Figure 1

Tumour angiogenesis: molecular pathways and potential interventional strategies. VEGF axis is recognised as the primary factor responsible for tumour angiogenesis resistance. Upon VEGF binding, the receptor tyrosine is activated. VEGF/VEGFR activates oncogenic signalling via mitogen-activated protein kinase (ERK/MAPK) pathway, the phosphotidylinositol 3 kinase (PI3K-AKT) pathway, and the phospholipase-C-γ (PLC-γ) pathway leading to cell proliferation, survival, migration, and vascular permeability. Chronic VEGF/VEGFR inhibition has been found to lead to the emergence of compensatory signalling pathways that sustain angiogenesis. Several of these VEGF-independent signalling pathways, rely on key proteins, including the FGF/FGFR, angiopoietin-2 (Ang2), and the MET oncogene. Complementary therapies focused on these alternative pathways have been developed to abrogate acquired resistance. Pan-FGFR inhibitors are used to inhibit the FGF/FGFR axis. The MET/HGF pathway is inhibited by HGF antagonists and by the anti-MET antibody cabozantinib. Ang-Tie axis can be targeted with trebananib, a peptibody that inhibits the binding of Ang1/2 to their receptor. Tumour microenvironment and interactions between tumour cells and non-malignant cells as fibroblast and leukocytes also affect angiogenesis by interfering with the signalling pathways required for cell recruitment and vascular construction.