Abstract 3966: The procancer effects of obesity can be reversed by moderate weight loss or an anti-inflammatory drug in a mouse model of colon cancer
Authors: Bowers Laura W. , Punjala Arunima , Jeffries Alison Q. , Montgomery Stephanie A. , Dannenberg Andrew J. , Hursting Stephen D. 
Published: September 2020

Abstract
Purpose: Obesity is associated with an increased risk of colon cancer. Our current study examines whether moderate weight loss or treatment with the non-steroidal anti-inflammatory drug sulindac suppresses the tumor-promoting effects of obesity in a mouse model of colon cancer.
Methods: Male FVB mice were treated with azoxymethane (10 mg/kg i.p.) for 5 weeks, then randomized to a control (10% kcal from fat) or diet-induced obesity (DIO, 60% kcal from fat) diet. After 15 weeks, there was an interim sacrifice of 5 mice/group. The DIO mice were then further randomized to remain on DIO or switch to control diet to induce weight loss and become formerly obese mice (FOB), and within each diet group (control, DIO, and FOB), half the mice were randomized to start sulindac treatment (140 ppm in the diet). Eight weeks later, all mice were euthanized.
Results: The DIO mice, compared to controls, had significantly greater body weight and body fat (P&lt;0.05), while FOB mice had intermediate levels of adiposity. Sulindac did not affect adiposity in any diet group. At the interim timepoint, DIO mice had 10-fold greater tumor multiplicity relative to control mice (P=0.07). At study endpoint, DIO mice had greater tumor multiplicity compared to both control (P&lt;0.05) and FOB (P&lt;0.01) mice, which did not significantly differ from each other. Sulindac reduced tumor multiplicity in both control (P&lt;0.05) and DIO (P&lt;0.0001) mice, but not FOB mice. Serum levels of several inflammation-related proteins, including interleukin 6, chemokine (C-X-C motif) ligand 1, monocyte chemoattractant protein 1, and vascular endothelial growth factor, were elevated in DIO mice versus control (P&lt;0.05) and DIO+sulindac (P&lt;0.01) mice, but not in comparison to FOB mice. Gene expression in paired colon tumor and mesenteric adipose tissue samples was assessed by microarray. Ingenuity pathway analysis (IPA) of the significant (P&lt;0.05) differentially expressed tumor genes indicated that both weight loss and sulindac reduced signaling related to matrix metalloproteinases (MMPs) and inflammation. In the visceral adipose tissue, IPA demonstrated that weight loss reduced signaling related to B cell receptors and glucose/fatty acid metabolism while sulindac decreased MMP, prostaglandin, and PPAR signaling. Additional analyses to explore the potential role of cross-talk between these two tissues are being performed, and key findings will be validated in the tissues at the protein level and via mechanistic cell culture experiments.
Conclusions: Both moderate weight loss and sulindac treatment completely reverse the effects of chronic obesity on colon tumorigenesis, the latter independent of any change in adiposity. Our findings suggest that an investigation regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese patients is warranted, particularly for those unable to achieve moderate weight loss.
Citation Format: Laura W. Bowers, Arunima Punjala, Alison Q. Jeffries, Stephanie A. Montgomery, Andrew J. Dannenberg, Stephen D. Hursting. The procancer effects of obesity can be reversed by moderate weight loss or an anti-inflammatory drug in a mouse model of colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3966.