Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model

U. Dougherty, A. Sehdev, S. Cerda, R. Mustafi, N. Little, W. Yuan, S. Jagadeeswaran, A. Chumsangsri, J. Delgado, M. Tretiakova, L. Joseph, J. Hart (+4 others)
2008 Clinical Cancer Research  
Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased h-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic
more » ... or flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P < 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the upregulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-h, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P < 0.05). Gefitinib also inhibited the activations of extracellular signal^regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis. Results Male Fisher-344 rats were treated with azoxymethane or saline, and provided with AIN-76A chow or chow supplemented with gefitinib as summarized in the experimental protocol
doi:10.1158/1078-0432.ccr-07-4926 pmid:18413814 fatcat:ehplmhaftzdplm4hoynyskrcii