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Epidermal growth factor receptor inhibition attenuates liver fibrosis and
development of hepatocellular carcinoma
#MMPMID24677197
Fuchs BC
; Hoshida Y
; Fujii T
; Wei L
; Yamada S
; Lauwers GY
; McGinn CM
; DePeralta DK
; Chen X
; Kuroda T
; Lanuti M
; Schmitt AD
; Gupta S
; Crenshaw A
; Onofrio R
; Taylor B
; Winckler W
; Bardeesy N
; Caravan P
; Golub TR
; Tanabe KK
Hepatology
2014[Apr]; 59
(4
): 1577-90
PMID24677197
show ga
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 using
Food and Drug Administration-approved inhibitors provides 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.
|*Disease Progression
[MESH]
|Animals
[MESH]
|Bile Ducts/physiopathology
[MESH]
|Carbon Tetrachloride/adverse effects
[MESH]
|Carcinoma, Hepatocellular/pathology/*prevention & control
[MESH]
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