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1.
Medicine (Baltimore) ; 99(4): e18732, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977864

RESUMO

BACKGROUND: The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients were adults with newly diagnosed untreated, unresectable esophageal cancer in stages I to IV with lymph node metastases or cervical esophageal cancer. Patients received nedaplatin 25 mg/m per day on day 1-3, raltitrexed 3 mg/m on days 1 repeated every 21 days for 2 cycles, and combined concurrent radiotherapy (2 Gy/fraction, total dose of 60 Gy). RESULT: Thirty patients were included with squamous cell carcinoma. The median follow-up duration was 24 months. The overall response rate was 90%. The 1-year and 2-year overall survival rates for all patients were 70.4% and 55.7% with a median survival time of 30 months, and the median progression free survival was 20 month. The major toxicities were leukopenia and thrombopenia, with grade 3 to 4 leukopenia and thrombopenia were 50% and 30% of patients. CONCLUSION: Concurrent chemoradiotherapy with raltitrexed and nedaplatin agents frequently caused myelosuppression but was highly active and suggested to be a promising treatment option for locally advanced ESCC.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Quimiorradioterapia/métodos , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/terapia , Compostos Organoplatínicos/administração & dosagem , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta à Radiação , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Estudos Retrospectivos , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Resultado do Tratamento
2.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(11): 1104-1109, 2019 Nov 06.
Artigo em Chinês | MEDLINE | ID: mdl-31683395

RESUMO

Objective: To analyze the related factors of esophageal squamous cell carcinoma and precancerous lesions among residents aged 40-69 years old in rural areas of Shandong Province. Methods: In October 2018, 300 villages in 13 counties of the Shandong upper gastrointestinal cancerearly diagnosis and treatment projectin 2017 were selected as research areas, and 30 400 residents aged 40-69 were recruited in this study. The demographic characteristics, health status and lifestyle information were collected through the questionnaire survey, and endoscope iodine staining and indicative biopsy methods were used for cancer screening among eligible people.The multivariate logistic regression model was used to analyze the risk factors for esophageal cancer and precancerous lesions. Results: The subjects in this study were (56.42±7.24) years old, including 13 193 males (43.40%).There were 936 cases of esophageal cancer and precancerous lesions (3.08%), including 521 males and 415 females.Compared with women, 40-49 years old, high level education, drinking tap water, regular intake of meat, eggs and milk, and family average annual income more than 30 000 RMB, men (OR=1.90, 95%CI: 1.65-2.19), 60-69 years old (OR=5.28, 95%CI: 4.11-7.30), primary school education or below (OR=1.50, 95%CI: 1.20-1.89), drinking groundwater (OR=1.71, 95%CI: 1.38-2.13), never eating meat, eggs and milk (OR=1.48, 95%CI: 1.22-1.80), and family average annual income less than 30 000 RMB (OR=1.41, 95%CI: 1.16-1.70) would increase the risk of esophageal cancer and precancerous lesions. Conclusion: The gender, age, educational level, annual household income, drinking water source, the frequency of eating meat, egg and milk were related to the occurrence of esophageal cancer and precancerous lesions among 40-69 years old residents in rural areas of Shandong Province.


Assuntos
Detecção Precoce de Câncer , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Lesões Pré-Cancerosas/patologia , População Rural/estatística & dados numéricos , Adulto , Idoso , Biópsia , China/epidemiologia , Endoscopia , Neoplasias Esofágicas/epidemiologia , Carcinoma de Células Escamosas do Esôfago/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/epidemiologia , Fatores de Risco
3.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(11): 1124-1129, 2019 Nov 06.
Artigo em Chinês | MEDLINE | ID: mdl-31683399

