Fig. 5.

Effects of tumor-derived SEMA4D and VEGF on vasculature. VEGF production by tumors drives stem cells towards endothelial cell differentiation, enhancing angiogenesis in the tumor stroma. In the absence of VEGF, for example during anti-VEGF therapy, tumor cell SEMA4D would predominate. SEMA4D favors stem cell differentiation toward pericytes via endothelial production of PDGF-B and induces endothelial production of ANGPTL4, which itself is pro-angiogenic and promotes vascular permeability. In the absence of SEMA4D endothelial cells would fail to make PDGF-B, thus reducing the number of pericytes, and the remaining vessels would be less permeable concurrent with a reduction in ANGPTL4