Date of Award

12-15-2014

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

E. Angela Murphy

Abstract

The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. Tumors associated macrophages drive the pro-inflammatory response in the tumor micro-environment and are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. In chapter 1, we examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the ApcMin/+ mouse. Then, in chapter 2, we examined the role of MCP-1 on tumor associated macrophages, inflammation, and intestinal tumorigenesis in ApcMin/+ mice. In chapter 3, we examined the effects of exercise on markers associated with macrophages and select T cell populations in ApcMin/+ mice and related this to polyp characteristics. The results in chapter 1 show that the increase in polyp burden with age is positively correlated with the increase in intestinal inflammatory cytokine expression (mRNA and protein) of MCP-1, IL-1β, IL-6 and TNF-α, with MCP-1 showing the highest association. Similarly, circulating MCP-1 was increased at 12 wks (P<0.05) and then again at 20 wks (P<0.05). MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P<0.05). In chapter 2, we show that MCP-1 deficiency decreased F4/80 positive cells in both the polyp tissue and surrounding intestinal tissue (P<0.05) as well as expression of markers associated with M1 (IL-12 & IL-23) and M2 macrophages (IL-13, CD206, TGFβ & CCL17) (P<0.05). MCP-1 knockout was also associated with increased CTLs and decreased Tregs (P<0.05). In chapter 3, we show that while there was no significant difference in overall polyp number between the groups (Sed: 23.3 ± 4.3 and Ex: 16.5 ± 4.3), Ex did have a reduction in the number of large polyps (Sed:6.1 ± 1.1 and Ex: 3.0 ± 0.6) (P<0.05). Similarly, Ex reduced mRNA expression of overall macrophages (F4/80) as well as markers associated with both M1 (IL-12) and M2 (CD206, CCL22, & Arg-1) subtypes (P<0.05). CD8 expression was increased while Foxp3 expression was decreased with Ex (P<0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer. This data also provides important new information on immune regulation as a possible mechanism for the documented benefits of exercise training on reducing colon cancer progression.

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