الفهرس 
Liver cancerOnly 14 pages are availabe for public view
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Abstract
The increasing incidence of hepatocellular carcinoma coupled with this cancer’s high mortality is a public health problem. Until now, we still need to devlop a method that could detect and monitor tumor growth as early as possible so a combination of in vivo imaging modalities and the use of genetic mouse models of cancer may successfully be applied for the early detection of hazardous drugs and chemicals. µCT and 18F-FDG µPET were used to detect and quantify tumor lesions after treatment with the genotoxic carcinogen NDEA, the tumor promoting agent BHT or the hepatotoxin paracetamol. Tumor growth was investigated between the age of 4 to 8.5 months. Indeed, contrast-enhanced µCT imaging detected liver lesions as well as metastatic spread with high sensitivity and accuracy as evidenced by histopathology. Significant differences in the onset of tumor growth, tumor load and glucose metabolism were observed, when the NDEA treatment group was compared with the other treatment groups. The application of in vivo imaging techniques will significantly reduce the use of laboratory animals and likely enable earlier detection of hazardous drugs and chemicals. The present study evidences a complex interplay between pErk, c-myc and EGFR in liver cancer. Mitogenic EGFR signaling is associated with increased c-Myc and cyclin D1 activity However, EGFR was degraded in 12 month old c-Myc transgenic animals with highly differentiated tumors. Despite significant degradation of EGFR oncogenic signaling of pErk remained active where as other members of the MAPK pathway was unchanged. For comparison, EGFR activity in an EGF transgenic mouse model of liver cancer was also investigated. Here, EGFR remained activated in EGF transgenic mouse model of liver cancer, even though many factors contributing to its degradation were in part, highly expressed as well. The common feature amongst both model of liver cancer was highly activated pErk, particularly with the c-Myc transgenic disease model. While the causes for hyperactive pErk may be different in the two transgenic mouse models inhibition of Mek provides a rationale for Erk inhibiton owing to the fact that the later kinase is the only substrate for Mek. Consequently, targeting pErk directly may enable as yet unknown possibilities in the treatment of cancers, particularly of those cancers that appear to be resistant to anti EGFR or otherwise multi tyrosine kinase inhibition strategies. Targeting the c-Met signaling pathway in cancer is the subject of intense research and significant progress has been made in the development of novel inhibitor with nearly 20 pathway inhibitors now being evaluated in clinical trials. However, the present study demonstrates a complex inhibitory crosstalk between HGF/c-Met and EGFR signaling that appears to be essential in EGF induced liver cancer. Thus, research is needed to evaluate – case by case – the usefulness of c-Met inhibition in the combat of different cancers.