Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma

Vejchapipat, Paisarn; Tangkijvanich, Pisit; Theamboonlers, Apiradee; Chongsrisawat, Voranush; Chittmittrapap, Soottiporn; Poovorawan, Yong

doi:10.1007/s00535-004-1469-8

Cited by 56 publications

(41 citation statements)

References 25 publications

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“…In mouse models, HGF through activation of Met signaling pathway may promote carcinogenesis because of the presence of Met receptors on HCC cells. 13,34 In our study we have demonstrated elevated levels of both HGF and EGF in patients with HBV infection compared to healthy controls. We have not, however, investigated the source of EGF or HGF.…”

Section: Discussionsupporting

confidence: 49%

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Barreiros

Sprinzl

Rosset

et al. 2008

Intl Journal of Cancer

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The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus-infected liver cells to apoptosis may play a role in the failure to remove virus-infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV-infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show that HGF and EGF have a protective effect against CD95-mediated apoptosis and cytotoxic T-cell killing. Simultaneous treatment with both regeneration factors enhanced the cytoprotective effect. The PI 3-K/Akt kinase inhibitor, wortmannin, and the STAT3 pathway inhibitor, Tyrphostin AG490, both effectively attenuated the cytoprotective effect of HGF and EGF. Furthermore, we show an EGF/HGF-dependent upregulation of b 1 -integrin chains, increased adhesion to extracellular matrix and an increase in focal adhesions, suggesting outside-in signaling from the extracellular matrix as an additional cytoprotective mechanism. Our study demonstrates that HGF and EGF can interfere with CD95-mediated apoptosis and the action of cytotoxic T-cells through multiple mechanisms in human hepatocytes. Together our results argue that a survival mileau generated by activation of liver regeneration factors may be a risk factor for establishing viral persistence.

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Section: Discussionsupporting

confidence: 49%

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Barreiros

Sprinzl

Rosset

et al. 2008

Intl Journal of Cancer

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“…Additionally, overexpression of MET is detected predominantly in poorly differentiated HCCs (Daveau et al, 2003). Although one study does not demonstrate a correlation of HGF expression levels with patient survival or clinicopathological parameters (Ueki et al, 1997), recently published data show that higher HGF serum levels negatively correlate with patient survival time (Vejchapipat et al, 2004) and positively correlate with tumor size (Yamagamim et al, 2002).…”

Section: Transforming Growth Factor B Signaling Axismentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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“…Therefore, novel treatment strategies are urgently needed. HCC tissues express higher levels of HGF than dysplastic nodules (15), and high levels of plasma HGF in HCC patients indicate a grave prognosis, suggesting that HGF plays important and active roles in the progression of HCC (16).…”

Section: Introductionmentioning

confidence: 99%

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

Shen¹,

Yang

Gao³

et al. 2008

Cancer Research

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The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0 -G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and B fibroblast growth factor (bFGF)/B fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2 -kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. [Cancer Res 2008;68(2):404-14]

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Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma

Cited by 56 publications

References 25 publications

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Dysregulation of growth factor signaling in human hepatocellular carcinoma

The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma

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