Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor
Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor
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DOI：
10.1111/j.1349-7006.2003.tb01397.x
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发表时间：
2003-12-01
期刊：
影响因子：
5.7
通讯作者：
Kawase, I
中科院分区：
文献类型：
--
作者：
Okuda, Y;Nakamura, H;Kawase, I
肝细胞源性生长因子（HDGF）在肿瘤细胞中高表达，并刺激其增殖。在本研究中，我们研究了HDGF在肿瘤发生中的作用并阐明了作用机制。过表达 HDGF 的 NIH3T3 细胞的稳定转染子在软琼脂测定中未显示出显着的贴壁依赖性生长。然而，这些过度表达 HDGF 的稳定转染子在裸鼠中产生了肉瘤。这些肿瘤肉眼可见呈红色，组织学上显示出丰富的血管。使用 CD31 抗体进行的免疫组织化学分析显示新血管形成。重组HDGF以剂量依赖性方式刺激人脐静脉内皮细胞增殖，并刺激肾小管形成。此外，通过免疫组织化学方法在肿瘤组织中检测到血管内皮生长因子（VEGF）。使用 VEGF 基因启动子进行的报告测定表明，HDGF 的瞬时表达诱导 VEGF 基因和蛋白质表达。施用抗VEGF中和抗体显着抑制但不阻断裸鼠中HDGF过表达细胞的肿瘤生长。因此，这些发现表明HDGF诱导的体内肿瘤形成涉及VEGF的诱导以及直接的血管生成活性。
Hepatoma-derived growth factor (HDGF) is highly expressed in tumor cells, and stimulates their proliferation. In the present study, we investigated the role of HDGF in tumorigenesis and elucidated the mechanism of action. Stable transfectants of NIH3T3 cells overexpressing HDGF did not show significant anchorage-independent growth in soft agar assay. However, these stable transfectants overexpressing HDGF generated sarcomatous tumors in nude mice. These tumors were red-colored macroscopically, and histologically showed a rich vascularity. Immunohistochemical analysis using CD31 antibody showed new vessel formation. Recombinant HDGF stimulated proliferation of human umbilical vein endothelial cells in a dose-dependent manner, and stimulated tubule formation. Furthermore, vascular endothelial growth factor (VEGF) was detected immunohistochemically in the tumor tissues. Transient expression of HDGF induced both VEGF gene and protein expression as demonstrated by a reporter assay using VEGF gene promoter. The administration of anti-VEGF neutralizing antibody significantly suppressed, but did not block, the tumor growth of HDGF-overexpressing cells in nude mice. Thus, these findings suggested that HDGF-induced tumor formation in vivo involves induction of VEGF as well as direct angiogenic activity.