Overexpression of platelet-derived growth factor-BB increases tumor pericyte content via stromal-derived factor-1alpha/CXCR4 axis.
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.
Song
Nan
N
Department of Biological Sciences and Biotechnology, National Engineering Laboratory for Antitumor Protein Therapeutics, Tsinghua University, Beijing, PR China.
Huang
Yujie
Y
Shi
Hubing
H
Yuan
Shaopeng
S
Ding
Yanping
Y
Song
Xiaomin
X
Fu
Yan
Y
Luo
Yongzhang
Y
D000818:Animals; D000077214:Becaplermin; D001943:Breast Neoplasms / Q000098:blood supply; D002460:Cell Line; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D014158:Transcription, Genetic; D015854:Up-Regulation
D054377:Chemokine CXCL12; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt