Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis

AUTOR(ES)

Roberts, Reade B.

FONTE

The National Academy of Sciences

RESUMO

We used the hypomorphic Egfrwa2 allele to genetically examine the impact of impaired epidermal growth factor receptor (Egfr) signaling on the ApcMin mouse model of familial adenomatous polyposis. Transfer of the ApcMin allele onto a homozygous Egfrwa2 background results in a 90% reduction in intestinal polyp number relative to ApcMin mice carrying a wild-type Egfr allele. This Egfr effect is potentially synergistic with the actions of the modifier-of-min (Mom1) locus. Surprisingly, the size, expansion, and pathological progression of the polyps appear Egfr-independent. Histological examination of the ilea of younger animals revealed no differences in the number of microadenomas, the presumptive precursor lesions to gross intestinal polyps. Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase inhibitor, produced similar results in the ApcMin model. These data suggest that normal Egfr activity is required for establishment of intestinal tumors in the ApcMin model between initiation and subsequent expansion of initiated tumors. The role of Egfr signaling during later stages of tumorigenesis was examined by using nude mice xenografts of two human colorectal cancer cell lines. Treatment with EKI-785 produced a dose-dependent reduction in tumor growth, suggesting that Egfr inhibitors may be useful for advanced colorectal cancer treatment.

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