JOSE PINHATA OTOCH
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cirurgia, Faculdade de Medicina - Docente
DVCLCIR-62, Hospital Universitário
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
DVCLCIR-62, Hospital Universitário
LIM/26 - Laboratório de Pesquisa em Cirurgia Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
5 resultados
Resultados de Busca
Agora exibindo 1 - 5 de 5
- 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.
- High levels of modified ceramides are a defining feature of murine and human cancer cachexia(2020) MORIGNY, Pauline; ZUBER, Julia; HAID, Mark; KALTENECKER, Doris; RIOLS, Fabien; LIMA, Joanna D. C.; SIMOES, Estefania; OTOCH, Jose Pinhata; SCHMIDT, Soeren Fisker; HERZIG, Stephan; ADAMSKI, Jerzy; SEELAENDER, Marilia; DIAZ, Mauricio Berriel; ROHM, MariaBackground Cancer cachexia (CCx) is a multifactorial energy-wasting syndrome reducing the efficiency of anti-cancer therapies, quality of life, and survival of cancer patients. In the past years, most studies focused on the identification of tumour and host-derived proteins contributing to CCx. However, there is still a lack of studies addressing the changes in bioactive lipids. The aim of this study was to identify specific lipid species as a hallmark of CCx by performing a broad range lipid analysis of plasma from well-established CCx mouse models as well as cachectic and weight stable cancer patients. Methods Plasma from non-cachectic (PBS-injected mice, NC26 tumour-bearing mice), pre-cachectic and cachectic mice (C26 and LLC tumour-bearing mice, Apc(Min/+)mutant mice), and plasma from weight stable and cachectic patients with gastrointestinal cancer, were analysed using the Lipidyzer (TM) platform. In total, 13 lipid classes and more than 1100 lipid species, including sphingolipids, neutral and polar glycerolipids, were covered by the analysis. Correlation analysis between specific lipid species and readouts of CCx were performed. Lipidomics data were confirmed by gene expression analysis of metabolic organs to analyse enzymes involved in sphingolipid synthesis and degradation. Results A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl-ceramides (HCERs) and lactosyl-ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumour tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in CCx. LPC(16:1), LPC(20:3), SM(16:0), SM(24:1), CER(16:0), CER(24:1), HCER(16:0), and HCER(24:1) were the most consistently affected lipid species between mice and humans and correlated negatively (LPCs) or positively (SMs, CERs and HCERs) with the severity of body weight loss. Conclusions High levels of sphingolipids, specifically ceramides and modified ceramides, are a defining feature of murine and human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the inhibition of anabolic signals. The progressive increase in sphingolipids during cachexia development supports their potential as early biomarkers for CCx.
- Peritumoural adipose tissue pro-inflammatory cytokines are associated with tumoural growth factors in cancer cachexia patients(2018) PINTO NETO, Nelson Inacio; MURARI, Ariene Soares de Pinho; OYAMA, Lila Missae; OTOCH, Jose Pinhata; ALCANTARA, Paulo Sergio Martins; TOKESHI, Flavio; FIGUEREDO, Raquel Galvao; ALVES, Michele Joana; LIMA, Joanna Darck Carola Correia; MATOS-NETO, Emidio Marques de; SEELAENDER, Marilia; NASCIMENTO, Claudia Maria Oller doBackground Cancer cachexia (CC) is a multifactorial syndrome, often irreversible, that affects patients with cancer influenced, in part, by the inflammatory condition. Peritumoural adipose tissue produces adipokines and angiogenic, apoptotic, and growth factors; given the possible crosstalk between the peritumoural adipose tissue and tumour, these may play an important role in cancer biology and carcinogenesis. Methods Results The aim of this study was to evaluate the factors produced by peritumoural adipose tissue in a cohort of 16 colorectal cancer patients with either weight-stable cancer (WSC; n = 7) or CC (n = 9). The study was approved by the Ethics Research Committee (972.914). Samples of peritumoural adipose tissue were analysed for concentrations of TNF-alpha, IL-1 beta, STAT-1, STAT-3, RANTES, IL-1Ra, IP-10, IL-15, MCP-1, IFN-alpha, GCSF, FADD, and TGF-beta. The cytokines and proteins were measured using Multiplex. Correlations between the proteins and cytokines were evaluated. TNF-alpha, STAT-1, and FADD, a factor involved in apoptosis, were significantly higher in CC group than in the WSC group. In the peritumoural adipose tissue of the CC group, RANTES showed a significant positive correlation with IL-1Ra and IP-10 and a negative correlation with IFN-alpha; and GCSF showed significant negative correlations with IL-1Ra, IP-10, IL-15, and MCP-1 and a positive correlation with IFN-alpha. In the peritumoural adipose tissue of the WSC group, no significant correlations were detected between RANTES, GCSF, IL-3, FADD, and STAT-1 and the cytokines/chemokines analysed. Conclusions These results indicated that inflammatory and tumorigenic pathways were altered in peritumoural adipose tissue in CC. Furthermore, inflammatory cytokines were correlated with growth factors in the peritumoural adipose tissue of cachectic patients, suggesting that inflammatory cytokines modulated the proliferative environment closely linked to the tumour.
- Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients(2016) BATISTA JR., Miguel L.; HENRIQUES, Felipe S.; NEVES, Rodrigo X.; OLIVAN, Mireia R.; MATOS-NETO, Emidio M.; ALCANTARA, Paulo S. M.; MAXIMIANO, Linda F.; OTOCH, Jose P.; ALVES, Michele J.; SEELAENDER, MariliaBackground and aimsCachexia is a syndrome characterized by marked involuntary loss of body weight. Recently, adipose tissue (AT) wasting has been shown to occur before the appearance of other classical cachexia markers. We investigated the composition and rearrangement of the extracellular matrix, adipocyte morphology and inflammation in the subcutaneous AT (scAT) pad of gastrointestinal cancer patients. MethodsSurgical biopsies for scAT were obtained from gastrointestinal cancer patients, who were signed up into the following groups: cancer cachexia (CC, n=11), weight-stable cancer (WSC, n=9) and weight-stable control (non-cancer) (control, n=7). The stable weight groups were considered as those with no important weight change during the last year and body mass index <25kg/m(2). Subcutaneous AT fibrosis was quantified and characterized by quantitative PCR, histological analysis and immunohistochemistry. ResultsThe degree of fibrosis and the distribution and collagen types (I and III) were different in WSC and CC patients. CC patients showed more pronounced fibrosis in comparison with WSC. Infiltrating macrophages surrounding adipocytes and CD3 Ly were found in the fibrotic areas of scAT. Subcutaneous AT fibrotic areas demonstrated increased monocyte chemotactic protein 1 (MCP-1) and Cluster of Differentiation (CD)68 gene expression in cancer patients. ConclusionsOur data indicate architectural modification consisting of fibrosis and inflammatory cell infiltration in scAT as induced by cachexia in gastrointestinal cancer patients. The latter was characterized by the presence of macrophages and lymphocytes, more evident in the fibrotic areas. In addition, increased MCP-1 and CD68 gene expression in scAT from cancer patients may indicate an important role of these markers in the early phases of cancer.
- 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.