Jorge Delgado

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

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 β-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for 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 up-regulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-β, 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.

Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor-α and PTGS2

Purpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined. Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR. Results:Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P < 0.05) and cancer incidence (43.9 versus 16.7; P < 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon. Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)

Mantle cell lymphoma in a tubular adenoma: unusual presentation with synchronous colonic carcinoma

An 80-year-old man underwent sigmoidectomy for adenocarcinoma. Six months later, after a near-syncope incident, pancytopenia was detected in the absence of occult blood in the stools. A bone marrow biopsy showed malignant lymphoma, suggestive of mantle cell lymphoma (MCL). Colonoscopy at this time revealed 3 colonic tubular adenomas. Reassessment of the histology of the colonic polyps and appropriate immunohistochemical stains showed that the lamina propria of one of the tubular adenomas was infiltrated by MCL. Reexamination of the sections taken at the time of the original sigmoidectomy showed MCL in 2 of the regional lymph nodes removed at that time, but no evidence of lymphoma in the colon was found. To our knowledge, this is the fifth reported case of synchronous occurrence of intestinal MCL and colonic carcinoma and the first report of MCL presenting in a tubular adenoma of the colon.

Sustained virologic response to treatment in 100% of patients recently infected, nosocomially, with HCV genotype 2.

Objective In 2003, a cluster of hepatitis C virus (HCV)-infected patients with a common history of a surgical procedure, performed during 2001 to 2003, was identified in a medical center. An epidemiologic investigation linked a physician, infected with HCV genotype 2, as the possible source of infection in 35 patients. The evaluation, therapy, and outcome of this unique cohort are presented. Design HCV-RNA was isolated from sera of all patients and the double-stranded phosphorylation homology domain region was sequenced. After a routine clinical investigation 33 patients were offered antiviral therapy. Two patients were not treatment candidates due to old age and comorbidity. Results Twenty-two (66%) were women. The mean age was 48.5±16.9 years. Alanine aminotransferase level was 117±135u2009IU/L. Thirty patients were treated with pegylated interferon alpha 2a, 1 with pegylated interferon alpha 2b, and 1 with standard interferon. All received ribavirin 800u2009mg daily. One patient refused to be treated and was lost for follow-up. Time from acquisition of disease to initiation of therapy was 14.8±4.9 month (5.5 to 26). Therapy duration was 24 weeks except for 1 patient who stopped therapy after 16 weeks. Sustained virologic response was achieved in all 32 treated patients. The sequence motif of the phosphorylation homology domain region, studied in all patients, predicted good response to interferon. Conclusions Our excellent results can be explained by a constellation of favorable viral characteristics, a short-term disease and adherence to therapy.