytes to stimulate the proliferation and migration of pericyte precursors. CCs secrete IL-4, IL-13, IL-10, and lactic acid which leads to activated TAMs having anti-inflammatory attributes to predominate in the TME. Activated VEGFR-2 on M2 TAMS causes induction of VEGF secretion via activation of the Akt/mTOR pathway and promotes PDL-1 expression via activation of Nrf2. In CCs, VEGF-mediated Nrf2 induction causes upregulation of EMT components.

Fig. 5.

The interplay between VEGF signaling and cancer stemness. VEGF-NRP2 signaling in CSCs activates RAC1, inhibiting LATS and inducing TAZ activity. TAZ, along with TEAD, represses Rac GAP β2-chimerin, sustaining RAC1 in a positive feedback loop. Additionally, VEGF/NRP2 signaling induces α6β1 integrin-laminin 511 interaction, activating FAK/Ras pathway and Gli1-mediated expression of BMI-1. The combined activation of RAC1 and BMI-1 contributes to stem cell characteristics. VEGF/NRP1 interaction induces β-catenin that transcriptionally induces cMyc hence adding to cancer stemness. The interaction between VEGF-VEGFR-2 also results in upregulation of cMyc and Sox2 via JAK2-STAT3 pathway leading to cancer stemness. It is to be noted that both NRP1 and NRP2 when activated by VEGF causes signal transductions that involves stemness factors result in VEGF expression (marked in the figure by *), hence setting up a positive feedback loop. The broken arrows indicate that the signal transduction involves multiple intermediate processes that have not been depicted in the figure.”