Abstract
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.
Highlights
There is convincing evidence that excess body weight is associated with increased risk for late onset (> 50 years of age) colorectal cancer (CRC) [1, 2]
high-fat diet (HFD) increased tumor growth 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)
Summary
There is convincing evidence that excess body weight is associated with increased risk for late onset (> 50 years of age) colorectal cancer (CRC) [1, 2]. Evidence suggests that postmenopausal women have an increased risk of CRC but this effect may be limited to individuals not currently using hormone replacement therapy (HRT) [7,8,9,10]. The current literature suggests that 1) sex disparities are evident in obesity-enhanced CRC, and 2) hormonal status likely plays a role in CRC risk in women. Despite these findings, controlled animal studies to substantiate www.oncotarget.com these claims and to determine potential mechanisms are lacking. 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. Controlled animal studies to substantiate these claims and the mechanisms involved are lacking
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