Fig. 7.

Model for dual time-dependent effects of PDGF-BB. PDGF-BB exerts dual time-dependent effects on stromal fibroblasts that provide a possible explanation for the benign tumor phenotype. In the early phase (left), PDGF-BB secreted by the epithelium activates PDGFR-positive fibroblasts, leading to the up-regulation of VEGF-A and Hepatocyte growth factor (HGF), which is a potent stimulatory factor for epithelial cells and promotes epithelial proliferation. VEGF-A in turn activates the dermal endothelial cells devoid of PDGFR, up-regulates their VEGFR expression, and induces angiogenesis, possibly also supported by the action of HGF. During late phase (right), prolonged exposure to PDGF-BB down-regulates VEGF secretion by dermal fibroblasts, an effect that could be mediated by endostatin (an angiogenesis inhibitor) up-regulation, induces their differentiation into myofibroblasts. Blood vessel maturation is accompanied by VEGFR down-regulation. At the same time, the strong and ongoing increase in HGF secretion continues to stimulate the proliferation of the epithelial cells.