Abstract
Cancer cachexia is a multifactorial metabolic syndrome that causes up to 20% of cancer-related deaths. Muscle atrophy, the hallmark of cancer cachexia, strongly impairs the quality of life of cancer patients; however, the underlying pathological process is still poorly understood. Investigation of the disease pathogenesis largely relies on cachectic mouse models. In our study, the transcriptome of the cachectic gastrocnemius muscle in the C26 xenograft model was integrated and compared with that of 5 more different datasets. The bioinformatic analysis revealed pivotal gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the disease, and the key genes were validated. Construction of the protein-protein interaction network and the comparison of pathways enriched in cancer cachexia with 5 other muscle atrophy models revealed Ddit4 (DNA damage-inducible transcript 4), as a key protein in cancer cachexia. The higher expression of Ddit4 in cachectic muscle was further validated in animal models and cachectic cancer patients. Further study revealed that p38 induced the expression of Ddit4, which in turn inhibited the mTOR pathway in atrophic cells.
Highlights
Cancer cachexia is a multifactorial metabolic syndrome that affects approximately 50–80% of cancer patients, especially in the advanced disease stages [1]
C26-xenografted mice manifested cachexia wasting syndrome characterized by progressive body weight loss (~20% at 15 days post C26 cell inoculation) and a reduction of skeletal muscle (20.7% vs. control) (Fig. 1A–C)
Cancer cachexia is a severe condition that occurs in 50–80% of cancer patients, especially in the late stage [2]
Summary
Cancer cachexia is a multifactorial metabolic syndrome that affects approximately 50–80% of cancer patients, especially in the advanced disease stages [1]. It is characterized by a negative energy balance of reduced food intake and exceeded metabolism and causes up to 20% of cancer deaths [2]. Muscle atrophy is the hallmark of cancer cachexia. It causes physical malfunction, compromises the immune system, leads to insulin resistance and fatigue, and strongly impairs patients’ quality of life [4, 5]. Protection from muscle loss is vital in the treatment of cancer cachexia. A profound understanding of the alteration in muscle atrophy at the molecular level is urgently needed
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