PAULO SERGIO MARTINS DE ALCANTARA
Projetos de Pesquisa
Unidades Organizacionais
DVCLCIR-62, Hospital Universitário
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina
4 resultados
Resultados de Busca
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- Tumour-derived transforming growth factor-beta signalling contributes to fibrosis in patients with cancer cachexia(2019) 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.; FELIPE-SILVA, Aloisio S.; TOKESHI, Flavio; OTOCH, Jose P.; ALCANTARA, Paulo; CABRAL, Fernanda J.; FERRO, Emer S.; LAVIANO, Alessandro; SEELAENDER, MariliaBackground 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.
- Myokines in treatment-na & iuml;ve patients with cancer-associated cachexia(2021) CASTRO, Gabriela S. de; CORREIA-LIMA, Joanna; SIMOES, Estefania; ORSSO, Camila E.; XIAO, Jingjie; GAMA, Leonardo R.; GOMES, Silvio P.; GONCALVES, Daniela Caetano; COSTA, Raquel G. F.; RADLOFF, Katrin; LENZ, Ulrike; TARANKO, Anna E.; BIN, Fang Chia; FORMIGA, Fernanda B.; GODOY, Louisie G. L. de; SOUZA, Rafael P. de; NUCCI, Luis H. A.; FEITOZA, Mario; CASTRO, Claudio C. de; TOKESHI, Flavio; ALCANTARA, Paulo S. M.; OTOCH, Jose P.; RAMOS, Alexandre F.; LAVIANO, Alessandro; COLETTI, Dario; MAZURAK, Vera C.; PRADO, Carla M.; SEELAENDER, MariliaCancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-na & iuml;ve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways. (c) 2020 The Author(s).
- Plasma Lipid Profile and Systemic Inflammation in Patients With Cancer Cachexia(2020) RICCARDI, Daniela Mendes dos Reis; NEVES, Rodrigo Xavier das; MATOS-NETO, Emidio Marques de; CAMARGO, Rodolfo Gonzalez; LIMA, Joanna Darck Carola Correia; RADLOFF, Katrin; ALVES, Michele Joana; COSTA, Raquel Galvao Figueredo; TOKESHI, Flavio; OTOCH, Jose Pinhata; MAXIMIANO, Linda Ferreira; ALCANTARA, Paulo Sergio Martins de; COLQUHOUN, Alison; LAVIANO, Alessandro; SEELAENDER, MariliaCancer cachexia affects about 80% of advanced cancer patients, it is linked to poor prognosis and to date, there is no efficient treatment or cure. The syndrome leads to progressive involuntary loss of muscle and fat mass induced by systemic inflammatory processes. The role of the white adipose tissue (WAT) in the onset and manifestation of cancer cachexia gained importance during the last decade. WAT wasting is not only characterized by increased lipolysis and release of free fatty acids (FFA), but in addition, owing to its high capacity to produce a variety of inflammatory factors. The aim of this study was to characterize plasma lipid profile of cachectic patients and to correlate the FA composition with circulating inflammatory markers; finally, we sought to establish whether the fatty acids released by adipocytes trigger and/or contribute to local and systemic inflammation in cachexia. The study selected 65 patients further divided into 3 groups: control (N); weight stable cancer (WSC); and cachectic cancer (CC). The plasma FA profile was significantly different among the groups and was positively correlated with pro-inflammatory cytokines expression in the CC patients. Therefore, we propose that saturated to unsaturated FFA ratio may serve as a means of detecting cachexia.
- Cancer cachexia induces morphological and inflammatory changes in the intestinal mucosa(2019) COSTA, Raquel G. F.; CARO, Paula L.; MATOS-NETO, Emidio M. de; LIMA, Joanna D. C. C.; RADLOFF, Katrin; ALVES, Michele J.; CAMARGO, Rodolfo G.; PESSOA, Ana Flavia M.; SIMOES, Estefania; GAMA, Patricia; CARA, Denise C.; SILVA, Aloisio S. F. da; PEREIRA, Welbert O.; MAXIMIANO, Linda F.; ALCANTARA, Paulo S. M. de; OTOCH, Jose P.; TRINCHIERI, Giorgio; LAVIANO, Alessandro; MUSCARITOLI, Maurizio; SEELAENDER, MariliaBackground Cachexia is a multifactorial and multiorgan syndrome associated with cancer and other chronic diseases and characterized by severe involuntary body weight loss, disrupted metabolism, inflammation, anorexia, fatigue, and diminished quality of life. This syndrome affects around 50% of patients with colon cancer and is directly responsible for the death of at least 20% of all cancer patients. Systemic inflammation has been recently proposed to underline most of cachexia-related symptoms. Nevertheless, the exact mechanisms leading to the initiation of systemic inflammation have not yet been unveiled, as patients bearing the same tumour and disease stage may or may not present cachexia. We hypothesize a role for gut barrier disruption, which may elicit persistent immune activation in the host. To address this hypothesis, we analysed the healthy colon tissue, adjacent to the tumour. Methods Blood and rectosigmoid colon samples (20 cm distal to tumour margin) obtained during surgery, from cachectic (CC = 25) or weight stable (WSC = 20) colon cancer patients, who signed the informed consent form, were submitted to morphological (light microscopy), immunological (immunohistochemistry and flow cytometry), and molecular (quantification of inflammatory factors by Luminex (R) xMAP) analyses. Results There was no statistical difference in gender and age between groups. The content of plasma interleukin 6 (IL-6) and IL-8 was augmented in cachectic patients relative to those with stable weight (P = 0.047 and P = 0.009, respectively). The number of lymphocytic aggregates/field in the gut mucosa was higher in CC than in WSC (P = 0.019), in addition to those of the lamina propria (LP) eosinophils (P < 0.001) and fibroblasts (P < 0.001). The area occupied by goblet cells in the colon mucosa was decreased in CC (P = 0.016). The M1M2 macrophages percentage was increased in the colon of CC, in relation to WSC (P = 0.042). Protein expression of IL-7, IL-13, and transforming growth factor beta 3 in the colon was significantly increased in CC, compared with WSC (P = 0.02, P = 0.048, and P = 0.048, respectively), and a trend towards a higher content of granulocyte-colony stimulating factor in CC was also observed (P = 0.061). The results suggest an increased recruitment of immune cells to the colonic mucosa in CC, as compared with WSC, in a fashion that resembles repair response following injury, with higher tissue content of IL-13 and transforming growth factor beta 3. Conclusions The changes in the intestinal mucosa cellularity, along with modified cytokine expression in cachexia, indicate that gut barrier alterations are associated with the syndrome.