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- and PTGS2

Abstract

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 (Egfr wt ) or loss-offunction waved-2 Egfr (Egfr wa2 ) received azoxymethane followed by standard (5% fat) or western-style (20% fat) diet. As F 1 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 realtime PCR. Results: Egfr wt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfr wa2 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 Egfr wt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfr wt mice. In tumors, dietary fat and Egfr wt upregulated transforming growth factor-α, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfr wt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor-α 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):6780-9)

Epidermal growth factor receptor inhibits colitis-associated cancer in mice

“…Moreover, colitis was worsened by EGFR inactivation, with a 44% mortality rate among Egfr wa5 mice during DSS administration, whereas no wild-type mice died during this period. These data differ from those of Dougherty et al, who showed that EGFR inactivation (Egfr wa2/wa2 ) reduced tumorigenesis following AOM/DSS, albeit only in the setting of diet-induced obesity (34). However, their conclusions are complicated by their use of mice on a mixed A/J × C57BL/6 background, since A/J mice are exquisitely susceptible to AOM-induced colon tumorigenesis, even without an inflammatory stimulus (58).…”

“…However, a major criticism of this approach is that EGFR activation might accelerate tumorigenesis (29). Indeed, EGFR is widely considered a tumor promoter; its expression or activation is increased in many colonic precancerous lesions and tumors (30)(31)(32), and EGFR is implicated in animal models of gastrointestinal tumorigenesis (25,(33)(34)(35)(36). Moreover, EGFR monoclonal antibodies are approved for metastatic colorectal cancer treatment (cetuximab and panitumumab) (37).…”

The Role of Aspirin, Vitamin D, Exercise, Diet, Statins, and Metformin in the Prevention and Treatment of Colorectal Cancer

“…A placebo-controlled RCT in individuals with FAP found decreased incidence of adenoma with administration of 2 g/day of omega-3 PUFAs for 6 months [96]. In preclinical animal studies, dietary fat has been linked to higher incidence of colon cancer, [97] and a number of animal studies have demonstrated efficacy of several fish oil preparations against CRC [98][99][100][101].…”

Canola Oil Influence on Azoxymethane-induced Colon Carcinogenesis, Hypertriglyceridemia and Hyperglycemia in Kunming Mice

“…In a study of A/J x C57BL6/J mice (obesity prone) versus wild type mice, showed the involvement of epidermal growth factor receptors (EGFR) in controlled azoxymethane tumorigenesis using a normal (5%) fat diet, versus high fat western diet (20%). On a high fat diet, mice displayed more weight gain and also insulin resistance with significantly increased tumor and cancer incidence, suggesting EGFR as a pivotal gene up-regulated for obesity and tumour growth (Dougherty et al, 2009).…”