Recombinant CCL2 prevents the protective effects of exercise training on colorectal carcinogenesis

Physical activity is associated with reduced colorectal cancer (CRC) risk. Preclinical models suggest that the mechanism responsible for these beneficial effects may be due to reducing inflammatory bone marrow-derived cell production and migration to the colon by CCL2 signaling. However, whether CCL2 signaling is a mechanism for exercise-induced early CRC protection is unknown. We sought to establish this link by inducing bone marrow-derived cell mobilization via the CCL2 signaling axis during exercise training in a chemically induced CRC model in which aberrant crypt foci (ACF) are a measure of early CRC. Mice were randomized to sedentary (SED) or exercise training (EX; treadmill: 3x/week, up to 1hr/d conditions; n=9-17/group) at age 21 weeks after having received 4 weekly doses of azoxymethane to initiate ACF. From age 21-24, mice received nine CCL2 recombinant (CCL2r) injections to induce marrow-derived cell mobilization during CRC initiation, with control mice injected with PBS. Tissues were collected at age 47 weeks to quantify CRC initiation, marrow-derived immune cells, and colon proliferative (β-catenin), and inflammatory (STAT3, NF-κB) signaling. EX reduced CRC in control mice; however, ACF were significantly more abundant in EX-CCL2r compared to EX-PBS (n=6/group). In the colon, the exercise-induced significant reduction of non-classical monocytes was prevented by CCL2r, and total and bone-marrow derived M2 macrophages trended lower with exercise independent of CCL2r (P = 0.095). Colon β-catenin trended lower in EX compared to SED (P = .0734). Our results recombinant CCL2 injections reverses the protective effects of exercise training on ACF formation, suggesting that CCL2 signaling is a relevant mechanism for exercise-induced protection.