RESUMO
BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.
Assuntos
Proteínas ADAM/genética , Adenocarcinoma/genética , Proteína C-Reativa/metabolismo , Neoplasias Esofágicas/genética , Metaloproteinases da Matriz/genética , Neoplasias Gástricas/genética , Inibidores Teciduais de Metaloproteinases/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC). METHODS: Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of > or =10 mg l(-1) or modified Glasgow prognostic score (mGPS) of > or =1), and nutritional status were assessed in newly diagnosed OGC patients (n=293). Healthy volunteers (n=35) served as controls. RESULTS: MIC-1 was elevated in patients (median=1371 pg ml(-1); range 141-39 053) when compared with controls (median=377 pg ml(-1); range 141-3786; P<0.001). Patients with gastric tumours (median=1592 pg ml(-1); range 141-12 643) showed higher MIC-1 concentrations than patients with junctional (median=1337 pg ml(-1); range 383-39 053) and oesophageal tumours (median=1180 pg ml(-1); range 258-31 184; P=0.015). Patients showed a median weight loss of 6.4% (range 0.0-33.4%), and 42% of patients had an mGPS of > or =1 or plasma CRP of > or =10 mg l(-1) (median=9 mg l(-1); range 1-200). MIC-1 correlated positively with disease stage (r(2)=0.217; P<0.001), age (r(2)=0.332; P<0.001), CRP (r(2)=0.314; P<0.001), and mGPS (r(2)=0.336; P<0.001), and negatively with Karnofsky Performance Score (r(2)=-0.269; P<0.001). However, although MIC-1 correlated weakly with dietary intake (r(2)=0.157; P=0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median=204 days; 95% CI 157-251) when compared with patients with MIC-1 levels in the lower three quartiles (median=316 days; 95% CI 259-373; P=0.036), but MIC-1 was not an independent prognostic indicator. CONCLUSIONS: There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.
Assuntos
Adenocarcinoma/mortalidade , Neoplasias Esofágicas/mortalidade , Fator 15 de Diferenciação de Crescimento/sangue , Inflamação/sangue , Estado Nutricional/fisiologia , Neoplasias Gástricas/mortalidade , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Análise de SobrevidaRESUMO
Although weight loss is often a dominant symptom in patients with upper gastrointestinal malignancy, there is a lack of objective evidence describing changes in nutritional status and potential associations between weight loss, food intake, markers of systemic inflammation and stage of disease in such patients. Two hundred and twenty patients diagnosed with gastric/oesophageal cancer were studied. Patients underwent nutritional assessment consisting of calculation of body mass index, measurement of weight loss, dysphagia scoring and estimation of dietary intake. Serum acute-phase protein concentrations were determined by enzyme-linked immunosorbent assay. In all, 182 (83%) patients had lost weight at diagnosis (median loss, 7% body weight). Weight loss was associated with poor performance status, advanced disease stage, dysphagia, reduced dietary intake and elevated serum C-reactive protein (CRP) concentrations. Multiple regression identified dietary intake (estimate of effect, 38%), serum CRP concentrations (estimate of effect, 34%) and stage of disease (estimate of effect, 28%) as independent variables in determining degree of weight loss. Mechanisms other than reduced dietary intake or mechanical obstruction by the tumour appear to be involved in the nutritional decline in patients with gastro-oesophageal malignancy. Recognition that systemic inflammation plays a role in nutritional depletion may inform the development of appropriate therapeutic strategies to ameliorate weight loss, making patients more tolerant of cancer-modifying treatments such as chemotherapy.
Assuntos
Neoplasias Esofágicas/metabolismo , Inflamação/metabolismo , Estado Nutricional , Neoplasias Gástricas/metabolismo , Redução de Peso , Proteínas de Fase Aguda/análise , Idoso , Transtornos de Deglutição/metabolismo , Ingestão de Alimentos , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologiaRESUMO
Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), gastric (20), pancreatic (five), bile duct (one) and prostatic (52) carcinomas as well as 30 benign tissue samples, for assessment of dermcidin mRNA levels using real-time PCR. Dermcidin expression was assessed in prostatic and pancreatic cancer cell lines, with and without induction of hypoxia or oxidative stress. Dermcidin mRNA expression was very low or absent in both unstressed and stressed prostate cell lines. None of the primary prostate tissue, benign or malignant, expressed dermcidin mRNA. Only two (4%) of the gastro-oesophageal cancer samples expressed moderate quantities of dermcidin mRNA. However, three (60%) of the pancreatic cancer samples and the single cholangiocarcinoma specimen had moderate/high levels of dermcidin expression. Of the two pancreatic cancer cell lines, one expressed dermcidin moderately but neither showed a response to hypoxia or oxidative stress. Expression of dermcidin in human primary tumours appears highly variable and is not induced substantially by hypoxia/oxidative stress in cell line model systems. The relationship of these findings to dermcidin protein levels and cell survival remains to be determined.
