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

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorALVES, Michele Joana
dc.contributor.authorFIGUEREDO, Raquel Galvao
dc.contributor.authorAZEVEDO, Flavia Figueiredo
dc.contributor.authorCAVALLARO, Diego Alexandre
dc.contributor.authorPINTO NETO, Nelson Inacio
dc.contributor.authorLIMA, Joanna Darck Carola
dc.contributor.authorMATOS-NETO, Emidio
dc.contributor.authorRADLOFF, Katrin
dc.contributor.authorRICCARDI, Daniela Mendes
dc.contributor.authorCAMARGO, Rodolfo Gonzalez
dc.contributor.authorALCANTARA, Paulo Sergio Martins De
dc.contributor.authorOTOCH, Jose Pinhata
dc.contributor.authorBATISTA JUNIOR, Miguel Luiz
dc.contributor.authorSEELAENDER, Marilia
dc.date.accessioned2017-06-09T15:17:16Z
dc.date.available2017-06-09T15:17:16Z
dc.date.issued2017
dc.description.abstractBackground: 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.
dc.description.indexMEDLINE
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP) [2012/50079-0]
dc.description.sponsorshipCAPES
dc.identifier.citationBMC CANCER, v.17, article ID 190, 12p, 2017
dc.identifier.doi10.1186/s12885-017-3178-8
dc.identifier.issn1471-2407
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/19884
dc.language.isoeng
dc.publisherBIOMED CENTRAL LTD
dc.relation.ispartofBMC Cancer
dc.rightsopenAccess
dc.rights.holderCopyright BIOMED CENTRAL LTD
dc.subjectCancer cachexia
dc.subjectFibrosis
dc.subjectAdipose tissue
dc.subjectExtracellular matrix
dc.subjectTGF beta
dc.subject.otherplasminogen-activator inhibitor-1
dc.subject.otherextracellular-matrix
dc.subject.othermolecular-mechanisms
dc.subject.otherchronic inflammation
dc.subject.otherfibrotic response
dc.subject.otherobesity
dc.subject.othermacrophages
dc.subject.otheradipocytes
dc.subject.otherexpression
dc.subject.othercells
dc.subject.wosOncology
dc.titleAdipose tissue fibrosis in human cancer cachexia: the role of TGF beta pathway
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.author.externalALVES, Michele Joana:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil
hcfmusp.author.externalFIGUEREDO, Raquel Galvao:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil
hcfmusp.author.externalAZEVEDO, Flavia Figueiredo:Univ Estadual Campinas, Fac Nursing, Campinas, Brazil
hcfmusp.author.externalCAVALLARO, Diego Alexandre:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil; Univ Fed Sao Paulo, Dept Nutr, Sao Paulo, Brazil
hcfmusp.author.externalPINTO NETO, Nelson Inacio:Univ Fed Sao Paulo, Dept Nutr, Sao Paulo, Brazil
hcfmusp.author.externalLIMA, Joanna Darck Carola:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil
hcfmusp.author.externalMATOS-NETO, Emidio:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil
hcfmusp.author.externalRADLOFF, Katrin:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil
hcfmusp.author.externalCAMARGO, Rodolfo Gonzalez:Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Sao Paulo, Brazil
hcfmusp.author.externalBATISTA JUNIOR, Miguel Luiz:Univ Mogi das Cruzes, Biotechnol Grp, Lab Adipose Tissue Biol, Mogi Das Cruzes, Brazil
hcfmusp.citation.scopus53
hcfmusp.contributor.author-fmusphcPAULO SERGIO MARTINS DE ALCANTARA
hcfmusp.contributor.author-fmusphcJOSE PINHATA OTOCH
hcfmusp.contributor.author-fmusphcMARILIA CERQUEIRA LEITE SEELAENDER
hcfmusp.description.articlenumber190
hcfmusp.description.volume17
hcfmusp.origemWOS
hcfmusp.origem.pubmed28288584
hcfmusp.origem.scopus2-s2.0-85014879834
hcfmusp.origem.wosWOS:000397775800004
hcfmusp.publisher.cityLONDON
hcfmusp.publisher.countryENGLAND
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