Abstract A46: Dietary weight loss and sulindac treatment each reverse obesity-associated inflammation and tumorigenesis in a mouse model of carcinogen-induced colon cancer
Authors: Hursting Stephen D. , Bowers Laura W. , Punjala Arunima , Dannenberg Andrew J. 
Published: June 2022

Purpose: We previously showed diet-induced obesity (DIO) increases (and calorie restriction decreases) systemic markers of inflammation and azoxymethane (AOM)-induced colon carcinogenesis in FVB/N mice. Our current study examines whether moderate weight loss via low-fat diet (LFD) and/or treatment with the nonsteroidal anti-inflammatory drug sulindac reverses the inflammatory and tumor-promoting effects of DIO in the AOM-induced mouse model of colon cancer.

Methods: Male FVB/N mice were treated with AOM (10 mg/kg i.p.) for 5 weeks, then randomized to a control (10% kcal from fat) or DIO (60% kcal from fat) diet. After 15 weeks on diet, 5 mice/group were killed and their tissues collected for interim timepoint analysis. The remaining DIO mice were further randomized to either remain on DIO or switch to control diet to induce weight loss (formerly obese [FOb] mice), and within each diet group (control, DIO, and FOb), half the mice were randomized to receive sulindac treatment (140 ppm in the diet). Eight weeks later, all mice were killed and their serum, tumors, and other tissues collected for analysis.

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 weight and 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&lt;0.01) and Fob mice (p&lt;0.01). The control and FOb groups did not significantly differ from each other. At study termination sulindac significantly reduced tumor multiplicity in both control (P&lt;0.05) and DIO (P&lt;0.0001) mice, but not FOb mice. In the mice that received sulindac, tumor multiplicity did not significantly differ between diet groups. Tumor multiplicity in the DIO+sulindac, FOb, and FOb+sulindac groups was also significantly lower than the interim timepoint DIO mice (P&lt;0.05), suggesting the interventions induced tumor regression. 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 controls (P&lt;0.05), but did not differ between FOb and control mice. Sulindac treatment significantly reduced serum levels of these proteins in DIO mice (P&lt;0.01). Gene expression in paired colon tumor and mesenteric adipose tissue samples is currently being assessed by microarray analysis to investigate crosstalk between these tissues and inform the design of future studies on the mechanism(s) mediating sulindac’s effects.

Conclusions: Both moderate weight loss and sulindac treatment reverse the effects of chronic obesity on AOM-induced colon tumorigenesis. The anticancer effects of sulindac were independent of any change in adiposity. Given the challenges of losing weight, our findings suggest that further investigation of the effects of NSAID treatment on colon cancer risk and/or progression in obese patients is warranted.

Citation Format: Stephen D. Hursting, Laura W. Bowers, Arunima Punjala, Andrew J. Dannenberg. Dietary weight loss and sulindac treatment each reverse obesity-associated inflammation and tumorigenesis in a mouse model of carcinogen-induced colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A46.