Does Exercise Reduce Colorectal Cancer Risk in Obesity by Preventing Bone Marrow-Derived Cell Infiltration Into the Colon?

Abstract

Colorectal cancer (CRC) is the 3rd most prevalent cancer type in Canada, a leading cause of cancer deaths, and is increasing amongst young adults who are below the age for regular preventative screening (Brenner et al., 2019). This increasing prevalence is suggested to be related to the rise in obesity and physical inactivity (Brenner et al., 2019). Evidence has linked obesity and physical inactivity with an increased risk for CRC (Robsahm et al., 2013), whereas regular exercise is shown to decrease CRC incidence and mortality (Je et al., 2013). While there is strong evidence suggesting that exercise training reduces the incidence of colorectal carcinogenesis, the mechanisms remain unknown (Oruç & Kaplan, 2019). The CCL2-CCR2 axis responsible for bone marrow-derived monocyte mobilization and infiltration in peripheral tissues is a potential mechanistic explanation for these findings (Melgarejo et al., 2009). Exercise training-induced reduction in CRC in high-fat diet (HFD)-induced obese mice is shown to be independent of weight loss, and this reduction in CRC is associated with reduced production of inflammatory cells from hematopoietic stem cells (myelopoiesis) in an exercise-trained group (Emmons, Xu, et al., 2019). Our group recently investigated the time course for inflammatory myeloid cell infiltration into the colon during early colorectal carcinogenesis in HFD-induced obesity and exercise and found that obesity promoted preneoplastic lesions indicative of CRC initiation, potentially through early inflammatory cell accumulation (Vanhie, Orloff, et al., 2025). While these associations between myelopoiesis with colorectal carcinogenesis are compelling, a direct mechanistic link explaining the opposing effects of obesity and exercise on myelopoiesis and differential colorectal carcinogenesis is a critical gap in knowledge. Therefore, the overall objective of this thesis was to determine whether mobilization and recruitment of bone marrow-derived myeloid cells mechanistically explains the opposing effects of obesity and exercise on myelopoiesis and colorectal carcinogenesis. The specific aims were: (1) Determine if bone marrow-derived cell infiltration into the colon is necessary for colorectal carcinogenesis in the absence of CCR2 despite a HFD, (2) determine if increasing bone marrow-derived cell infiltration into the colon with recombinant CCL2 (CCL2r) is sufficient to reverse the beneficial effects of exercise training on colorectal carcinogenesis, and (3) confirm this relationship between myelopoiesis and CRC in humans by exploring circulating monocyte levels and CRC incidence in adults who are physically active or sedentary, and with and without obesity, from the Framingham Heart Study database. Our main findings were that CCR2 deficiency prevented HFD-induced early colorectal carcinogenesis, CCL2r prevented the protective effect of exercise training on CRC initiation, and myeloid skewing was associated with higher adiposity, lower physical activity, and increased CRC hazard in humans (HRs 1.30-1.37). Together, these findings identify bone marrow-derived myeloid cell mobilization, particularly via the CCL2-CCR2 signaling axis, as a key pathway linking obesity, exercise, and early colorectal carcinogenesis.