Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine

Horiguchi, Norio; Takayama, Hisashi; Toyoda, Mitsuo; Otsuka, Toshiyuki; Fukusato, Toshio; Merlino, Glenn; Takagi, Hitoshi; Mori, Masatomo

doi:10.1038/sj.onc.1205248

Cited by 107 publications

(77 citation statements)

References 52 publications

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“…Its tumor promoting role has also been demonstrated in the DEN mouse model of liver cancer (51). In our study, we find that c-met is increased in the blood serum of mice bearing hepatocellular adenomas and that its increased serum levels are not affected by anti-Wnt-1 treatment.…”

Section: Discussionsupporting

confidence: 55%

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

et al. 2017

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Abstract. Recent evidence has suggested that downregulation of the Wnt/β-catenin signaling pathway may contribute to the development and growth of HCC. Consequently, elements of this pathway have begun to emerge as potential targets for improving outcomes of anti-HCC. Thus, the present study sought to examine the effects of Wnt-1 blockade using the classical diethylnitrosamine (DEN)-induced chemical carcinogenesis mouse model of HCC. The depletion of Wnt-1 using neutralizing antisera was done for ten consecutive days at the age of 9 months and mice were examined for the following 20 days. At that time, DEN-treated mice had multiple variably-sized hepatic cell adenomas. Anti-Wnt-1 was particularly potent in suppressing the expression of critical elements of the Wnt/β-catenin signaling pathway, such as β-catenin and Frizzled-1 receptor, however, not Dickkopf-related protein 1. This effect co-existed with the suppression of Cyclin D1, FOXM1, NF-κΒ and c-Jun commensurate with proliferation and apoptosis blockade in hepatocellular adenomas, and reduced Bcl-2 and c-Met in the serum of mice. Nonetheless, tumor size and multiplicity were found to be unaffected, suggesting that apoptosis may be equally important to proliferation in the context of counteracting DEN induced hepatocellular adenomas of mice.

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Section: Discussionsupporting

confidence: 55%

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

et al. 2017

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“…Kupffer cells produce TNF-␣ and IL-6, and endothelial cells produce TNF-␣, whereas HGF is mainly produced by HSC, which are related to myofibroblasts (40). The role of these mitogens in hepatocyte proliferation after partial hepatectomy is well established (41,42), and HGF is required for DEN-induced hepatocarcinogenesis (43). Disruption of JNK1 modestly reduces the expression of intrahepatic TNF-␣ and IL-6 mRNAs but has a more dramatic effect on the expression of intrahepatic HGF mRNA.…”

Section: Discussionmentioning

confidence: 99%

Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation

Sakurai

Maeda

Chang

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

384

396

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A major link between inflammation and cancer is provided by NF-B transcription factors. Ikk␤ ⌬hep mice, which specifically lack IB kinase ␤ (IKK␤), an activator of NF-B, in hepatocytes, are unable to activate NF-B in response to proinflammatory stimuli, such as TNF-␣. Surprisingly, Ikk␤ ⌬hep mice are hypersusceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Because defective NF-B activation promotes sustained c-Jun N-terminal kinase (JNK) activation in cells exposed to TNF-␣, whose expression is induced by DEN, and JNK activity is required for normal hepatocyte proliferation, we examined whether increased susceptibility to DEN-induced hepatocarcinogenesis in Ikk␤ ⌬hep mice requires JNK activation. Hepatocytes express both JNK1 and JNK2, but previous studies indicate that JNK1 is more important for hepatocyte proliferation. We therefore investigated this hypothesis using mice homozygous for a JNK1 deficiency either in wild-type or Ikk␤ ⌬hep backgrounds. In both cases, mice lacking JNK1 were much less susceptible to DEN-induced hepatocarcinogenesis. This impaired tumorigenesis correlated with decreased expression of cyclin D and vascular endothelial growth factor, diminished cell proliferation, and reduced tumor neovascularization. Whereas hepatocyte-specific deletion of IKK␤ augmented DEN-induced hepatocyte death and cytokine-driven compensatory proliferation, disruption of JNK1 abrogated this response. In addition to underscoring the importance of JNK1-mediated hepatocyte death and compensatory proliferation, these results strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver carcinogenesis.hepatocellular carcinoma H epatocellular carcinoma (HCC), the most common type of liver cancer, is the third leading cause of cancer deaths worldwide (1). Epidemiological studies suggest that the major risk factors for HCC are persistent infection with hepatitis B and C virus (HBV and HCV) and exposure to genotoxic and cytotoxic chemicals, including high levels of ethanol, all of which cause chronic liver injury and inflammation (2). Although relatively uncommon in the U.S., the incidence of HCC has been increasing rapidly in the past decade because of the current HCV epidemic, affecting nearly 2% of the U.S. population. In humans, HCC almost inevitably develops in the setting of chronic hepatitis or cirrhosis, conditions in which hepatocytes are killed and resident inflammatory cells (Kupffer cells), as well as newly recruited inflammatory cells (macrophages, neutrophils, NK and NKT cells), are activated to produce cytokines that drive the compensatory proliferation of surviving hepatocytes. Although the precise molecular role of chronic liver inflammation in the pathogenesis of HCC remains to be fully elucidated, it is likely to promote HCC development through cycles of hepatocyte death and compensatory proliferation (3). For instance, infection with woodchuck hepatitis virus, which eventually culminates in HCC, greatly enhances the proliferative acti...

