{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:29:22Z","timestamp":1765758562115,"version":"build-2065373602"},"reference-count":137,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T00:00:00Z","timestamp":1567123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR063786 and AR067319"],"award-info":[{"award-number":["AR063786 and AR067319"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA203108"],"award-info":[{"award-number":["CA203108"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cancer-associated cachexia (cancer cachexia) is a major contributor to the modality and mortality of a wide variety of solid tumors. It is estimated that cachexia inflicts approximately ~60% of all cancer patients and is the immediate cause of ~30% of all cancer-related death. However, there is no established treatment of this disorder due to the poor understanding of its underlying etiology. The key manifestations of cancer cachexia are systemic inflammation and progressive loss of skeletal muscle mass and function (muscle wasting). A number of inflammatory cytokines and members of the TGF\u03b2 superfamily that promote muscle protein degradation have been implicated as mediators of muscle wasting. However, clinical trials targeting some of the identified mediators have not yielded satisfactory results. Thus, the root cause of the muscle wasting associated with cancer cachexia remains to be identified. This review focuses on recent progress of laboratory studies in the understanding of the molecular mechanisms of cancer cachexia that centers on the role of systemic activation of Toll-like receptor 4 (TLR4) by cancer-released Hsp70 and Hsp90 in the development and progression of muscle wasting, and the downstream signaling pathways that activate muscle protein degradation through the ubiquitin\u2013proteasome and the autophagy\u2013lysosome pathways in response to TLR4 activation. Verification of these findings in humans could lead to etiology-based therapies of cancer cachexia by targeting multiple steps in this signaling cascade.<\/jats:p>","DOI":"10.3390\/cancers11091272","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T10:31:17Z","timestamp":1567161077000},"page":"1272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cancer Takes a Toll on Skeletal Muscle by Releasing Heat Shock Proteins\u2014An Emerging Mechanism of Cancer-Induced Cachexia"],"prefix":"10.3390","volume":"11","author":[{"given":"Thomas K","family":"Sin","sequence":"first","affiliation":[{"name":"Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guohua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zicheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA"},{"name":"The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA"},{"name":"Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-2790","authenticated-orcid":false,"given":"Yi-Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","article-title":"Cancer cachexia: Mediators, signaling, and metabolic pathways","volume":"16","author":"Fearon","year":"2012","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S0959-8049(97)10090-9","article-title":"Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies?","volume":"34","author":"Andreyev","year":"1998","journal-title":"Eur. 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