Hypoxia-induced Secretion of Platelet-derived Growth Factor-BB by Hepatocellular Carcinoma Cells Increases Activated Hepatic Stellate Cell Proliferation, Migration and Expression of Vascular Endothelial Growth Factor-A

Angiogenesis has an important function in the proliferation and metastasis of hepatocellular carcinoma (HCC) under a hypoxic tumor microenvironment. Activated hepatic stellate cells (HSCs) infiltrate the stroma of liver tumors and potently increase angiogenesis through tumor-stromal interactions, however, the exact mechanism by which this occurs is unknown. The present study aimed to investigate the paracrine effects of HCC-derived platelet-derived growth factor-BB (PDGF-BB) on HSCs under hypoxic conditions. It was demonstrated that PDGF-BB expression was markedly increased in HepG2 cells exposed to hypoxia. Conditioned medium (CM) from HepG2 cells stimulated LX-2 cell proliferation, migration and vascular endothelial growth factor-A (VEGF-A) expression. It was then determined that blocking PDGF-BB expression in HepG2-CM abolished these effects on LX-2 cells. The ectopic expression of PDGF-BB in HepG2 cells strongly affected LX-2 cell proliferation, migration and VEGF-A expression. In conclusion, the present study suggests that hypoxia-induced PDGF-BB secretion by HCC cells stimulates HSCs to accumulate and proliferate in the tumor stroma and the enhanced VEGF-A expression in HSCs may promote HCC angiogenesis.