Molecular polarity in endothelial cells and tumor-induced angiogenesis.
Endothelial cells expose receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) at the abluminal, basal surface that work as basic regulators of tumor-induced angiogenesis. Their specific localization makes them susceptible to the activity of tumor-released stimulatory factors, like VEGF/VPF, which induce proliferation of the endothelial cell toward the extracellular matrix. At the same time, VEGF/VPF stimulates endothelial cells to expose tissue factor (TF), the high-affinity transmembrane receptor and cofactor for cellular initiation of the plasma coagulation protease cascades through the extrinsic pathway, so generating thrombin. Thrombin exerts a number of activities: it forms an extracellular fibrin barrier from the VEGF/VPF-dependent fibrinogen extravasation; it activates progelatinase-A (pro-MMP-2), which destroys the basal membrane, allowing proliferation of endothelial cells (ECs) in the novel tumoral fibrin matrix; finally, it induces EC proliferation, potentiating the VEGF effect. Another important factor exposed at the abluminal endothelial cell surface is membrane type 1 matrix metalloproteinase (MT1-MMP), a membrane-bound metalloproteinase, 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 activity, essential for tubulogenesis of the novel outsprouting capillary.
Chiarugi
V
V
Department of Pathology and Experimental Oncology, University of Firenze, Italy.
Ruggiero
M
M
Magnelli
L
L
D001812:Blood-Brain Barrier / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology*; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000502:physiology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D004792:Enzyme Precursors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005337:Fibrin; D013925:Thromboplastin; D013917:Thrombin; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase