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

Imagem de Miniatura
Arquivos
art_ALVES_Adipose_tissue_fibrosis_in_human_cancer_cachexia_the_2017.PDF (7.15 MB)
Citações na Scopus
51
Tipo de produção
article
Data de publicação
2017
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
BIOMED CENTRAL LTD
Autores
ALVES, Michele Joana
FIGUEREDO, Raquel Galvao
AZEVEDO, Flavia Figueiredo
CAVALLARO, Diego Alexandre
PINTO NETO, Nelson Inacio
LIMA, Joanna Darck Carola
MATOS-NETO, Emidio
RADLOFF, Katrin
RICCARDI, Daniela Mendes
CAMARGO, Rodolfo Gonzalez
Citação
BMC CANCER, v.17, article ID 190, 12p, 2017
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
Palavras-chave
Cancer cachexia, Fibrosis, Adipose tissue, Extracellular matrix, TGF beta
URI
https://observatorio.fm.usp.br/handle/OPI/19884
Referências
  1. Alessi MC, 2000, DIABETES, V49, P1374, DOI 10.2337/diabetes.49.8.1374
  2. Ali AT, 2013, EUR J CELL BIOL, V92, P229, DOI 10.1016/j.ejcb.2013.06.001
  3. Argiles JM, 2015, MEDIAT INFLAMM, DOI 10.1155/2015/182872
  4. Argiles JM, 2014, NAT REV CANCER, V14, P754, DOI 10.1038/nrc3829
  5. Batista ML, 2013, CYTOKINE, V61, P532, DOI 10.1016/j.cyto.2012.10.023
  6. Batista ML, 2012, CYTOKINE, V57, P9, DOI 10.1016/j.cyto.2011.10.008
  7. Batista ML, 2016, J CACHEXIA SARCOPENI, V7, P37, DOI 10.1002/jcsm.12037
  8. Bing C, 2006, BRIT J CANCER, V95, P1028, DOI 10.1038/sj.sjc.6603360
  9. Borthwick LA, 2016, MUCOSAL IMMUNOL, V9, P38, DOI 10.1038/mi.2015.34
  10. Brenner David A, 2012, Fibrogenesis Tissue Repair, V5, pS17, DOI 10.1186/1755-1536-5-S1-S17
  11. Camargo RG, 2015, NUTRIENTS, V7, P4465, DOI 10.3390/nu7064465
  12. CHU ML, 1988, J BIOL CHEM, V263, P18601
  13. Dahlman I, 2010, BRIT J CANCER, V102, P1541, DOI 10.1038/sj.bjc.6605665
  14. David CJ, 2016, CELL, V164, P1015, DOI [10.1016/j.cell.2016.01.009, 10.1016/j.cell.2016.05.032]
  15. Divoux A, 2011, OBES REV, V12, pe494, DOI 10.1111/j.1467-789X.2010.00811.x
  16. Ebadi M, 2015, MEDIAT INFLAMM, DOI 10.1155/2015/820934
  17. Evans WJ, 2008, CLIN NUTR, V27, P793, DOI 10.1016/j.clnu.2008.06.013
  18. Fain JN, 2005, METABOLISM, V54, P1546, DOI 10.1016/j.metabol.2005.05.024
  19. Fearon K, 2011, LANCET ONCOL, V12, P489, DOI [10.1016/S1470-2045(10)70218-7, 10.1016/51470-2045(10)70218-7]
  20. Flanders KC, 2004, INT J EXP PATHOL, V85, P47, DOI 10.1111/j.0959-9673.2004.00377.x
  21. Gioulbasanis I, 2012, NUTR CANCER, V64, P41, DOI 10.1080/01635581.2012.630157
  22. Hara Y, 2011, SCI SIGNAL, V4, DOI 10.1126/scisignal.2001227
  23. Harris WT, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0070196
  24. Hinz B, 2015, MATRIX BIOL, V47, P54, DOI 10.1016/j.matbio.2015.05.006
  25. Isailovic N, 2015, J AUTOIMMUN, V60, P1, DOI 10.1016/j.jaut.2015.04.006
  26. Jensen Jorgen, 2011, Archives of Physiology and Biochemistry, V117, P45, DOI 10.3109/13813455.2010.547862
  27. Khan T, 2009, MOL CELL BIOL, V29, P1575, DOI 10.1128/MCB.01300-08
  28. Leask A, 2004, FASEB J, V18, P816, DOI 10.1096/fj.03-1273rev
