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CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models
Nadia Alissa1, Wei Bin Fang2, Marcela Medrano2
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Abstract:
Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.
Insights
C-C chemokine ligand 2 (CCL2) signaling drives skeletal muscle wasting (SMW) in breast cancer patients. Targeting the CCL2-CCR2 pathway may offer new therapeutic strategies to combat this common side effect.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Skeletal muscle wasting (SMW) affects 25% of breast cancer patients, impacting mobility, treatment tolerance, and survival.
- Understanding the molecular drivers of SMW is crucial for developing effective interventions.
- C-C chemokine ligand 2 (CCL2) is overexpressed in breast cancer, correlating with poor prognosis and potentially systemic effects.
Purpose of the Study:
- To investigate the role of CCL2 signaling in skeletal muscle wasting (SMW) in both tumor and non-tumor contexts.
- To elucidate the molecular mechanisms by which CCL2 influences muscle function.
Main Methods:
- In vitro studies using myoblasts and myotubes exposed to varying CCL2 concentrations.
- In vivo experiments in mice involving recombinant CCL2 protein administration and tumor-derived CCL2 knockdown.
- Analysis of signaling pathways including JNK, SMAD3, and AMPK.
Main Results:
- CCL2 inhibited myoblast and myotube function in vitro via C-C chemokine receptor 2 (CCR2)-dependent pathways.
- Recombinant CCL2 induced dose-dependent SMW in healthy mice.
- Reducing tumor-derived CCL2 partially mitigated SMW in vivo.
Conclusions:
- Chronic, elevated CCL2-CCR2 signaling is a key regulator of skeletal muscle wasting (SMW) in breast cancer.
- The CCL2-CCR2 pathway presents a potential therapeutic target for managing SMW in cancer patients.
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