Vinorelbine Inhibits Angiogenesis and 95D Migration Via Reducing Hypoxic Fibroblast Stromal Cell-derived Factor 1 Secretion

Tumor stroma plays a prominent role in cancer progression. Fibroblasts constitute a majority of the stromal cells in tumor, and yet the functional contributions of these cells to tumor angiogenesis and invasion are poorly understood, especially the anticancer drug interference to these processes. To estimate the effects of vinorelbine (VNR) on fibroblast-associated tumor invasion and angiogenesis, we evaluated the response of 95D and human umbilical vein endothelial cell (HUVEC) migration, tube formation in vitro, as well as capillary formation of rat thoracic aorta rings to hypoxic MRC-5 conditioned medium (CM) by VNR pretreatment. Our results demonstrated that VNR significantly inhibited 95D and HUVEC migration and angiogenesis induced by hypoxic MRC-5 cells. We also showed that hypoxic MRC-5 CM (Hypo-CM) had a higher level of stromal cell-derived factor 1 (SDF-1) secretion, while Hypo-CM up-regulated the CXCR4 expression in HUVECs and 95Ds. This increased activity of SDF-1/CXCR4 paracrine was clearly attenuated by VNR pretreatment. It was further found that pretreating HUVECs and 95Ds with AMD3100, a CXCR4 antagonist, markedly reversed the Hypo-CM promoting cell migration and angiogenesis, while adding exogenous SDF-1 attenuated the inhibition effects of CM collected from VNR-pretreated hypoxic MRC-5 (Hypo-CMV). These data indicate that VNR indirectly decreased 95D migration and angiogenesis through its effect on hypoxic MRC-5, via impacting SDF-1/CXCR4 paracrine, suggesting that VNR could interrupt the influence of fibroblasts on HUVECs and 95Ds to exert an anticancer role. Therefore, fibroblasts should be taken into consideration when evaluating and developing anticancer drugs.