Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2013 May 28;8(5):e63765. doi: 10.1371/journal.pone.0063765. Print 2013.
Hepatocyte growth factor (HGF) and its receptor, c-Met, are important regulators of growth and differentiation of healthy hepatocytes. However, upregulation of HGF and c-Met have been associated with tumor progression and metastasis in hepatocellular carcinoma (HCC). Hematogenous dissemination is the most common route for cancer metastasis, but the role of HGF and c-Met in circulating tumor cells (CTCs) is unknown. We have isolated and established a circulating tumor cell line from the peripheral blood of a mouse HCC model. Our studies show that these CTCs have increased expression of HGF and c-Met in comparison to the primary tumor cells. The CTCs display phenotypic evidence of epithelial-mesenchymal transition (EMT) and the EMT appears to be inducible by HGF. Epigenetic analysis of the c-Met promoter identified significant loss of DNA methylation in CTCs which correlated with overexpression of c-Met and increased expression of HGF. Six specific CpG sites of c-Met promoter demethylation were identified. CTCs show significantly increased tumorigenicity and metastatic potential in a novel orthotopic syngeneic model of metastatic HCC. We conclude that during hematogenous dissemination in HCC, CTCs undergo EMT under the influence of increased HGF. This process also involves up regulation of c-Met via promoter demethylation at 6 CpG sites. Consequently, targeting HGF and c-Met expression by CTCs may be a novel non-invasive approach with potential clinical applications in HCC management.
肝细胞生长因子 (HGF) 和其受体 c-Met 是调节健康肝细胞生长和分化的重要因子。然而，HGF 和 c-Met 的上调与肝细胞癌 (HCC) 的肿瘤进展和转移有关。血源性播散是癌症转移最常见的途径，但 HGF 和 c-Met 在循环肿瘤细胞 (CTC) 中的作用尚不清楚。我们已经从 HCC 模型的外周血中分离并建立了一个循环肿瘤细胞系。我们的研究表明，与原代肿瘤细胞相比，这些 CTC 中 HGF 和 c-Met 的表达增加。CTC 表现出上皮-间充质转化 (EMT) 的表型证据，并且 EMT 似乎可被 HGF 诱导。c-Met 启动子的表观遗传学分析表明，CTC 中存在明显的 DNA 甲基化缺失，这与 c-Met 的过表达和 HGF 表达增加相关。鉴定出 c-Met 启动子去甲基化的 6 个特定 CpG 位点。CTC 在新型同源性原位转移性 HCC 模型中显示出显著增加的致瘤性和转移潜能。我们得出结论，在 HCC 的血源性播散过程中，CTC 在 HGF 的影响下发生 EMT。这个过程还涉及通过 6 个 CpG 位点的启动子去甲基化来上调 c-Met。因此，通过 CTC 靶向 HGF 和 c-Met 的表达可能是一种新的非侵入性方法，在 HCC 管理中具有潜在的临床应用价值。
