Matrix control of tumor angiogenesis

Endothelial cell migration is a key feature of angiogenesis. Epidermal Growth Factor (EGF) or Tumor Angiogenesis Factor (TAF) induce cell migration and angiogenesis. When the matrix components, collagen or fibronectin, were used as a substratum in the phagokinesis assays, EGF- or TAF-induced cell migration was inhibited. It has been proposed that TAF activates cellular protease causing the matrix degradation that is evident during neovascularization in vitro. If such degradation leads to cell migration and angiogenesis, then other agents that interfere with the synthesis or assembly of matrix components should stimulate cell migration and angiogenesis. The proline analogues cis hydroxyproline, azetidine and dehydroproline are known modulators of cellular collagen synthesis. At optimal concentration (10(-5)M) these analogues caused 3-fold increases in endothelial cell migration rates in vivo as tested by a subcutaneous implant assay. We conclude from these studies that: (i) matrix components control cellular migration rates; high concentration of collagen or fibronectin inhibit angiogenically active inducers of endothelial cell migration. (ii) Intracellular modulation of synthesis of collagens leads to angiogenesis by stimulating cell migration. These findings relate to tumor angiogenesis and that TAF might trigger angiogenesis either by activation of latent proteases or by some modification of matrix assembly during synthesis that affects cell adhesion and migration.