Abstract

Cancer cachexia is a syndrome of weight loss that results from the selective depletion of skeletal muscle mass and contributes significantly to cancer morbidity and mortality. The driver of skeletal muscle atrophy in cancer cachexia is systemic inflammation arising from both the cancer and cancer treatment. While the importance of tumor derived inflammation is well described, the mechanism by which cytotoxic chemotherapy contributes to cancer cachexia is relatively unexplored. We found that the administration of chemotherapy to mice produces a rapid inflammatory response. This drives activation of the hypothalamic-pituitary-adrenal axis, which increases the circulating level of corticosterone, the predominant endogenous glucocorticoid in rodents. Additionally, chemotherapy administration results in a significant loss of skeletal muscle mass 18 hours after administration with a concurrent induction of genes involved with the ubiquitin proteasome and autophagy lysosome systems. However, in mice lacking glucocorticoid receptor expression in skeletal muscle, chemotherapy-induced muscle atrophy is completely blocked. This demonstrates that cytotoxic chemotherapy elicits significant muscle atrophy driven by the production of endogenous glucocorticoids. Further, it argues that pharmacotherapy targeting the glucocorticoid receptor, given in concert with chemotherapy, is a viable therapeutic strategy in the treatment of cancer cachexia.

Highlights

  • Cachexia is a progressive syndrome of weight loss that complicates numerous chronic diseases

  • To investigate whether chemotherapy induces a systemic inflammatory response, we treated wild type mice with CAF, a common chemotherapy regimen utilized in breast cancer that contains the anthracycline doxorubicin as well as the nucleoside analogue 5-fluorouracil and the alkylating agent cyclophosphamide

  • This demonstrates that the direct cytotoxic effects of chemotherapy on skeletal muscle are dispensable or at least not sufficient in isolation to drive the process of muscle atrophy

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Summary

Introduction

Cachexia is a progressive syndrome of weight loss that complicates numerous chronic diseases. Marked by a significant loss of skeletal muscle mass, the presence of cachexia is an independent predictor of mortality in multiple disease states [1,2]. It is estimated that cachexia is directly responsible for 20% of cancer deaths [3]. Declining performance status often precludes more aggressive and potentially curative anti-neoplastic treatment. Numerous preclinical studies have investigated the mechanism by which cancer produces muscle atrophy [4,5,6]. Relatively few studies have explored the contribution of cancer treatment to the development of cachexia [7]

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