Abstract
Cancer cachexia is a debilitating condition characterized by an extreme loss of skeletal muscle mass, which negatively impacts patients’ quality of life, reduces their ability to sustain anti-cancer therapies, and increases the risk of mortality. Recent discoveries have identified the myostatin/activin A/ActRIIB pathway as critical to muscle wasting by inducing satellite cell quiescence and increasing muscle-specific ubiquitin ligases responsible for atrophy. Remarkably, pharmacological blockade of the ActRIIB pathway has been shown to reverse muscle wasting and prolong the survival time of tumor-bearing animals. To explore the implications of this signaling pathway and potential therapeutic targets in cachexia, we construct a novel mathematical model of muscle tissue subjected to tumor-derived cachectic factors. The model formulation tracks the intercellular interactions between cancer cell, satellite cell, and muscle cell populations. The model is parameterized by fitting to colon-26 mouse model data, and the analysis provides insight into tissue growth in healthy, cancerous, and post-cachexia treatment conditions. Model predictions suggest that cachexia fundamentally alters muscle tissue health, as measured by the stem cell ratio, and this is only partially recovered by anti-cachexia treatment. Our mathematical findings suggest that after blocking the myostatin/activin A pathway, partial recovery of cancer-induced muscle loss requires the activation and proliferation of the satellite cell compartment with a functional differentiation program.
Highlights
Cancer cachexia is a condition identified by an ongoing and irreversible loss of skeletal muscle and adipose tissue [1,2,3,4]
We considered three molecular signaling events that may contribute to muscle wasting in cancer cachexia that are downstream of myostatin and would be affected by ActRIIB blockade treatment
We mathematically investigate cancer-associated muscle wasting through the intracellular ActRIIB signaling pathway
Summary
Cancer cachexia is a condition identified by an ongoing and irreversible loss of skeletal muscle and adipose tissue [1,2,3,4]. Pro-inflammatory cytokines including tumor necrosis factor α (TNFα) and interleukins 1, 6, and 10 (IL-1, IL-6 and IL-10) have been associated with the cachectic phenotype in several cancer models [20,21,22,23] These cytokines activate the STAT3 and NF-κB signaling pathways, leading to protein degradation [11,24,25]. Recent work by Zhou et al [31] demonstrated that blocking the activation of ActRIIB and the subsequent downstream signaling events could stop muscle loss in cancerous mice They assessed the effects of an ActRIIB decoy receptor in several mouse models of cancer cachexia, including a murine colon-26 carcinoma and two xenograft models: human G361 melanoma and human TOV-21G ovarian carcinoma. We extend the model to include a growing tumor that interferes with the intercellular signals and, with the feedback control This dysregulation leads to muscle loss in the model. Model simulations suggest that satellite cell reactivation is the primary target for muscle recovery through the myostatin/activin A/ActRIIB signaling pathway
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