Assuntos
Neoplasias/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Hipóxia/fisiopatologia , Estresse Oxidativo/fisiologia , Peptídeos , Reação em Cadeia da Polimerase , RNA Mensageiro/biossínteseRESUMO
INTRODUCTION: Cancer cachexia is a severe debilitating disorder, which causes significant morbidity and mortality. In clinical practice, cachexia is often not treated until a late stage, when therapeutic options are limited. OBJECTIVE: It is therefore of great interest to analyse early biomarkers of this syndrome. CONCLUSION: In this review article, we summarise recent biomarkers found in various body compartments. We also explore the likelihood of a genetic predisposition to cachexia and focus on the potential role of single nucleotide polymorphisms in genes coding for pro- and anti-inflammatory cytokines, and 'atrogenes' associated with wasting in skeletal muscle.
Assuntos
Biomarcadores Tumorais/genética , Caquexia/genética , Neoplasias/complicações , Biomarcadores Tumorais/análise , Predisposição Genética para Doença , Genótipo , HumanosRESUMO
Previous studies suggest that the activation (autophosphorylation) of dsRNA-dependent protein kinase (PKR) can stimulate protein degradation, and depress protein synthesis in skeletal muscle through phosphorylation of the translation initiation factor 2 (eIF2) on the alpha-subunit. To understand whether these mediators are important in muscle wasting in cancer patients, levels of the phospho forms of PKR and eIF2alpha have been determined in rectus abdominus muscle of weight losing patients with oesophago-gastric cancer, in comparison with healthy controls. Levels of both phospho PKR and phospho eIF2alpha were significantly enhanced in muscle of cancer patients with weight loss irrespective of the amount and there was a linear relationship between phosphorylation of PKR and phosphorylation of eIF2alpha (correlation coefficient 0.76, P=0.005). This suggests that phosphorylation of PKR led to phosphorylation of eIF2alpha. Myosin levels decreased as the weight loss increased, and there was a linear relationship between myosin expression and the extent of phosphorylation of eIF2alpha (correlation coefficient 0.77, P=0.004). These results suggest that phosphorylation of PKR may be an important initiator of muscle wasting in cancer patients.
Assuntos
Adenocarcinoma/complicações , Fator de Iniciação 2 em Eucariotos/metabolismo , Neoplasias Gastrointestinais/complicações , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Redução de Peso , eIF-2 Quinase/metabolismo , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Caquexia/etiologia , Caquexia/metabolismo , Feminino , Neoplasias Gastrointestinais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fosforilação , Regulação para Cima , Redução de Peso/fisiologiaAssuntos
Neoplasias Esofágicas/genética , Proteoglicanas/genética , RNA Mensageiro/genética , Neoplasias Gástricas/genética , Animais , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Músculo Esquelético/patologia , Proteoglicanas/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
BACKGROUND: Accurate prediction of prognosis in gastro-oesophageal cancer remains challenging. The aim of this study was to develop a robust model for outcome prediction. METHODS: The study included 220 patients with gastric or oesophageal cancer newly diagnosed over a 2-year period. Patients were staged and underwent treatment following discussion at a multidisciplinary team (MDT) meeting. Clinical and investigative variables were collected, including performance and nutritional status, and serum C-reactive protein (CRP) level. Primary endpoints were death within 12 and 24 months. RESULTS: Overall median survival was 13 months. Advanced clinical stage (P < 0.001), reduced performance score (P < 0.001), weight loss exceeding 2.75 per cent per month (P = 0.026) and serum CRP concentration above 5 mg/l (P = 0.031) were identified as independent prognostic indicators in multivariable analysis. A prognostic score was constructed using these four variables to estimate a probability of death. Applying the model gave an area under the receiver-operator characteristic curve of 0.84 and 0.85 for prediction of death at 12 and 24 months respectively (both P < 0.001). CONCLUSION: This model accurately estimated the probability of death within 12 and 24 months. This may aid the MDT decision-making process.