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“…HGF is the ligand for the receptor tyrosine kinase c-MET. The HGF-MET cascade is associated with hepatocarcinogenesis (19). Elevated HGF levels have been associated with poor prognosis in patients with hepatocellular carcinoma (15), and high expression of c-MET has been associated with poor outcomes in patients with hepatocellular carcinoma treated with sorafenib (20).…”

Section: Discussionmentioning

confidence: 99%

Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial

Zhu

Kang

Rosmorduc

et al. 2016

Clinical Cancer Research

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Purpose: Sorafenib is the current standard therapy for advanced hepatocellular carcinoma, but validated biomarkers predicting clinical outcomes are lacking. This study aimed to identify biomarkers predicting prognosis and/or response to sorafenib, with or without erlotinib, in hepatocellular carcinoma patients from the phase III SEARCH trial.Experimental Design: A total of 720 patients were randomized to receive oral sorafenib 400 mg twice daily plus erlotinib 150 mg once daily or placebo. Fifteen growth factors relevant to the treatment regimen and/or to hepatocellular carcinoma were measured in baseline plasma samples.Results: Baseline plasma biomarkers were measured in 494 (69%) patients (sorafenib plus erlotinib, n ¼ 243; sorafenib plus placebo, n ¼ 251). Treatment arm-independent analyses showed that elevated hepatocyte growth factor [HGF; HR, 1.687 (high vs. low expression); endpoint multiplicity adjusted (e-adj) P ¼ 0.0001] and elevated plasma VEGFA (HR, 1.386; e-adj P ¼ 0.0377) were significantly associated with poor overall survival (OS) in multivariate analyses, and low plasma KIT [HR, 0.75 (high vs. low); P ¼ 0.0233; e-adj P ¼ 0.2793] tended to correlate with poorer OS. High plasma VEGFC independently correlated with longer TTP (HR, 0.633; e-adj P ¼ 0.0010) and trended toward associating with improved disease control rate (univariate: OR, 2.047; P ¼ 0.030; e-adj P ¼ 0.420). In 67% of evaluable patients (339/494), a multimarker signature of HGF, VEGFA, KIT, EPGN, and VEGFC correlated with improved median OS in multivariate analysis (HR, 0.150; P < 0.00001). No biomarker predicted efficacy from erlotinib.Conclusions: Baseline plasma HGF, VEGFA, KIT, and VEGFC correlated with clinical outcomes in hepatocellular carcinoma patients treated with sorafenib with or without erlotinib. These biomarkers plus EPGN constituted a multimarker signature for improved OS.

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Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine

Cited by 107 publications

References 52 publications

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Loss of hepatic NF-κB activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation

Biomarker Analyses of Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib with or without Erlotinib in the SEARCH Trial

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