Cancer is a complex disease wherein tumours impact surrounding cells and tissue functionality. In addition, systemic effects of cancer can affect distant tissues, such as skeletal muscle, thereby reducing the fitness of patients. Skeletal muscle wasting (SMW) is a key feature of cancer cachexia, a debilitating syndrome that reduces quality of life and limits the ability of patients to tolerate anticancer treatment. At present, there is no cure for cancer cachexia and the underlying mechanisms are poorly understood.
In this issue of DMM, Alissa et al. explore SMW in breast cancer and focus on the role of the chemokine C-C motif ligand 2 (CCL2). Using an orthotopic mouse model of breast cancer, the authors show increased systemic and intramuscular levels of CCL2 compared with those in healthy control animals. Further analysis indicates reduced myofiber size and increased expression of atrophy-related proteins involved in degradation pathways (i.e. atrogin-1, MuRF1 and LC3B) in the quadriceps of tumour-bearing animals. Tumour-targeted silencing of Ccl2 was achieved using intratumoral delivery of siRNA complexed with cell-penetrating peptides. This decreased CCL2 levels not only in cancer cells, but also in serum and muscle, and reduced signs of muscle atrophy. Collectively, these data provide in vivo evidence for tumour-derived CCL2 as a mediator of SMW. The authors performed mechanistic in vitro studies showing that CCL2-mediated effects on skeletal muscle cells could be reversed with an antagonist of CCR2, a CCL2 receptor. Pharmacological inhibition experiments indicate that the cellular response to CCL2 is multifactorial and mediated through known regulators of SMW (e.g., JNK, AMPK and SMAD3).
Breast cancer is the most commonly diagnosed cancer. Based on body weight loss, cachexia is more prevalent in other disease indications, such as pancreatic, lung and gastrointestinal cancers. However, treatment-related gains in fat mass post diagnosis are common in breast cancer and this may mask incidence of SMW. Low skeletal muscle mass associates with poorer survival and increased treatment-related toxicity in both early and advanced breast cancer; hence, a better understanding of its underlying mechanisms is required. Here, Alissa et al. add evidence to studies showing relevance for the CCL2–CCR2 axis in cachexia. Further investigation is required to test the potential of targeted therapies to alleviate tissue wasting in breast cancer and to study the dynamic effects of CCL2 on skeletal muscle during standard-of-care therapy.
The image shows a schematic representation of the effects of intratumoral delivery of control siRNA or siRNA targeting Ccl2 in an orthotopic mouse model of breast cancer using 4T1 cells. CSA, cross-sectional area.
DMM Research or Resources & Methods articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.