RESUMO

Objective: To investigate the association between the whole blood riboflavin level and the occurrence, development and prognosis of esophageal squamous cell carcinoma (ESCC) in China. Methods: From March 2014 to September 2018, ESCC patients from three hospitals (the Affiliated Hospital of Medical College of Shantou University, Shantou Central Hospital in Southern Chaoshan area and First Affiliated Hospital of Zhengzhou University in Northern Taihang Mountain) were selected as a case group; non-esophageal patients who had a physical examination were selected as a control group. The case and control group were paired by age (±5 years) and a 1:1 ration. A total of 1 528 subjects were enrolled including 764 patients in the case group and 764 patients in the control group. About 3-5 ml venous blood samples were collected, and the erythrocyte glutathione reductase activity coefficient (GRAC) was measured to assess the whole blood riboflavin level. A multivariate conditional logistic regression model was used to analyze the association between the GRAC and the risk of ESCC. The association between the GRAC and the prognosis of ESCC was analyzed by using Cox proportional risk regression model based on 288 patients with complete survival data. They were divided into two groups, the high GRAC group (GRAC≥7.87) group and the low GRAC group (GRAC<7.87) according to the strongest correlation between the total survival time, survival outcome and GRAC (GRAC=7.87). Results: Among the 1 528 patients, 958 patients were from Southern Chaoshan area, including 479 patients in the case group with an average age about (59.90±9.34) years and 479 patients in the control group with an average age about (59.55±8.77) years. Other 570 patients were from Northern Taihang Mountain area, including 285 patients in the case group with an average age (58.39±5.19) years and 285 patients in the control group with an average age about (58.74±4.57) years. The multivariate conditional logistic regression showed that the OR (95%CI) of the GRAC and the risk of ESCC was 1.009 (0.998-1.019). The Cox proportional hazard regression model analysis showed that the HR (95%CI) of the high GRAC group was 1.712 (1.034-2.824) compared with the low GRAC group in the 50-70 years group. Conclusion: The whole blood riboflavin level might not be associated with the occurrence of ESCC. The high whole blood riboflavin level would be more beneficial to the prognosis of ESCC patients aged 50-70 years.


Assuntos
Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/mortalidade , Riboflavina/sangue , Idoso , Estudos de Casos e Controles , China/epidemiologia , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico
4.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(11): 1176-1182, 2019 Nov 06.
Artigo em Chinês | MEDLINE | ID: mdl-31683410

RESUMO

Abnormal genomic DNA methylation is an important epigenetic change in malignant tumors. Esophageal squamous cell cancer is one of common malignant tumors in our country. In this paper summarized and discussed the progress of genomic DNA methylation in the esophageal squamouscell cancer, including the level of genomic DNA methylation, frequent abnormally methylated genes, methylation markers and potential targets, etc. This paper might provide candidate biomarkers and targets for further studies on the mechanism of the tumorigenesis and development of the esophagealsquamouscell cancer, as well as for the clinical application of esophageal cancer.


Assuntos
Metilação de DNA , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Biomarcadores Tumorais , Epigênese Genética , Genômica , Humanos , Regiões Promotoras Genéticas
5.
Cancer Sci ; 110(12): 3677-3688, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646712

RESUMO

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by reexpression of Id-1. In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteína 1 Inibidora de Diferenciação/genética , MicroRNAs/fisiologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/farmacologia , Humanos , Masculino , Camundongos , MicroRNAs/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica
6.
Medicine (Baltimore) ; 98(43): e17531, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651855

RESUMO

Lymph node metastasis (LNM) of esophageal squamous cell carcinoma (ESCC) has important prognostic significance. In this study, we examined the correlations between lymph node metastatic sites and prognosis in patients with resectable ESCC.A total of 960 patients who received curative esophagectomy with systemic lymphadenectomy between 1996 and 2014 were included in the retrospective analysis. The Kaplan-Meier method and log-rank test were used to perform the survival analysis. The prognostic significance of LNM site was evaluated by Cox regression analysis.The LNM in middle paraesophageal (P < .001), subcarinal (P < .001), lower paraesophageal (P < .001), recurrent laryngeal nerve (P = .012), paratracheal (P = .014), and perigastric (P < .001) sites were associated with poor prognosis in univariate analysis. In multivariate analysis, only middle paraesophageal LNM (MPLNM, P = .017; HR, 1.33; 95%CI, 1.05-1.67) was the independent factor for worse prognosis. Additionally, patients with MPLNM had a lower 5-year survival rate (15.6%) than those with LNM at other sites. Furthermore, upper or middle tumor location and relatively late pN stage were associated with increased risk of MPLNM.Our findings suggested MPLNM could be a characteristic indicating the worst prognosis. Preoperative examinations should identify the existences of MPLNM, especially on patients with risk factors. And patients with MPLNM should be considered for more aggressive multidisciplinary therapies.


Assuntos
Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/mortalidade , Esofagectomia/mortalidade , Excisão de Linfonodo/mortalidade , Linfonodos/patologia , Idoso , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Esôfago/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
7.
Eur J Radiol ; 120: 108671, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629121

