[MCE] Cytokines & Growth Factors in Angiogenesis

The angiogenic switch indicates a point where pro-angiogenic factors exceed the anti-angiogenic factors and lead to the development of new blood vessels in increasing tumor growth. The angiogenic switch begins tumor progression and development, and continuous activation in response to the stimulation of angiogenic regulators is critical for tumor growth and metastasis [2].

Vascular endothelial growth factor (VEGF) is one of the major angiogenic regulators, regulating angiogenesis through its three tyrosine kinases receptors (VEGFR 1-3). VEGF-A coordinates the growth of new blood vessels during embryonic and postnatal development [3]. Notably, MMP-9 and MMP-2 promote angiogenesis in cancer by activating and releasing latent TGF-β and VEGF ligands [4]. VEGF is also involved in regulating angiogenesis by epidermal growth factor (EGF) [5].

Angiopoietin 1 is critical in vascular maturation through tyrosine kinase receptors and its signaling pathways influencing angiogenesis. Angiopoietin 2, expressed mainly on endothelial cells, may promote the formation of new blood vessels alone or together with other pro-angiogenic factors such as VEGF [6].

Transforming growth factor-β (TGF-β) acts in a pro-angiogenic role by upregulating VEGF and MMP when its levels are low and as an anti-angiogenic factor by inhibiting the growth and proliferation of endothelial cells when its levels are high [4]. Fibroblast growth factor (FGF) generally follows signalings of the mitogen-activated protein kinase (MAPK) and PI3k/Akt cascades, which be indicated to be responsible for the maintenance of tumor angiogenesis when their expression is chronically upregulated [7]. Apart from this, platelet-derived growth factor (PDGF) is involved in vascular maturation and pericyte recruitment through the four isoforms PDGF A-D [8].