Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice

Son, Gakuhei; Hirano, Toshio; Seki, Ekihiro; Iimuro, Yuji; Nukiwa, Toshihiro; Matsumoto, Kunio; Nakamura, Toshikazu; Fujimoto, Jiro

doi:10.1016/j.jhep.2006.04.011

Cited by 25 publications

(14 citation statements)

References 46 publications

(48 reference statements)

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“…Recent studies suggest that hepatocyte growth factor (HGF) up regulation is associated with acquisition of mesenchymal characteristics, development of HCC and metastasis [20], [27]–[29]. However, the role of HGF and its receptor the proto-oncogene c-Met in hematogenous dissemination of HCC has never been studied.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

et al. 2013

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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.

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Section: Resultsmentioning

confidence: 99%

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

et al. 2013

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“…Serum HGF levels are strongly associated with liver diseases including insulin resistance and nonalcoholic steatohepatitis. Blockage of HGF suppresses HCC in mice by inhibiting tumor cell motility and angiogenesis (44). FGF2, VEGF, and PDGFB are potent mitogenic and angiogenic factors and stimulate tumor growth (45).…”

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Activation Impairs Hepatocytic Differentiation and Targets Genes Moderating Lipid Homeostasis and Hepatocellular Growth

2007

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“…The exact role of this pathway in the pathogenesis of HCC has not been clearly elucidated. Blocking the HGF/c‐MET pathway during the orthotopic transplant of HCC models induced growth suppression and a decrease in angiogenesis (50). Foretinib was found to be potentially active in preclinical HCC models with inhibition of tumour angiogenesis, tumour cell proliferation and metastasis (51).…”

Section: Anti‐angiogenic Agents In Clinical Developmentmentioning

confidence: 99%

Novel molecular therapies in hepatocellular carcinoma

Faivre

Bouattour

Raymond

2011

Liver International

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The approval of sorafenib as the standard of care (SOC) for advanced hepatocellular carcinoma (HCC) fostered interest to further evaluate several other targeted therapies and extend the positioning of sorafenib alone and in combination with other drugs and local therapies at earlier stages and in an adjuvant setting. This review highlights current research using targeted therapies in HCC. Information for this review was compiled by searching PubMed and MEDLINE databases for articles published until September 2010. Several small molecules and humanized antibodies with anti-angiogenic and antiproliferative properties are currently being investigated in preclinical and/or clinical trials. Results are awaited from these clinical trials and offer promise for extending the current treatment options in HCC. Currently published data suggest that substantial progress may be achieved in the treatment of patients with HCC in the next 10 years.

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Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice

Cited by 25 publications

References 46 publications

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

Epigenetic Upregulation of HGF and c-Met Drives Metastasis in Hepatocellular Carcinoma

Mammalian Target of Rapamycin Activation Impairs Hepatocytic Differentiation and Targets Genes Moderating Lipid Homeostasis and Hepatocellular Growth

Novel molecular therapies in hepatocellular carcinoma

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