Abstract 14: Resolution of obesity-driven proinflammatory adipose signaling by weight loss or an NSAID is associated with reduced tumor burden in a mouse model of colon cancer
Authors: Glenny Elaine M. , Bowers Laura W. , Coleman Michael F. , Roper Jatin , Hursting Stephen D. 
Published: June 2022

Abstract
Obesity increases the incidence and progression of colon cancer. The chronic low-grade inflammation that often accompanies obesity is purported to promote these adverse outcomes. In obesity, remodeling of visceral white adipose tissue contributes to an inflammatory state via increased immune cell recruitment and production of proinflammatory cytokines. The aim of this study in a mouse model of obesity and colon carcinogenesis was to compare the effects of weight loss versus treatment with a nonsteroidal anti-inflammatory drug (sulindac) on tumor development and adipose and tumoral transcriptional changes. Azoxymethane (10 mg/kg) was intraperitoneally injected weekly into FVB/N male mice for 5 weeks to induce colon tumors. Mice were then randomized to an ad libitum 10 kcal% fat diet (control, n=20) or 60 kcal% fat diet to promote diet-induced obesity (DIO, n=55). After 15 weeks, DIO mice were randomized again to receive for an additional 7 weeks either: a) DIO diet (n=18); b) DIO diet supplemented with 140ppm sulindac (DIO+Su, n=19), or c) 10 kcal% fat control diet to generate formerly obese (FOb-LFD) mice (n=18). Mesenteric fat and colon tumors were collected for an Affymetrix Clariom D mouse gene expression microarray (n=5-6/group). FOb-LFD mice, but not DIO+Su mice, lost significant body weight and body fat. Relative to DIO mice, tumor burden and multiplicity were lower in control, DIO+Su, and FOb-LFD mice. Gene set enrichment analysis (GSEA) using the Hallmark gene sets revealed strikingly concordant transcriptional changes in the control, DIO+Su, and FOb-LFD mesenteric fat depots compared with DIO mice. Of the 8 immune related gene sets, 7 were uniformly suppressed (Normalized enrichment score (NES) &gt;1.66, FDR q&lt;0.05) across all groups relative to DIO. Moreover, compared with DIO, metabolism gene sets (e.g., FATTY_ACID_ METABOLISM, GLYCOLYSIS) were significantly enriched (NES &gt;1.45, FDR q&lt;0.05), and none were suppressed in control, DIO+Su, and FOb+LFD tumors. Tumor transcriptional changes were less coherent with EPITHELIAL_MESENCHYMAL_TRANSITION and COAGULATION being the only gene sets commonly suppressed across all groups relative to DIO. A leading-edge analysis revealed that Lum, Pthlh, Sfrp4, Mmp8, and Serpine1 were commonly suppressed amongst tumors from groups other than DIO mice. Both weight loss and sulindac impeded the effects of chronic obesity on colon tumorigenesis. GSEA analyses of immune related gene sets indicated that weight loss and sulindac effectively suppressed inflammation in the adipose tissue but not in the tumor. The conserved immunological and metabolic transcriptional programs in the adipose tissue relative to the tumor suggests the possibility that paracrine signaling from the adipose to the tumor may underpin the observed beneficial effects of these interventions on obesity-driven colon tumor growth.
Citation Format: Elaine M. Glenny, Laura W. Bowers, Michael F. Coleman, Jatin Roper, Stephen D. Hursting. Resolution of obesity-driven proinflammatory adipose signaling by weight loss or an NSAID is associated with reduced tumor burden in a mouse model of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 14.