title: Adipose tissue fibrosis in human cancer cachexia: the role of TGFβ pathway.
abstract: 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 (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.
  
  
  
  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. 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.
  
  
  
  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 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.
  
  
  
  Cancer cachexia promotes the development of AT fibrosis, in association with altered TGFβ signaling, compromising AT organization and function.
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil. michelejalves@usp.br.
authors.forename: Michele Joana
authors.identifier: 0000-0003-0773-7470
authors.initials: MJ
authors.lastname: Alves
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Raquel Galvão
authors.initials: RG
authors.lastname: Figuerêdo
authors.affiliation: Faculty of Nursing, University of Campinas, Campinas, Brazil.
authors.forename: Flavia Figueiredo
authors.initials: FF
authors.lastname: Azevedo
authors.affiliation: 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.
authors.forename: Diego Alexandre
authors.initials: DA
authors.lastname: Cavallaro
authors.affiliation: Department of Nutrition, Federal University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Nelson Inácio Pinto
authors.initials: NI
authors.lastname: Neto
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Joanna Darck Carola
authors.initials: JD
authors.lastname: Lima
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Emidio
authors.initials: E
authors.lastname: Matos-Neto
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Katrin
authors.initials: K
authors.lastname: Radloff
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Daniela Mendes
authors.initials: DM
authors.lastname: Riccardi
authors.affiliation: Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Rodolfo Gonzalez
authors.initials: RG
authors.lastname: Camargo
authors.affiliation: Department of Clinical Surgery, Hospital University, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Paulo Sérgio Martins
authors.initials: PS
authors.lastname: De Alcântara
authors.affiliation: 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.
authors.forename: José Pinhata
authors.initials: JP
authors.lastname: Otoch
authors.affiliation: Biotechnology Group, Laboratory of Adipose Tissue Biology, University of Mogi das Cruzes, Mogi das Cruzes, Brazil.
authors.forename: Miguel Luiz Batista
authors.initials: ML
authors.lastname: Junior
authors.affiliation: 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.
authors.forename: Marília
authors.initials: M
authors.lastname: Seelaender
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000473:pathology*; D000328:Adult; D000368:Aged; D002100:Cachexia / Q000150:complications / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000150:complications; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D002135:Calcium-Binding Proteins; D020033:Protein Isoforms; D000071999:S100 Calcium-Binding Protein A4; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C077591:S100A4 protein, human
keywords: Adipose tissue; Cancer cachexia; Extracellular matrix; Fibrosis; TGFβ