Abstract
Progressive weight loss combined with skeletal muscle atrophy, termed cachexia, is a common comorbidity associated with cancer that results in adverse consequences for the patient related to decreased chemotherapy responsiveness and increased mortality. Cachexia’s complexity has provided a barrier for developing successful therapies to prevent or treat the condition, since a large number of systemic disruptions that can regulate muscle mass are often present. Furthermore, considerable effort has focused on investigating how tumor derived factors and inflammatory mediators directly signal skeletal muscle to disrupt protein turnover regulation. Currently, there is developing appreciation for understanding how cancer alters skeletal muscle’s complex microenvironment and the tightly regulated interactions between multiple cell types. Skeletal muscle microenvironment interactions have established functions in muscle response to regeneration from injury, growth, aging, overload-induced hypertrophy, and exercise. This review explores the growing body of evidence for immune cell modulation of the skeletal muscle microenvironment during cancer-induced muscle wasting. Emphasis is placed on the regulatory network that integrates physiological responses between immune cells with other muscle cell types including satellite cells, fibroblast cells, and endothelial cells to regulate myofiber size and plasticity. The overall goal of this review is to provide an understanding of how different cell types that constitute the muscle microenvironment and their signaling mediators contribute to cancer and chemotherapy-induced muscle wasting.
Highlights
Cachexia is a perilous comorbidity occurring with many chronic diseases that are defined by progressive weight loss, skeletal muscle atrophy, and the inability to be fully prevented or treated by nutritional support (Fearon et al, 2011)
The complex nature of the skeletal muscle microenvironment invites difficulty in identifying key regulators of muscle mass and function loss with cancer and chemotherapy; targeting inflammation and immune cells prior to‐ or during cachexia’s progression could promote widespread benefits given their regulatory roles in several skeletal muscle processes
While several inflammatory mediators (IL-6, tumor necrosis factor α (TNF-α), TWEAK, TRAF6, INF-γ, and leukemia inhibitory factor (LIF)) have been implicated as drivers of cancer-associated wasting, very little is known about their origin, whether skeletal muscle, immune cell, or tumor-derived (Flint et al, 2016; Jackman et al, 2017)
Summary
Cachexia is a perilous comorbidity occurring with many chronic diseases that are defined by progressive weight loss, skeletal muscle atrophy, and the inability to be fully prevented or treated by nutritional support (Fearon et al, 2011). While inflammation’s contribution to initiating and accelerating cancer cachexia has been widely investigated (Evans et al, 2008; Carson and Baltgalvis, 2010), a major focus of this research has centered on circulating inflammatory mediators and how they directly regulate muscle intracellular signaling to disrupt protein turnover and metabolism to drive wasting (Talbert et al, 2018). To this end, significant gaps remain in our understanding of other aspects of the complex relationship between the immune system and the regulation of skeletal muscle mass. The current understanding of chemotherapy as an underlying pathology that could disrupt immune cell interaction with the skeletal muscle microenvironment is discussed
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