Obesity Promotes Marrow-Derived Myeloid Cell Accumulation while Exercise Reduces Proliferative Signaling in Colon Cancer.

Obesity increases colon cancer risk that has been previously linked to marrow-derived myeloid cells. We previously demonstrated that exercise training (EX) prevents colon cancer initiation, potentially through reduced myelopoiesis. However, it remains unknown whether early myeloid cell accumulation and inflammation in the colon precedes carcinogenesis with high-fat diet (HFD)-induced obesity, and if EX can attenuate these effects. We hypothesized that obesity would promote colon carcinogenesis that was preceded by myeloid cell accumulation and inflammation that would be attenuated by EX. C57BL/6 mice were randomized to a HFD or control (CON) diet for 8 weeks. The HFD mice switched to CON diet and all mice were given intraperitoneal injections of azoxymethane (AOM) to induce colon cancer and randomized into EX or sedentary (SED) conditions. HFD mice developed more aberrant crypt foci (ACF), a marker for early carcinogenesis, compared to CON (p < 0.01), and EX developed fewer ACF compared to SED (p < 0.0001). Marrow-derived (p < 0.001) CD206+ macrophages were elevated in HFD compared to CON at study week 16 (p < 0.01). Marrow-derived CD206- macrophages (p < 0.05) and marrow-derived (p < 0.05) CD206+ macrophages were more abundant in HFD compared to CON at study week 42. EX did not alter colon immune cell populations. β-Catenin protein was higher in HFD compared to CON at study week 42 (p < 0.05), and STAT3 protein content was lower at study week 28 with EX compared to SED (p < 0.05). The results suggest that obesity promotes colon ACF formation, potentially through early inflammatory myeloid cell accumulation. Despite attenuating ACF, EX did not alter myeloid cell accumulation in the colon, suggesting that EX inhibits ACF formation through alternative mechanisms which may include reduced β-Catenin and STAT3 signaling.

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Conflict of Interest and Funding Source: This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2017-04320) and the American Institute for Cancer Research. J.V. was supported by the uOttawa/CHEO Research Institute’s Doctoral Fellowship for Advancement of Biological Perspectives for Exercise Interventions Across the Lifespan and the Ontario Graduate Scholarship (OGS). N.C was supported by The Chilean National Agency for Research and Development (Agencia Nacional de Investigacion y Desarrollo [ANID]), the uOttawa/CHEO Research Institute’s Doctoral Fellowship for Advancement of Biological Perspectives for Exercise Interventions Across the Lifespan, and the uOttawa Eric Poulin Centre for Neuromuscular Disease (CNMD) Scholarship in Translational Research (STaR). The authors declare no conflict of interest.