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

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Lima, Joanna D. C. C. ^[1] ; Simoes, Estefania ^[1] ; de Castro, Gabriela ^[1] ; Morais, Mychel Raony P. T. ^[1] ; de Matos-Neto, Emidio M. ^[2] ; Alves, Michele J. ^{[3, 1]} ; Pinto, I, Nelson ; Figueredo, Raquel G. ^[1] ; Zorn, Telma M. T. ^[1] ; Felipe-Silva, Aloisio S. ^[4] ; Tokeshi, Flavio ^[5] ; Otoch, Jose P. ^[5] ; Alcantara, Paulo ^[5] ; Cabral, Fernanda J. ^[6] ; Ferro, Emer S. ^[7] ; Laviano, Alessandro ^[8] ; Seelaender, Marilia ^{[5, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Canc Metab Res Grp, Av Prof Lineu Prestes, 1524 4th Floor Room, BR-05529000 Butanta, SP - Brazil

^[2] Fed Univ Piau, Dept Phys Educ, Piau - Brazil

^[3] Ohio State Univ, Dept Pathol, Columbus, OH 43210 - USA

^[4] Univ Sao Paulo, Serv Pathol Anat, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Dept Clin Surg, Sao Paulo - Brazil

^[6] Univ Estadual Campinas, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[8] Sapienza Univ Rome, Dept Clin Med, Rome - Italy

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE; v. 10, n. 5, p. 1045-1059, OCT 2019.
• Citações Web of Science: 0

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. (AU)

• Processo FAPESP: 16/04000-3 - Farmacologia de oligopeptidases e peptídeos intracelulares
• Beneficiário: Emer Suavinho Ferro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/50079-0 - Inflamação sistêmica em pacientes com caquexia associada ao câncer: mecanismos e estratégias terapêuticas, uma abordagem em medicina translacional
• Beneficiário: Marilia Cerqueira Leite Seelaender
• Modalidade de apoio: Auxílio à Pesquisa - Temático