Author

Jackie Bader

Date of Award

Summer 2019

Document Type

Open Access Dissertation

First Advisor

E. Angela Murphy

Abstract

Colorectal Cancer (CRC) is the third-most common malignancy for men or women, with chronic inflammation considered as a primary risk factor. Obesity is also considered a chronic inflammatory disease and is associated with increased CRC incidence. Further, obesity and CRC occur in men and women differently with the highest incidence of either disease found in men, suggesting that female sex hormones may play a protective role in inflammatory diseases. Macrophages can promote inflammation and are a driving force in obesity-associated metabolic dysfunction. Conversely, macrophages also contribute to pro-tumoral responses including, proliferation, angiogenesis and tissue remodeling. This heterogeneity of macrophage behavior and function within these diseases encourages the need for macrophage targeted studies. Currently, the specific role of macrophages throughout the initiation and progression of these diseases remains unclear. Utilizing clodronate liposomes to target macrophages, we have uncovered that during late stage CRC, macrophage depletion is effective at reducing tumor-promoting macrophage signaling that contributed to reduced tumor burden and a more beneficial microbial composition. However, clodronate mediated macrophage depletion was ineffective at rescuing obesity induced insulin resistance due to compensatory neutrophil associated inflammation. In addition, we examined macrophage behavior within obesity driven CRC. Using a subcutaneous tumor model following diet induced obesity, we found that both insulin resistance and tumor growth presented differently in males, females and ovariectomized (OVX) females. Interestingly, the most severe obesity enhanced tumor growth was found in the obese OVX mice. This was consistent with increased M2-like tumor associated macrophages, increased subcutaneous adiposity and enhanced macrophage associated adipose tissue inflammation compared to obese females. These results suggest a protective role of female sex hormones in obesity enhanced CRC which is potentially mediated by macrophage associated inflammation. Taken together, our findings confirm a unique role of macrophages and macrophage associated inflammation in CRC, obesity and obesity-enhanced CRC. These findings are significant in further elucidating macrophage behavior through the progression of inflammatory driven diseases and contribute to the mechanistic understanding of sex disparities in obesity associated CRC.

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