Pro-inflammatory cytokine-driven molecular signaling in skeletal muscle during cancer cachexia.

Abstract

Cancer cachexia is a multifactorial syndrome characterized by the progressive loss of muscle and fat, commonly observed among patients with cancer. It is very distinct from other skeletal muscle wasting such as sarcopenia and malnutrition and is known to reduce cancer treatment effectiveness. Cachexia progression is driven by a combination of factors, including hormonal dysregulation, anorexia, tumor-derived catabolic factors (in cancer cachexia), and systemic or muscular inflammation, all of which worsen overall muscle health. In this review, we will probe the role of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-α, TGF-β, IL-1β, and IL-8, in driving the systemic inflammation and disruption of muscle metabolic homeostasis that support the development of cachexia. These cytokines may be produced from various organs, including the adipose depots that contribute to muscle wasting and metabolic dysfunction by disrupting the equilibrium between anabolic and catabolic processes. The ubiquitin-proteasome system, NF-κB, and JAK/STAT3 are important molecular pathways that mediate cytokine-induced catabolic signaling. The review further analyzes the context-dependent dual functions of these cytokines and the molecular mechanisms underlying the loss of their regulatory control during cancer progression. The limited success of current therapeutic approaches for cancer cachexia highlights the urgent need for evaluation of more targetable mechanisms for the treatments. Here, one of our main objectives is to probe whether suppression of pro-inflammatory cytokine signaling and activation of anti-inflammatory pathways can be utilized to modulate the tumor microenvironment, thereby countering cancer cachexia.