Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis

Abstract

Platelet-derived growth factor-BB (PDGF-BB) is a well-characterized growth factor displaying potent biological effects on angiogenesis. Recent studies reveal that overexpression of PDGF-BB within tumors results in increased pericyte coverage, suggesting that PDGF-BB signaling is also essential for the cancerous pericyte recruitment process. However, the molecular mechanism underlying this regulation remains obscure. In the current study, we show that tumor-derived PDGF-BB induces SDF-1alpha expression in endothelial cells (EC), resulting in the formation of SDF-1alpha chemotaxis gradient, which coincides with the PDGF-BB-induced pericyte recruitment during angiogenesis. PDGF-BB dramatically up-regulates SDF-1alpha secretion through the activation of PDGFRbeta in tumor-associated ECs, whereas this up-regulation can be substantially inhibited by either blockade of the phosphatidylinositol 3-kinase/Akt/mTOR pathway with chemical inhibitors or the inactivation of HIF-1alpha through small interfering RNA interference. On the other hand, we reveal that SDF-1alpha can increase pericytes motility in vitro. Blockade of the SDF-1alpha/CXCR4 axis prevents the PDGF-BB-induced pericyte recruitment not only in three in vitro recruitment models but also in the PDGF-BB-overexpressing tumor xenograft models. These results highlight that the involvement of SDF-1alpha/CXCR4 axis is essential for the pericyte recruitment within the PDGF-BB-overexpressing tumors and raise the possibility that blockade of the SDF-1alpha/CXCR4 axis may provide a therapeutic synergy with antiangiogenic molecules that selectively target ECs.