Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway

BMC Cancer

Research Article

Miguel Luiz Batista Junior¹  Rodolfo Gonzalez Camargo²  Raquel Galvão Figuerêdo²  Katrin Radloff²  Michele Joana Alves²  Daniela Mendes Riccardi²  Joanna Darck Carola Lima²  Emidio Matos-Neto²  Diego Alexandre Cavallaro³  Marília Seelaender⁴  Paulo Sérgio Martins De Alcântara⁵  Nelson Inácio Pinto Neto⁶  José Pinhata Otoch⁷  Flavia Figueiredo Azevedo⁸ 

[1] Biotechnology Group, Laboratory of Adipose Tissue Biology, University of Mogi das Cruzes, Mogi das Cruzes, Brazil;Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil;Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil;Department of Nutrition, Federal University of Sao Paulo, Sao Paulo, Brazil;Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil;Department of Surgery, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil;Department of Clinical Surgery, Hospital University, University of Sao Paulo, Sao Paulo, Brazil;Department of Nutrition, Federal University of Sao Paulo, Sao Paulo, Brazil;Department of Surgery, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil;Department of Clinical Surgery, Hospital University, University of Sao Paulo, Sao Paulo, Brazil;Faculty of Nursing, University of Campinas, Campinas, Brazil;

关键词: Cancer cachexia;    Fibrosis;    Adipose tissue;    Extracellular matrix;    TGFβ;   

DOI  :  10.1186/s12885-017-3178-8

 received in 2016-11-01, accepted in 2017-03-08,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundCancer cachexia is a multifactorial syndrome that dramatically decreases survival. Loss of white adipose tissue (WAT) is one of the key characteristics of cachexia. WAT wasting is paralleled by microarchitectural remodeling in cachectic cancer patients. Fibrosis results from uncontrolled ECM synthesis, a process in which, transforming growth factor-beta (TGFβ) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGFβ in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGFβ pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients.MethodsAfter signing the informed consent form, patients were enrolled into the following groups: cancer cachexia (CC, n = 21), weight-stable cancer (WSC, n = 17), and control (n = 21). The total amount of collagen and elastic fibers in the subcutaneous AT was assessed by histological analysis and by immunohistochemistry. TGFβ isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (αSMA), fibroblast-specific protein (FSP1), Smad3 and 4 were quantified by qPCR and/or by immunohistochemistry. Interleukin (IL) 2, IL5, IL8, IL13 and IL17 content, cytokines known to be associated with fibrosis, was measured by Multiplex assay.ResultsThere was an accumulation of collagen and elastic fibers in the AT of CC, as compared with WSC and controls. Collagens type I, III, VI, and fibronectin expression was enhanced in the tissue of CC, compared with both WSC and control. The pronounced expression of αSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts; particularly in CC. TGFβ1 and TGFβ3 levels were up-regulated by cachexia in AT, as well in the isolated adipocytes. Smad3 and Smad4 labeling was found to be more evident in the fibrotic areas of CC adipose tissue.ConclusionsCancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.

【 授权许可】

CC BY   
© The Author(s). 2017