Figure 1.

Angiogenic signaling pathway and angiogenesis. Tumor cell induces a complex cascade of angiogenic signaling and activates downstream cellular events in multiple cell types, especially the endothelial cells, leading to angiogenesis. Pro-angiogenic factors include fibroblast growth factor (FGF) families, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factors-alpha/beta (TGF-α/β), and angiopoietin (Ang 1,2) and the associated receptors. The detachment of the perivascular cells from the mature blood vessels initiates vessel remodeling and endothelial cell proliferation. Platelets become activated and recruited to the sites of the exposed basement membrane. Tumor-associated macrophages (TAM) produce angiogenic factors such as VEGF, MMPs and urokinase-type plasminogen activator (uPA). On the other hand, precursor endothelial cells move to the perceived wound site and release angiogenic factors. The activated endothelial cells release proteases and lead to extracellular matrix (ECM) remodeling, followed by directional sprouting. The signaling cascades activate tube formation and branching, followed by vessel arterio-venous patterning and maturation. Cancer progenitor/stem cells can differentiate to endothelial cells, and thereby participates directly in angiogenesis.