Molecular polarity in endothelial cells and tumor-induced angiogenesis

Endothelial cells expose receptors for vascular endothelial growth factor/v ascular permeability factor (VEGF/VPF) at the abluminal, basal surface that work as basic regulators of tumor-induced angiogenesis. Their specific loc alization makes them susceptible to the activity of tumor-released stimulat ory factors, like VEGF/VPF, which induce proliferation of the endothelial c ell toward the extracellular matrix. At the same time, VEGFNPF stimulates e ndothelial cells to expose tissue factor (TF), the high-affinity transmembr ane receptor and cofactor for cellular initiation of the plasma coagulation protease cascades through the extrinsic pathway, so generating thrombin. T hrombin exerts a number of activities: it forms an extracellular fibrin bar rier from the VEGF/VPF-dependent fibrinogen extravasation; it activates pro gelatinase-A (proMMP-2), which destroys the basal membrane, allowing prolif eration of endothelial cells (ECs) in the novel tumoral fibrin matrix; fina lly, it induces EC proliferation, potentiating the VEGF effect. Another imp ortant factor exposed at the abluminal endothelial cell surface is membrane type 1 matrix metalloproteinase (MT1-MMP), a membrane-bound metalloprotein ase, which also activates progelatinase-A, allowing an alternative pathway to that of thrombin to destroy the basal membrane. In addition, we will see that MT1-MMP is also engaged in a direct, cell-associated fibrinolytic act ivity, essential for tubulogenesis of the novel outsprouting capillary.