Program in Molecular Medicine
Biochemical Phenomena, Metabolism, and Nutrition | Cellular and Molecular Physiology | Genetic Phenomena | Neoplasms | Nutritional and Metabolic Diseases | Pathological Conditions, Signs and Symptoms | Pharmacology, Toxicology and Environmental Health | Therapeutics
Cancer-induced cachexia, characterized by systemic inflammation, body weight loss, adipose tissue (AT) remodeling and muscle wasting, is a malignant metabolic syndrome with undefined etiology. Here, we show that both genetic ablation and pharmacological inhibition of TLR4 were able to attenuate the main clinical markers of cachexia in mice bearing Lewis lung carcinoma (LLC). AT remodelling was not found in LLC tumor-bearing (TB) TLR4(-/-) mice due to reduced macrophage infiltration and adipocyte atrophy. TLR4(-/-) mice were also resistant to cold-induced browning of subcutaneous AT (scAT). Importantly, pharmacological inhibition of TLR4 (Atorvastatin) reproduced the main protective effect against AT remodeling found in TLR4(-/-) TB mice. Moreover, the treatment was effective in prolonging survival and attenuating tumor mass growth when compared to non-treated-TB animals. Furthermore, tumor-induced elevation of circulating pro-inflammatory cytokines was similarly abolished in both genetic ablation and pharmacological inhibition of TLR4. These data suggest that TLR4 is a critical mediator and a promising target for novel anti-cachexia therapies.
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Copyright © The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Sci Rep. 2018 Dec 21;8(1):18024. doi: 10.1038/s41598-018-36626-3. Link to article on publisher's site
Henriques, Felipe; Lopes, Magno A.; Franco, Felipe O.; Knobl, Pamela; Santos, Kaltinaitis B.; Bueno, Luana L.; Correa, Victor A.; Bedard, Alexander H.; Guilherme, Adilson L.; Birbrair, Alexander; Peres, Sidney B.; Farmer, Stephen R.; and Batista, Miguel L. Jr., "Toll-Like Receptor-4 Disruption Suppresses Adipose Tissue Remodeling and Increases Survival in Cancer Cachexia Syndrome" (2018). Open Access Articles. 3694.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Biochemical Phenomena, Metabolism, and Nutrition Commons, Cellular and Molecular Physiology Commons, Genetic Phenomena Commons, Neoplasms Commons, Nutritional and Metabolic Diseases Commons, Pathological Conditions, Signs and Symptoms Commons, Pharmacology, Toxicology and Environmental Health Commons, Therapeutics Commons