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Reduced Colitis-Associated Colon Cancer in Fat-1 (n-3 Fatty Acid Desaturase) Transgenic Mice

¹ Department of Nutrition and Food Science, ² Intercollegiate Faculty of Nutrition, ³ Department of Veterinary Pathobiology, and ⁴ Center for Environmental and Rural Health, Texas A&M University; ⁵ Department of Microbial and Molecular Pathogenesis, Texas A&M University Health Science Center; ⁶ Vegetable and Fruit Improvement Center, College Station, Texas; ⁷ The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁸ Department of Medicine, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Robert S. Chapkin, Department of Nutrition and Food Science, Center for Environmental and Rural Health, Kleberg Biotechnology Center, MS 2253, Texas A&M University, College Station, TX 77843-2253. Phone: 979-845-0419; Fax: 979-862-2378; E-mail: r-chapkin{at}tamu.edu.

Key Words: inflammation • chemoprevention • dextran sodium sulfate • tumor promotion

Bioactive food components containing n-3 polyunsaturated fatty acids (PUFA) modulate multiple determinants that link inflammation to cancer initiation and progression. Therefore, in this study, fat-1 transgenic mice, which convert endogenous n-6 PUFA to n-3 PUFA in multiple tissues, were injected with azoxymethane followed by three cycles of dextran sodium sulfate (DSS) to induce colitis-associated cancer. Fat-1 mice exhibited a reduced number of colonic adenocarcinomas per mouse (1.05 ± 0.29 versus 2.12 ± 0.51, P = 0.033), elevated apoptosis (P = 0.03), and a decrease in n-6 PUFA–derived eicosanoids, compared with wild-type (wt) mice. To determine whether the chemoprotective effects of n-3 PUFA could be attributed to its pleiotropic anti-inflammatory properties, colonic inflammation and injury scores were evaluated 5 days after DSS exposure followed by either a 3-day or 2-week recovery period. There was no effect of n-3 PUFA at 3 days. However, following a 2-week recovery period, colonic inflammation and ulceration scores returned to pretreatment levels compared with 3-day recovery only in fat-1 mice. For the purpose of examining the specific reactivity of lymphoid elements in the intestine, CD3⁺ T cells, CD4⁺ T helper cells, and macrophages from colonic lamina propria were quantified. Comparison of 3-day versus 2-week recovery time points revealed that fat-1 mice exhibited decreased (P < 0.05) CD3⁺, CD4⁺ T helper, and macrophage cell numbers per colon as compared with wt mice. These results suggest that the antitumorigenic effect of n-3 PUFA may be mediated, in part, via its anti-inflammatory properties. [Cancer Res 2008;68(10):3985–91]