RESUMEN
UNLABELLED: 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.
Asunto(s)
Carcinoma Hepatocelular/prevención & control , Progresión de la Enfermedad , Receptores ErbB/antagonistas & inhibidores , Cirrosis Hepática/prevención & control , Neoplasias Hepáticas/prevención & control , Quinazolinas/uso terapéutico , Animales , Conductos Biliares/fisiopatología , Tetracloruro de Carbono/efectos adversos , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Dietilnitrosamina/efectos adversos , Modelos Animales de Enfermedad , Receptores ErbB/efectos de los fármacos , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Ligadura/efectos adversos , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos , Fosforilación/efectos de los fármacos , Pronóstico , Quinazolinas/farmacología , Ratas , Ratas Wistar , TranscriptomaRESUMEN
Herpes-mediated viral oncolysis alone is not sufficient to completely eradicate tumors. In this study we used a replication conditional, endostatin-expressing herpes simplex virus-1 mutant (HSV-Endo) in a murine lung cancer model. We hypothesized that the anti-angiogenic action of endostatin would improve upon the oncolytic effect of HSV-1. HSV-Endo was evaluated in a pulmonary metastases and orthotopic flank model, where there was significantly less tumor burden and reduced microvessel density compared to a control virus. Endostatin expression appears to improve the anti-tumor effect of HSV-1 in a lung cancer model.
