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The Complex Interactions between Genetics and Environment: Diet, Inflammation and Intestinal Tumorigenesis

Doerner, Stephanie Kay
http://rave.ohiolink.edu/etdc/view?acc_num=case1357830044

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Genetics.
Diet-induced obesity (DIO) and metabolic syndrome (MetS) are important factors that contribute to the development and progression of cancer, especially colon cancer. DIO and MetS have reached epidemic proportions in the United States and are heavily influenced by diets high in saturated and omega-6 polyunsaturated fatty acids. Using the ApcMin/+ model of intestinal neoplasia and diets constructed from 58% coconut, corn or olive oils, we demonstrate that high amounts of dietary fats can have differential effects on DIO and MetS, as well as on intestinal tumorigenesis when compared to ApcMin/+ fed corresponding calorically equivalent control diets that contained 10% fat from these same sources. Diets constructed from coconut or corn oil lead to more rapid tumor progression, elevated polyp number and mass, as well as increased mortality, thus eliciting a detrimental impact on disease outcome, while one created from olive oil fails to induce an increase in polyp burden and reduce cancer severity in mice with genetic predisposition to intestinal neoplasia. We demonstrate that the tumor promoting effects of different fats are associated with systemic and local intestinal inflammation and that excess nutritional richness from coconut or corn oil can increase pro-inflammatory factors such as IL-6, IL-1¿¿, TNF¿¿, COX-2 as well as pro-oncogenic factors such as Myc. Adipokines, such as adiponectin and leptin, are differentially modulated in response to different fat sources. Short dietary exposure is sufficient to induce inflammation and tumorigenesis before the onset of DIO or MetS, suggesting a potent effect of diet on intestinal immunity. Additionally, we demonstrate a novel mechanism for innate immunity in diet-induced intestinal cancer by demonstrating that complement signaling is activated in mice fed diets high in coconut oil. We show that pharmacological and genetic inhibition of complement factors can significantly reduce polyp number and mass in ApcMin/+. These results suggest that nutritional modification may be a useful approach to alter intestinal and systemic inflammation with potential preventative value for use in colon tumorigenesis and that diet, immunity and cancer are intrinsically related.
Nathan Berger, M.D. (Advisor)
Joseph Nadeau, Ph.D. (Advisor)
Zhenghe Wang, Ph.D. (Committee Chair)
Colleen Croniger, Ph.D. (Committee Member)
Helen Salz, Ph.D. (Committee Member)
272 p.
Genetics
Diet; Tumorigenesis; Dietary Fat; Obesity; Inflammation; Colon Cancer

Recommended Citations

Citations

  • Doerner, S. K. (2013). The Complex Interactions between Genetics and Environment: Diet, Inflammation and Intestinal Tumorigenesis [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1357830044

    APA Style (7th edition)

  • Doerner, Stephanie. The Complex Interactions between Genetics and Environment: Diet, Inflammation and Intestinal Tumorigenesis. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1357830044.

    MLA Style (8th edition)

  • Doerner, Stephanie. "The Complex Interactions between Genetics and Environment: Diet, Inflammation and Intestinal Tumorigenesis." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1357830044

    Chicago Manual of Style (17th edition)

case1357830044
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© 2013, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.