Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Oncol Res. 2009;18(2-3):117-25. doi: 10.3727/096504009789954627.
The purpose of this study was to determine whether vascular endothelial growth factor-165 (VEGF165) contributed to the osteolytic process in Ewing's sarcoma. VEGF165 induced osteoclast formation from murine bone marrow cells. Tartrate-resistant acid phosphatase (TRAP) staining demonstrated significantly fewer osteoclasts in VEGF-inhibited TC/siVEGF7-1 tumors compared to TC71 parental or TC/si-control tumors. Receptor activator NF-kappaB (RANKL), a critical osteoclastogenic factor, was decreased in TC/siVEGF7-1 cells. Incubation of these cells with recombinant VEGF165 upregulated RANKL in a dose- and time-dependent manner. The induction of (RANKL) by VEGF165 was also demonstrated in MC3T3-E1 mouse osteoblast cells and bone marrow stromal cells. This upregulation was transcriptionally mediated by an effect on the RANKL promoter. Both VEGF and EWS/FLI-1 increased RANKL promoter activity. Taken together, these data suggest that modulation of RANKL by VEGF165 may be one of the mechanisms responsible for the osteolytic process induced by Ewing's sarcoma cells. VEGF165 may, therefore, play an important role in modulating RANKL gene expression in the bone marrow microenvironment during the metastatic process, thereby contribution to tumor induced bone lysis.
这项研究的目的是确定血管内皮生长因子-165（VEGF165）是否有助于尤文肉瘤的溶骨性过程。VEGF165 诱导鼠骨髓细胞形成破骨细胞。抗酒石酸酸性磷酸酶（TRAP）染色显示，与 TC71 亲本或 TC/si-control 肿瘤相比，VEGF 抑制的 TC/siVEGF7-1 肿瘤中破骨细胞明显减少。核因子-κB 受体激活剂（RANKL）是一种关键的破骨细胞生成因子，在 TC/siVEGF7-1 细胞中减少。这些细胞与重组 VEGF165 孵育以剂量和时间依赖的方式上调 RANKL。VEGF165 还在 MC3T3-E1 小鼠成骨细胞和骨髓基质细胞中诱导了（RANKL）。这种上调是通过对 RANKL 启动子的影响转录介导的。VEGF 和 EWS/FLI-1 均增加了 RANKL 启动子活性。总之，这些数据表明，VEGF165 对 RANKL 的调节可能是尤文肉瘤细胞诱导的溶骨性过程的机制之一。因此，VEGF165 可能在转移过程中骨髓微环境中调节 RANKL 基因表达中发挥重要作用，从而有助于肿瘤诱导的骨溶解。
