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

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

Author Alves, Michele Joana Google Scholar
Figueredo, Raquel Galvao Google Scholar
Azevedo, Flavia Figueiredo Google Scholar
Cavallaro, Diego Alexandre Autor UNIFESP Google Scholar
Pinto Neto, Nelson Inacio Autor UNIFESP Google Scholar
Carola Lima, Joanna Darck Google Scholar
Matos-Neto, Emidio Google Scholar
Radloff, Katrin Google Scholar
Riccardi, Daniela Mendes Google Scholar
Camargo, Rodolfo Gonzalez Google Scholar
Martins De Alcantara, Paulo Sergio Google Scholar
Otoch, Jose Pinhata Google Scholar
Batista Junior, Miguel Luiz Google Scholar
Seelaender, Marilia Google Scholar
Abstract Background: Cancer 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 (TGF beta) plays a pivotal role. So far, the mechanisms involved in adipose tissue (AT) re-arrangement, and the role of TGF beta in inducing AT remodeling in weight-losing cancer patients are poorly understood. This study examined the modulation of ECM components mediated by TGF beta pathway in fibrotic AT obtained from cachectic gastrointestinal cancer patients. Methods: After 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. TGF beta isoforms expression was analyzed by Multiplex assay and by immunohistochemistry. Alpha-smooth muscle actin (aSMA), 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. Results: There 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 aSMA in the surrounding of adipocytes, and the increased mRNA content for FSP1 (20-fold) indicate the presence of activated myofibroblasts

particularly in CC. TGF beta 1 and TGF beta 3 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. Conclusions: Cancer cachexia promotes the development of AT fibrosis, in association with altered TGF beta signaling, compromising AT organization and function.
Keywords Cancer cachexia
Adipose tissue
Extracellular matrix
TGF beta
xmlui.dri2xhtml.METS-1.0.item-coverage London
Language English
Sponsor Sao Paulo Research Foundation (FAPESP)
Grant number FAPESP: 2012/50079-0
Date 2017
Published in Bmc Cancer. London, v. 17, p. -, 2017.
ISSN 1471-2407 (Sherpa/Romeo, impact factor)
Publisher Biomed Central Ltd
Extent -
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000397775800004

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