High-fat diet-fed ovariectomized mice are susceptible to accelerated subcutaneous tumor growth potentially through adipose tissue inflammation, local insulin-like growth factor release, and tumor associated macrophages
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Jackie Bader1, Meredith Carson1, Reilly Enos1, Kandy Velazquez1, Alexander Sougiannis1, Udai Singh2, William Becker1, Mitzi Nagarkatti1, Daping Fan3 and Angela Murphy1
1 Department of Pathology, Microbiology, & Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
2 Department of Medicine, University of Virginia Health Systems, Charlottesville, VA 22908, USA
3 Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
Keywords: colorectal cancer; obesity; metabolism; macrophage; inflammation
Received: July 09, 2020 Accepted: November 03, 2020 Published: December 08, 2020
Background: The association between obesity and colorectal cancer (CRC) risk has been well established. This relationship appears to be more significant in men than in women, which may be attributable to sex hormones. However, controlled animal studies to substantiate these claims and the mechanisms involved are lacking.
Materials and Methods: MC38 murine colon adenocarcinoma cells were injected subcutaneously into high-fat diet (HFD) fed male, female and ovariectomized (OVX) female C57BL/6 mice.
Results: HFD increased tumor growth (main effect) that was consistent with metabolic perturbations (P < 0.01). HFD OVX mice exhibited the most significant tumor growth compared to HFD male and female mice (p < 0.05) and this was associated with increased subcutaneous adipose tissue (p < 0.05). Further, the subcutaneous adipose tissue depots within HFD OVX mice exhibited more severe macrophage associated inflammation compared to female (P < 0.01), but not male mice. Conditioned media from subcutaneous adipose tissue of HFD OVX contained higher IGF-1 levels compared to male (P < 0.01), but not female mice. Finally, HFD OVX mice had increased M2-like gene expression in their tumor-associated macrophages (TAMs) compared to female mice (P < 0.01).
Conclusions: This work provides evidences suggesting adiposity, adipose specific IGF-1, macrophage associated adipose inflammation, and TAMs as potential mechanisms driving obesity-enhanced CRC in females lacking ovarian hormones.
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