SDF-1α Induces PDGF-B Expression and the Differentiation of Bone Marrow Cells into Pericytes

Platelet-derived growth factor B (PDGF-B) and its receptor, PDGFR-beta, play a critical role in pericyte maturation; however, the mechanisms by which PDGF-B is upregulated in the tumor microenvironment remain unclear. We previously showed that upregulating stromal-derived factor, SDF-1 alpha, in VEGF(165)-inhibited Ewing's sarcoma tumors (TC/siVEGF(7-1)) induced PDGF-B mRNA expression, increased infiltration and differentiation of bone marrow cells (BMC) into pericytes and, rescued tumor growth. The purpose of this study was to investigate the mechanism by which SDF-1 alpha increased PDGF-B expression and the role of this pathway in BM-derived pericyte differentiation. We showed that SDF-1 alpha induced expression of PDGF-B mRNA and protein both in vitro and in vivo. In contrast, inhibiting SDF-1 alpha downregulated PDGF-B. We cloned the 2-kb pdgf-b promoter fragment and showed that SDF-1 alpha activates PDGF-B via a transcriptional mechanism. Chromatin immunoprecipitation showed that the ELK-1 transcription factor binds to the pdgf-b promoter in response to SDF-1 alpha. We confirmed the correlation between the SDF-1 alpha/PDGF-B pathway and the differentiation of PDGFR-beta+ BMCs into mature pericytes using an in vitro assay. These findings show that SDF-1 alpha regulates PDGF-B expression and that this regulation plays a critical role in the differentiation of PDGFR-beta+ BMCs into mature pericytes. Mol Cancer Res; 9(11); 1462-70. (C) 2011 AACR.