Tumour-derived transforming growth factor-beta signalling contributes to fibrosis in patients with cancer cachexia

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art_LIMA_Tumourderived_transforming_growth_factorbeta_signalling_contributes_to_fibrosis_2019.PDF (1.48 MB)
Citações na Scopus
43
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
WILEY
Autores
LIMA, Joanna D. C. C.
SIMOES, Estefania
CASTRO, Gabriela de
MORAIS, Mychel Raony P. T.
MATOS-NETO, Emidio M. de
ALVES, Michele J.
I, Nelson Pinto
FIGUEREDO, Raquel G.
ZORN, Telma M. T.
Citação
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v.10, n.5, p.1045-1059, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Background Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro-environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro-environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. Methods 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. Results Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte-macrophage colony-stimulating factor, interferon-alpha, and interleukin (IL)-8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight-stable counterparts. Also, IL-8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of alpha-smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)-beta 1, TGF-beta 2, and TGF-beta 3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen-activated protein kinase alteration. Hypoxia-inducible factor-1 alpha mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight-stable group (P = 0.005). Conclusions Our results demonstrate TGF-beta pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF-beta-induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.
Palavras-chave
Tumour micro-environment, Cachexia, Epithelial-mesenchymal components, Fibrosis
URI
https://observatorio.fm.usp.br/handle/OPI/34541
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MPT
Artigos e Materiais de Revistas Científicas - FM/MCG
Artigos e Materiais de Revistas Científicas - HU
Artigos e Materiais de Revistas Científicas - LIM/14
Artigos e Materiais de Revistas Científicas - LIM/26
Artigos e Materiais de Revistas Científicas - ODS/03