Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy

Cancer-induced inflammation has been widely investigated as a driver of cachexia, and sex can affect the inflammatory response to cancer. We have an incomplete understanding of how anticancer treatments and sex impact the relationship between inflammatory responses and changes to body composition and physical function during cancer treatment. We investigated the effect of FOLFOX chemotherapy (5-fluorouracil, leucovorin, oxaliplatin) on circulating inflammatory cytokines, body composition, and physical function in CT26 tumor-bearing male and female mice. BALB/c mice were injected with CT26 tumor cells, and after the tumor was palpable, underwent three cycles of FOLFOX. FOLFOX reduced tumor mass in both sexes. CT26 induced plasma interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and tumor necrosis factor-alpha (TNF-α) in males and females. FOLFOX attenuated the CT26-induced IL-6 and LIF levels in males, but in females FOLFOX alone induced IL-6 and TNF-α, and did not attenuate their CT26 induction. In CT26 males, but not females, total lean and hindlimb mass were negatively associated with IL-6, and FOLFOX disrupted this association. The CT26-induced muscle p-STAT3 was inversely associated with muscle mass in males only and disrupted by FOLFOX. Circulating inflammatory cytokines were associated with body composition changes and functional deficits in CT26 males, but FOLFOX and female sex altered this relationship. Our results provide evidence that the female response to circulating inflammatory cytokines in the CT26 tumor environment, following FOLFOX chemotherapy, differs from that of males, and the physiological ramifications of this regulation warrant further investigation.<b>NEW & NOTEWORTHY</b> The present study demonstrates that in colon tumor-bearing mice, the administration of FOLFOX chemotherapy alters plasma inflammatory cytokines' relationship to tumor mass, body composition, and physical function. Furthermore, sex influences these responses. These findings have implications for mechanistically understanding sex-specific muscle wasting and metabolic complications experienced by patients with colorectal cancer undergoing chemotherapy treatment.