Assuntos
Neoplasias Esofágicas/mortalidade , Neoplasias Gástricas/mortalidade , Idoso , Proteína C-Reativa/metabolismo , Tomada de Decisões , Técnicas de Apoio para a Decisão , Neoplasias Esofágicas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Prognóstico , Medição de Risco/métodos , Índice de Gravidade de Doença , Neoplasias Gástricas/sangue , Redução de PesoRESUMO
Systemic inflammation is associated with adverse prognosis cancer but its aetiology remains unclear. We investigated the expression of proinflammatory cytokines within normal mucosa from healthy controls and tumour tissue in cancer patients and related these levels with markers of systemic inflammation and with the presence of a tumour inflammatory infiltrate. Tissue was collected from 56 patients with gastro-oesophageal cancer and from 12 healthy controls. Tissue cytokine mRNA concentrations were measured by real-time PCR and tissue protein concentrations by cytometric bead array. The degree of chronic inflammatory cell infiltrate was recorded. Serum cytokine and acute phase protein concentrations (including C-reactive protein (CRP)) were measured by enzyme-linked immunosorbent assay. Proinflammatory cytokines were significantly overexpressed (interleukin (IL)-1beta, IL-6, IL-8 and tumour necrosis factor-alpha) both at mRNA and protein levels in the cancer specimens compared with mucosa from controls. Interleukin-1beta was expressed in greatest (10-100-fold) concentration and protein levels correlated significantly with systemic inflammation (CRP) (P = 0.05, r = 0.31). A chronic inflammatory infiltrate was observed in 75% of the cancer specimens and was associated with systemic inflammation (CRP: P = 0.01). However, the presence of chronic inflammation per se was not associated with altered cytokine expression within the tumour. Both a chronic inflammatory infiltrate and systemic inflammation (CRP) were associated with reduced survival (P = 0.05 and P = 0.03, respectively). Tumour chronic inflammatory infiltrate and tumour tissue IL-1beta overexpression are potential independent factors influencing systemic inflammation in oesophagogastric cancer patients.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias Esofágicas/metabolismo , Junção Esofagogástrica/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas de Fase Aguda/análise , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/análise , Citocinas/análise , Ensaio de Imunoadsorção Enzimática , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de SobrevidaRESUMO
The object of this article is to assess current staging accuracies for individual modalities and to investigate the influence of the multidisciplinary team (MDT) on clinical staging accuracies and treatment selection for patients with gastro-esophageal cancer. Patients newly diagnosed with gastric or esophageal cancer and who were deemed suitable for surgical resection by the MDT were studied. Patients were staged with a combination of computerized tomography (CT), endoscopic ultrasound (EUS) and laparoscopic ultrasound (LUS). Additionally, the MDT determined an overall clinical stage for each patient after discussion at the MDT meeting. Treatments were selected according to this final clinical stage. Final histopathological staging (pTNM) was available for all patients and was used as the gold standard for determining staging accuracy. Suitability of treatment selection was assessed once final pTNM was available. One hundred and eighteen patients were studied. Endoscopic ultrasound was the most accurate individual staging modality for the loco-regional assessment of esophageal tumors (T stage accuracy 78%, N stage accuracy 70%). Laparoscopic ultrasound was the most accurate modality in T staging of gastric cancers (91%). The MDT stage was more accurate than each individual staging modality for T and N staging for both gastric and esophageal cancers (accuracy range: 88-89%) and was better for the assessment of nodal disease than each individual modality (CT P < 0.001, EUS P < 0.01, LUS P < 0.01). Overall staging accuracy as determined at the MDT meeting was increased and resulted in only 2/118 (2%) patients being under-treated. The MDT significantly improves staging accuracy for gastro-esophageal cancer and ensures that correct management decisions are made for the highest number of individual patients.
Assuntos
Adenocarcinoma/terapia , Neoplasias Esofágicas/terapia , Equipe de Assistência ao Paciente , Neoplasias Gástricas/terapia , Adenocarcinoma/diagnóstico por imagem , Idoso , Algoritmos , Endossonografia , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Gástricas/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Gastro-oesophageal cancer is associated with a high incidence of cachexia. Proteolysis-inducing factor (PIF) has been identified as a possible cachectic factor and studies suggest that PIF is produced exclusively by tumour cells. We investigated PIF core peptide (PIF-CP) mRNA expression in tumour and benign tissue from patients with gastro-oesophageal cancer and in gastro-oesophageal biopsies for healthy volunteers. Tumour tissue and adjacent benign tissue were collected from patients with gastric and oesophageal cancer (n=46) and from benign tissue only in healthy controls (n=11). Expression of PIF-CP mRNA was quantified by real-time PCR. Clinical and pathological information along with nutritional status was collected prospectively. In the cancer patients, PIF-CP mRNA was detected in 27 (59%) tumour samples and 31 (67%) adjacent benign tissue samples. Four (36%) gastro-oesophageal biopsies from healthy controls also expressed PIF-CP mRNA. Expression was higher in tumour tissue (P=0.031) and benign tissue (P=0.022) from cancer patients compared with healthy controls. In the cancer patients, tumour and adjacent benign tissue PIF-CP mRNA concentrations were correlated with each other (P<0.0001, r=0.73) but did not correlate with weight loss or prognosis. Although PIF-CP mRNA expression is upregulated in both tumour and adjacent normal tissue in gastro-oesophageal malignancy, expression does not relate to prognosis or cachexia. Post-translational modification of PIF may be a key step in determining the biological role of PIF in the patient with advanced cancer and cachexia.