Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer-related mortality in the United States. Because of the lack of viable treatment options for HCC, prevention in high risk patients has been proposed as an alternative strategy. The main risk factor for HCC is cirrhosis and several lines of evidence implicate epidermal growth factor (EGF) in the progression of cirrhosis and development of HCC. We therefore examined the effects of the EGF receptor (EGFR) inhibitor erlotinib on liver fibrogenesis and hepatocellular transformation in three different animal models of progressive cirrhosis – a rat model induced by repeated, low dose injections of diethylnitrosamine (DEN), a mouse model induced by carbon tetrachloride (CCl4) and a rat model induced by bile duct ligation (BDL). Erlotinib reduced EGFR phosphorylation in hepatic stellate cells (HSC), and reduced the total number of activated HSC. Erlotinib also decreased hepatocyte proliferation and liver injury. Consistent with all these findings, pharmacological inhibition of EGFR signaling effectively prevented the progression of cirrhosis and regressed fibrosis in some animals. Moreover, by alleviating the underlying liver disease, erlotinib blocked the development of HCC and its therapeutic efficacy could be monitored with a previously reported gene expression signature predictive of HCC risk in human cirrhosis patients. Conclusion These data suggest that EGFR inhibition with FDA-approved inhibitors presents a promising therapeutic approach for reduction of fibrogenesis and prevention of HCC in high risk cirrhosis patients who can be identified and monitored by gene expression signatures.

Inhibition of EGF Receptor Blocks the Development and Progression of Peritoneal Fibrosis

“…The antifibrotic effects of EGFR inhibition have been reported in several experimental models of chronic diseases, including renal fibrosis. 13,[17][18][19][20] However, the potential of EGFR inhibitors to act as therapeutic agents to ameliorate peritoneal membrane damage has not been studied yet. In this study, we showed that early or late administration of gefitinib, an EGFR inhibitor, reduced deposition of ECM with inactivation of myofibroblasts, suppression of inflammation responses, and attenuation of angiogenesis in the injured peritoneum.…”

“…15 STAT3 can also regulate expression of ECM proteins, such as type 1 collagen, and plays an important role in mediating the differentiation of renal interstitial fibroblasts to myofibroblasts and the development of renal fibrosis. 16 EGFR has been linked to tissue fibrosis in a variety of organs, including the liver, 17 lung, 18 and kidney. 13,19,20 However, it is unknown whether EGFR is activated in the peritoneum or whether it is involved in peritoneal fibrosis after injury.…”

Functions of Galectin-3 and Its Role in Fibrotic Diseases

“…Notably, a recent study confirms that the superstructure of galectins at the cell surface can bind cell-surface receptors such as epidermal growth factor receptor, which is a potent mitogen for collagen-producing mesenchymal cells (Partridge et al, 2004;Martinelli et al, 2011;Fuchs et al, 2014). Besides, Gal-3 exhibits high-affinity binding for the advanced glycosylation end product-binding proteins in macrophages, astrocytes, and endothelial cells.…”

Clinical Significance of Preoperative Liver Stiffness Measurements in Primary HBV-Positive Hepatocellular Carcinoma

“…Hepatic fibrosis is considered as a wound-healing response to chronic liver injury, which may result in liver cirrhosis and HCC, thus significantly correlated with prognosis of HCC [23,24]. The extent of hepatic fibrosis has usually been evaluated by histological exanimation.…”