Journal Article Ahead of print
PubMed: 41134647 DOI: 10.1152/ajpcell.00643.2025
Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.
Am J Physiol Cell Physiol
Authors: Jessica L Halle, Quan Zhang, Dryden R Baumfalk, Melissa J Puppa, Junaith S Mohamed, Evan S Glazer, Ashley J Smuder, Stephen E Alway, James A Carson
Affiliations
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN 38103, USA. Integrative Muscle Biology Lab, Department of Kinesiology & Sports Management, Texas A&M University, College Station, TX 77843, USA.
- Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL 32608, USA.
- College of Health Sciences, University of Memphis, Memphis, TN 38152, USA.
- Laboratory of Muscle and Nerve, Department of Diagnostic and Health Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
- Departments of Surgery and Cancer Center, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
- Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
- Integrative Muscle Biology Lab, Department of Kinesiology & Sports Management, Texas A&M University, College Station, TX 77843, USA.
- Huffines Institute for Sports Medicine & Human Performance, Kinesiology & Sports Management Department, Texas A&M University, College Station, TX 77843, USA.
Abstract
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 anti-cancer 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 IL-6, LIF, and 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.
MeSH
Cell Physiological Phenomena, Cytokines, Muscles, Neoplasms, Body Composition, Drug Therapy, Fluorouracil, Sex, Therapeutics, Colorectal Neoplasms, Chemotherapy