Hendrix M J, Seftor E A, Seftor R E, Kirschmann D A, Gardner L M, Boldt H C, Meyer M, Pe'er J, Folberg R
Department of Anatomy and Cell Biology, Iowa Cancer Center, The University of Iowa College of Medicine, Iowa City 52242-1109, USA.
Am J Pathol. 1998 Apr;152(4):855-63.
Human uveal melanoma disseminates initially and preferentially to the liver. This study describes the relationship between the expression of the c-met proto-oncogene (receptor for hepatocyte growth factor/scatter factor (HGF/SF)) in interconverted uveal melanoma cells (co-expressing vimentin and keratin intermediate filaments) and the regulation of their motogenic response to HGF/SF, a key step in local invasion and targeted dissemination to the liver. Expression of c-met in uveal melanoma cell lines correlates with both the appearance of an interconverted phenotype and invasive ability (measured in vitro). Using chemotactic checkerboard analysis, the greatest motogenic response to HGF/SF was achieved by invasive, interconverted, c-met-positive uveal melanoma cells. C-met was observed histologically in a uveal melanoma containing interconverted cells but was absent in a tumor composed of non-interconverted cells (vimentin positive/keratin negative). The c-met ligand, HGF/SF, although not expressed by uveal melanoma cell lines, was localized in tissue sections of primary uveal melanomas and metastatic melanoma to the liver. In the primary tumor, staining for HGF/SF was most intense at the level of the choriocapillaris, a finding that is significant because 1) highly remodeled neovascular loops and networks, which appear in tumors likely to disseminate, can be traced to the choriocapillaris and the draining vortex veins and 2) HGF/SF plays a role in tumor angiogenesis. Foci of metastatic melanoma to the liver stain diffusely for HGF/SF. Regulation of the uveal melanoma interconverted phenotype by HGF/SF may play an important role in the dissemination of this tumor.
人类葡萄膜黑色素瘤最初会优先扩散至肝脏。本研究描述了在相互转化的葡萄膜黑色素瘤细胞（共表达波形蛋白和角蛋白中间丝）中c-met原癌基因（肝细胞生长因子/分散因子（HGF/SF）的受体）的表达与它们对HGF/SF促运动反应的调节之间的关系，这是局部侵袭和靶向扩散至肝脏的关键步骤。c-met在葡萄膜黑色素瘤细胞系中的表达与相互转化表型的出现和侵袭能力（体外测量）均相关。使用趋化棋盘分析，侵袭性、相互转化、c-met阳性的葡萄膜黑色素瘤细胞对HGF/SF的促运动反应最强。在含有相互转化细胞的葡萄膜黑色素瘤中通过组织学观察到了c-met，但在由非相互转化细胞（波形蛋白阳性/角蛋白阴性）组成的肿瘤中未观察到。c-met配体HGF/SF虽然未由葡萄膜黑色素瘤细胞系表达，但定位于原发性葡萄膜黑色素瘤和肝脏转移性黑色素瘤的组织切片中。在原发性肿瘤中，HGF/SF染色在脉络膜毛细血管水平最为强烈，这一发现具有重要意义，因为1）高度重塑的新生血管环和网络出现在可能发生扩散的肿瘤中，可追溯至脉络膜毛细血管和引流涡静脉；2）HGF/SF在肿瘤血管生成中起作用。肝脏转移性黑色素瘤病灶对HGF/SF呈弥漫性染色。HGF/SF对葡萄膜黑色素瘤相互转化表型的调节可能在该肿瘤的扩散中起重要作用。