  29. Letilovic T, 2013, EUR J CLIN NUTR, V67, P797, DOI 10.1038/ejcn.2013.121
  30. Lok C, 2015, NATURE, V528, P182, DOI 10.1038/528182a
  31. Macias MJ, 2015, TRENDS BIOCHEM SCI, V40, P296, DOI 10.1016/j.tibs.2015.03.012
  32. Mariman ECM, 2010, CELL MOL LIFE SCI, V67, P1277, DOI 10.1007/s00018-010-0263-4
  33. Massague J, 2000, EMBO J, V19, P1745, DOI 10.1093/emboj/19.8.1745
  34. Massague J, 2000, NAT REV MOL CELL BIO, V1, P169, DOI 10.1038/35043051
  35. Massague J, 2000, GENE DEV, V14, P627
  36. Massague J, 2012, NAT REV MOL CELL BIO, V13, P616, DOI 10.1038/nrm3434
  37. Muscaritoli M, 2011, INTERN EMERG MED, V6, P105, DOI 10.1007/s11739-010-0426-1
  38. Nakajima I, 1998, DIFFERENTIATION, V63, P193, DOI 10.1111/j.1432-0436.1998.00193.x
  39. Nakayama Y, 2009, BIOCHEM BIOPH RES CO, V379, P288, DOI 10.1016/j.bbrc.2008.12.040
  40. Ouchi N, 2011, NAT REV IMMUNOL, V11, P85, DOI 10.1038/nri2921
  41. Pasarica M, 2009, J CLIN ENDOCR METAB, V94, P5155, DOI 10.1210/jc.2009-0947
  42. Pond CM, 2005, PROSTAG LEUKOTR ESS, V73, P17, DOI 10.1016/j.plefa.2005.04.005
  43. Reiman RM, 2006, INFECT IMMUN, V74, P1471, DOI 10.1128/IAI.74.3.1471-1479.2006
  44. Rockey DC, 2013, PLOS ONE, V8, DOI 10.1371/journal.pone.0077166
  45. RODBELL M, 1964, J BIOL CHEM, V239, P375
  46. Samad F, 1999, P NATL ACAD SCI USA, V96, P6902, DOI 10.1073/pnas.96.12.6902
  47. Shi YG, 2003, CELL, V113, P685, DOI 10.1016/S0092-8674(03)00432-X
  48. Singh P, 2010, ANNU REV CELL DEV BI, V26, P397, DOI 10.1146/annurev-cellbio-100109-104020
  49. Spencer M, 2010, AM J PHYSIOL-ENDOC M, V299, pE1016, DOI 10.1152/ajpendo.00329.2010
  50. Sutherland TE, 2014, NAT IMMUNOL, V15, P1116, DOI 10.1038/ni.3023
  51. Taleb S, 2006, ENDOCRINOLOGY, V147, P4950, DOI 10.1210/en.2006-0386
  52. Tisdale MJ, 2010, CURR OPIN GASTROEN, V26, P146, DOI 10.1097/MOG.0b013e3283347e77
  53. Trayhurn P, 2007, OBES REV, V8, P41, DOI 10.1111/j.1467-789X.2007.00316.x
  54. Tsoli M, 2013, TRENDS ENDOCRIN MET, V24, P174, DOI 10.1016/j.tem.2012.10.006
  55. Tsurutani Y, 2011, BIOCHEM BIOPH RES CO, V407, P68, DOI 10.1016/j.bbrc.2011.02.106
  56. Ueha S, 2012, FRONT IMMUNOL, V3, DOI 10.3389/fimmu.2012.00071
  57. van der Velden JLJ, 2012, AM J RESP CELL MOL, V47, P306, DOI 10.1165/rcmb.2011-0297OC
  58. Wynn TA, 2008, J PATHOL, V214, P199, DOI 10.1002/path.2277
  59. Wynn TA, 2003, ANNU REV IMMUNOL, V21, P425, DOI 10.1146/annurev.immunol.21.120601.141142
  60. Wynn TA, 2007, J CLIN INVEST, V117, P524, DOI 10.1172/JCI31487
  61. Wynn TA, 2016, IMMUNITY, V44, P450, DOI 10.1016/j.immuni.2016.02.015
  62. Wynn TA, 2012, NAT MED, V18, P1028, DOI 10.1038/nm.2807
  63. Zhang YE, 2017, CSH PERSPECT BIOL, V9, DOI 10.1101/cshperspect.a022129
  64. Ziora D, 2015, BMC PULM MED, V15, DOI 10.1186/s12890-015-0110-3

Coleções
Artigos e Materiais de Revistas Científicas - FM/MCG
Artigos e Materiais de Revistas Científicas - HU
Artigos e Materiais de Revistas Científicas - LIM/26
Artigos e Materiais de Revistas Científicas - ODS/03