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Article

MC38 Tumors Induce Musculoskeletal Defects in Colorectal Cancer

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Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2
Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Department of Otolaryngology—Head & Neck Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Cristina Peña
Int. J. Mol. Sci. 2021, 22(3), 1486; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031486
Received: 18 January 2021 / Revised: 27 January 2021 / Accepted: 29 January 2021 / Published: 2 February 2021
(This article belongs to the Section Molecular Endocrinology and Metabolism)
Colorectal cancer (CRC) is a leading cause of cancer-related death, and the prevalence of CRC in young adults is on the rise, making this a largescale clinical concern. Advanced CRC patients often present with liver metastases (LM) and an increased incidence of cachexia, i.e., musculoskeletal wasting. Despite its high incidence in CRC patients, cachexia remains an unresolved issue, and animal models for the study of CRC cachexia, in particular, metastatic CRC cachexia, remain limited; therefore, we aimed to establish a new model of metastatic CRC cachexia. C57BL/6 male mice (8 weeks old) were subcutaneously (MC38) or intrasplenically injected (mMC38) with MC38 murine CRC cells to disseminate LM, while experimental controls received saline (n = 5–8/group). The growth of subcutaneous MC38 tumors was accompanied by a reduction in skeletal muscle mass (−16%; quadriceps muscle), plantarflexion force (−22%) and extensor digitorum longus (EDL) contractility (−20%) compared to experimental controls. Meanwhile, the formation of MC38 LM (mMC38) led to heighted reductions in skeletal muscle mass (−30%; quadriceps), plantarflexion force (−28%) and EDL contractility (−35%) compared to sham-operated controls, suggesting exacerbated cachexia associated with LM. Moreover, both MC38 and mMC38 tumor hosts demonstrated a marked loss of bone indicated by reductions in trabecular (Tb.BV/TV: −49% in MC38, and −46% in mMC38) and cortical (C.BV/TV: −12% in MC38, and −8% in mMC38) bone. Cell culture experiments revealed that MC38 tumor-derived factors directly promote myotube wasting (−18%) and STAT3 phosphorylation (+5-fold), while the pharmacologic blockade of STAT3 signaling was sufficient to preserve myotube atrophy in the presence of MC38 cells (+21%). Overall, these results reinforce the notion that the formation of LM heightens cachexia in an experimental model of CRC. View Full-Text
Keywords: colorectal cancer; skeletal muscle; bone; cachexia; liver metastases colorectal cancer; skeletal muscle; bone; cachexia; liver metastases
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MDPI and ACS Style

Huot, J.R.; Pin, F.; Essex, A.L.; Bonetto, A. MC38 Tumors Induce Musculoskeletal Defects in Colorectal Cancer. Int. J. Mol. Sci. 2021, 22, 1486. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031486

AMA Style

Huot JR, Pin F, Essex AL, Bonetto A. MC38 Tumors Induce Musculoskeletal Defects in Colorectal Cancer. International Journal of Molecular Sciences. 2021; 22(3):1486. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031486

Chicago/Turabian Style

Huot, Joshua R., Fabrizio Pin, Alyson L. Essex, and Andrea Bonetto. 2021. "MC38 Tumors Induce Musculoskeletal Defects in Colorectal Cancer" International Journal of Molecular Sciences 22, no. 3: 1486. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031486

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