The role of VEGF in inflammation and tumourigenesis

VEGF overview

Vascular Endothelial Growth Factors (VEGFs) are a group of homodimeric polypeptides, and are master regulators of vascular development, maintenance and angiogenesis (Ferrara and Davis-Smyth, 1997). VEGF is also a potent growth factor, and is produced by macrophages and CD4+ and CD8+ T cells (Melter et al, 2000; Freeman et al, 1995). Members of the VEGF family include 5 structurally related proteins (VEGFA-D, and placental growth factor (PIGF), which are further individually subdivided based on alternative splicing (Ferrara, 2010; He et al, 1999). VEGF receptor activation leads to multiple complex signalling pathways, primarily inducing angiogenesis, and for this reason VEGF is a prime anti-tumour therapeutic target.

VEGF signalling

VEGF is upregulated in response to hypoxic and metabolic perturbations, such as dysregulated glucose levels, primarily by the activation of the transcription factor NF-kB (Tong et al, 2006; Schweiki et al, 1995; Schweiki et al, 1992). VEGFs bind with high affinity to one of the three tyrosine kinase receptors; VEGFR1, VEGFR2, and VEGFR3 (Ferrara and Davis-Smyth, 1997), which are expressed highly on endothelial cells and monocytes. It has also been demonstrated that VEGF can bind to several non-VEGF receptors, such as neuropilin receptors (NRP), and heparin sulphate peptidoglycans (HSPG), which act as co-receptors and facilitate complex downstream signalling (Teran and Nugent, 2015). Canonical VEGF signalling occurs mostly between a homodimeric VEGF molecule with a homodimeric VEGF receptor, and is induced upon ligation of VEGF to its membrane bound receptor VEGFR, leading to autophosphorylation of the cytoplasmic domains on the receptor and subsequent downstream signalling, initiated by the binding of adaptor molecules to the tyrosine residues of the VEGFR (Koch et al, 2011). However, heterodimeric VEGF receptor signalling has more recently been described (MacGabhann and Popel, 2007).

Canonical VEGF receptor signalling

Canonical VEGF signalling is typically mediated in a paracrine manner, however, recent studies have identified an autocrine method of VEGF-VEGFR stimulation in endothelial cell, although the precise metabolic signalling involved is still unclear (Domingan et al, 2015; Lee et al, 2007). VEGFR activation is tightly regulated on multiple mechanisms; levels of ligand and receptor expression, rate of receptor internalization by endocytosis, and by intracellular interactions with other signalling pathways, with evidence for cross-talk between VEGF and Integrin signalling pathways (Somanath et al, 2009). Activation of the distinct VEGF receptors leads to differential biological outcomes. The primary angiogenic signalling is initiated by the activation of VEGFR2, via stimulation with VEGFA. Activation of VEGF2 leads to downstream signalling via phospholipase-C (PLC) and protein kinase C (PKC) to activate mitogen-associated protein kinase (MAPK) pathways, inducing proliferation (Takahashi et al, 1999). VEGFR2 endocytosis occurs by clatherin-mediated endocytosis (Ballmer-Hofer et al, 2011). Interestingly, VEGFR2 stimulation and association with its co-receptor NRP1 has been demonstrated in vitro to promote adhesion of cells expressing one of either receptor (Koch et al, 2014). More recent research has identified a link between inflammatory mediators and VEGF expression, with activated T cells inducing VEGF in a CD40-dependent manner (Reinders et al, 2003). VEGF can also induce chemokine transcription, and it has been shown to upregulate the chemoattractant-inducting molecule IL-8 (Lee et al, 2002).

Non-canonical VEGF receptor signalling

Non-canonical VEGF signalling describes an alternative receptor activation, based on VEGF-independent VEGFR signalling; which can occur in a ligand-free environment via the phosphorylation of VEGFR form external stresses; or by the binding of non-VEGF receptors (Lemmon et al, 2010).

The role of VEGF in disease

VEGF is a proliferative and vascular inducing molecule and plays a vital role in the development and maintenance of tumours. Tumour-infiltrating lymphocytes (TILs) can induce the upregulation of VEGF, thereby promoting vascularity in the tumour microenvironment and promoting tumourigenesis, as VEGF can induce further polarization of T cells to the Th1 subset (Mor et al, 2004; Reinders et al, 2003). Moreover, autocrine VEGF signalling has generated a lot of interest in the triple negative breast cancer field, with a focus on VEGF - integrin signalling crosstalk (Goel et al, 2013). Additionally, VEGF is of key importance in the central nervous system, and mediates neuroprotection and neurogenesis, with VEGF levels dramatically decreased upon aging (Ahluwalia et al, 2014). The role of VEGF in the CNS is somewhat polarized, as VEGF can induce blood-brain barrier leakage upon injury, stroke and multiple neurodegenerative diseases (Lane et al, 2016; Zlokovic et al, 2011). Furthermore, ligand-independent activation of VEFR2 contributes to the pathogenesis of diabetes, via upregulated reactive oxygen species (Warren et al, 2014).

VEGF as a therapeutic target

The main anti-cancer target in VEGF signalling is VEGFA-VEGFR2 association, which has long been shown to inhibit tumour growth (Kim et al, 1993). Multiple drugs have been developed to target this interaction. Bevacizumab, a major breakthrough in anti-VEGF therapeutics, is a monoclonal antibody which neutralizes VEGFA and has been approved for use in treatments for colon cancer, glioblastoma and breast cancer (Peak and Levin, 2010). Several other molecules targeting this pathway include VEGFR neutralizing antibodies, soluble VEGFR peptides, and an anti-PIGF antibody (Van de Veire et al, 2010; Wada et al, 2005). Anti-VEGF therapy has also been demonstrated to improve the pathogenesis of rheumatoid arthritis, due to the resulting decreased levels of IL-6 (Yoo et al, 2005). VEGF is also an attractive target for pro-angiogenic therapy, such as following cardiac ischaemia and traumatic brain injuries, in order to regenerate cells. However, inducing VEGFA carries complications with an enhanced immune response (Oosthuyse et al, 2001).


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6th Oct 2021 Sinéad Kinsella PhD

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