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

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Genetics

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Doerner, Stephanie Kay

Contributors dc:contributor

• Berger, Nathan
• Nadeau, Joseph
• Wang, Zhenghe

• Genetics
• Diet
• Tumorigenesis
• Dietary Fat
• Obesity
• Inflammation
• Colon Cancer

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1357830044

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1357830044