Abstract
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.
Highlights
Over 90% of mortality from cancer is due to metastatic spread [1]
A novel PCRbased method that amplifies only one specific DNA segment of the mouse b-globin gene clearly verified that the novel established circulating tumor cell lines (OL0825, OL2548 and OL2549) are mouse cells just like the originally implanted BNL 1ME A.7R.1
Immunostaining for the hepatocyte-specific marker cAMP responsive element binding protein 3-like 3 (CREB3L3) using a specific antibody revealed that BNL 1ME A.7R.1, OL0825, OL2548 and OL2549 cells all express CREB3L3 verifying that the circulating tumor cells (CTCs) lines are from the originally implanted BNL 1ME A.7R.1 cell line (Figure S3)
Summary
Over 90% of mortality from cancer is due to metastatic spread [1]. In the majority of cancer patients, the primary tumor is unlikely to kill whereas the metastatic disease will result in mortality. While significant progress has been made in understanding the etiology and progression of many primary cancers, the basis for metastases of cancers remains largely unclear. The importance of understanding the biological basis of cancer metastasis has generated interest in this area of research and has led to the proposition of a number of biological concepts as potential mechanisms in cancer metastasis. One concept is that cancer cells undergo epithelial-mesenchymal transition (EMT) in order to acquire metastatic ability [2,3]. There remains an urgent need to clarify the exact role of EMT in cancer metastasis
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