Departments of Medicine, Health Studies, Surgery, and Pathology, University of Chicago, Chicago, Illinois , USA.
Clin Cancer Res. 2009 Nov 15;15(22):6780-9. doi: 10.1158/1078-0432.CCR-09-1678. Epub 2009 Nov 10.
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.
A/J x C57BL6/J mice with wild-type Egfr (Egfr(wt)) or loss-of-function 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 real-time PCR.
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-alpha, 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-alpha in normal colon.
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.
结肠癌是癌症死亡的主要原因。饮食因素是这种恶性肿瘤的主要风险因素。西式饮食促进了氧化偶氮甲烷诱导的结肠癌的发展。尽管我们已经证明表皮生长因子受体（EGFR）在标准脂肪条件下控制了氧化偶氮甲烷的肿瘤发生，但 EGFR 在高膳食脂肪促进肿瘤形成中的作用尚未得到检验。
具有野生型 Egfr（Egfr(wt)）或功能丧失型 waved-2 Egfr（Egfr(wa2)）的 A/J x C57BL6/J 小鼠接受氧化偶氮甲烷治疗，然后接受标准（5%脂肪）或西式（20%脂肪）饮食。由于 F(1) 小鼠对氧化偶氮甲烷有抗性，我们用氧化偶氮甲烷治疗小鼠，然后用一周期的诱导炎症的葡聚糖硫酸钠处理，以诱导肿瘤发生。小鼠在葡聚糖硫酸钠治疗 12 周后被处死。用免疫染色、Western 印迹和实时 PCR 评估肿瘤的组织学分级以及 EGFR 配体和原癌基因。
高脂肪饮食的 Egfr(wt) 小鼠比 Egfr(wa2) 小鼠体重显著增加，胰岛素抵抗明显增强。脂肪饮食仅在 Egfr(wt) 小鼠中促进肿瘤发生率（71.2%对 36.7%；P < 0.05）和癌症发生率（43.9%对 16.7%；P < 0.05）。富含脂肪的饮食也仅在 Egfr(wt) 小鼠中显著增加了肿瘤和癌症的多发性。在肿瘤中，脂肪饮食和 Egfr(wt) 上调了转化生长因子-α、 Amphiregulin、CTNNB1、MYC 和 CCND1，而只有 Egfr(wt) 小鼠中上调了前列腺素合成酶 2（PTGS2），并且脂肪饮食进一步上调了它。值得注意的是，脂肪饮食增加了正常结肠中的转化生长因子-α。
EGFR 是脂肪饮食诱导的体重增加和肿瘤促进所必需的。EGFR 依赖性受体配体和 PTGS2 的增加可能导致与饮食相关的肿瘤促进。