RESUMO

PURPOSE: To correlate the clinical stage and prognosis of oesophageal squamous cell carcinoma (SCC) using the imaging biomarkers from integrated positron emission tomography (PET)/magnetic resonance imaging (MRI). METHODS: In total, 54 consecutive patients with oesophageal SCC who receive PET/MRI scan were recruited before treatment. The imaging biomarkers used were the mean and minimal apparent diffusion coefficients (ADCmean and ADCmin), standardized uptake value (SUV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) of tumours. The correlation between each imaging biomarker and survival was investigated using the Cox proportional hazards model. RESULTS: ADCmean was negatively correlated with SUVmax (r = -0.414, P =  0.025). ADCmin was negatively correlated with SUVmax (r = -0.423, P =  0.001) and SUVpeak (r = -0.402, P =  0.003), and was significantly lower in M1 than in M0 tumours (829.6 vs. 1069.8, P = 0.005). MTV was significantly higher in T3 + (P <  0.001), N1 + (P = 0.014) and TNM stage III + (P <  0.001) tumours. TLG was significantly higher in T3 + (P <  0.001), N1 + (P <  0.001), M1 (P =  0.045) and TNM stage III + (P <  0.001) tumours. The MTV/ADCmin ratio exhibited the highest area under the receiver operating characteristic curve (AUROC) for predicting M1 and advanced TNM stage tumours. Multivariate analysis for progression-free survival (PFS) and overall survival (OS) showed that a larger MTV/ADCmin was associated with a shorter PFS and OS (P = 0.024 and 0.046, respectively). CONCLUSION: The imaging biomarkers in integrated PET/MRI may predict clinical stage and survival in patients with oesophageal SCC.


Assuntos
Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas do Esôfago/patologia , Fluordesoxiglucose F18 , Compostos Radiofarmacêuticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Glicólise/fisiologia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Carga Tumoral
8.
Medicine (Baltimore) ; 98(40): e17164, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577707

RESUMO

INTRODUCTION: The PD-1 inhibitors have shown good response in the treatment for many types of malignant tumors, but as monotherapy for advanced esophageal squamous carcinoma, the objective response rate is low. Here we report a case of the patient with advanced esophageal squamous cell carcinoma (ESCC) showing a completely response to nivolumab combined with a small molecule multi-target tyrosine kinase inhibitor (TKI) anlotinib. PATIENT CONCERNS: A 61-year-old male was put under a surgery as the response to the diagnosis of ESCC in March 2014. The post-operative follow-up in March 2018 suggested a recurrence based on imagological findings, and symptoms such as shortness of breath and cough were also observed in October 2018. DIAGNOSIS: The patient was diagnosed as advanced metastatic ESCC in October 2018. INTERVENTIONS: Radical resection and esophagogastrostomy under aortic arch with left thoracotomy was performed in March 2014. As a treatment against the post-surgical recurrence, 4 courses of paclitaxel combined with nedaplatin was administered in April 2018 with an outcome of PR, followed by a combined administration of Nivolumab and anlotinib in November 2018. OUTCOMES: Chest CT during a 3-month follow-up revealed the disappearance of all the metastases, and no adverse effect was observed during the treatment. CONCLUSION: The combined treatment of nivolumab and anlotinib is likely to be considered as an optional management of advanced ESCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Indóis/uso terapêutico , Nivolumabe/uso terapêutico , Quinolinas/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos
9.
Anticancer Res ; 39(10): 5675-5682, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570466

RESUMO

BACKGROUND/AIM: This study explored the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) and use of antibiotics in advanced esophageal squamous cell carcinoma (ESCC) patients receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: Patients were enrolled from two referral centers in Taiwan. Clinical benefit was defined as complete response, partial response, or a stable disease for ≥6 months via Response Evaluation Criteria In Solid Tumors 1.1. Clinicopathological factors' impact on overall survival (OS) and progression-free survival (PFS) was analyzed via Cox proportional hazards model. RESULTS: Forty-nine patients were enrolled. The median PFS and OS were 1.8 and 6.1 months, respectively. The median NLR at baseline was 6.40, and 21 patients received antibiotics. Both high NLR and use of antibiotics were associated with inferior PFS (p=0.028 and p<0.001, respectively) and OS (p<0.001 and p<0.001, respectively) in multivariate analysis. CONCLUSION: High NLR and use of antibiotics were associated with inferior survival in advanced ESCC patients receiving ICIs.


Assuntos
Antibacterianos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taiwan
10.
Medicine (Baltimore) ; 98(37): e17104, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517842

RESUMO

Esophageal cancer is a common human malignant tumor with high mortality. Glandular epithelial markers, such as CAM5.2, can be expressed in esophageal squamous cell carcinoma (ESCC), but the clinical significance of these cells in ESCC remains elusive.Immunohistochemical analysis of CAM5.2 was performed on 604 ESCC specimens using tissue microarray. Our study design and study population used retrospective cohorts based on the hospital information system and pathological information management system which included medical information, date of admission, procedures undergone, registration, examinations, and medication.In total, positive staining of CAM5.2 was 145 of 604 (24%). Statistical analysis showed that the expression of CAM5.2 had no relationship with sex, age, tumor differentiation, tumor size, tumor-node-metastasis (TNM) classification, and lymph node metastasis, but it was significantly associated with poor prognosis of overall survival (P = .0041) and disease-free survival (P = .0048) in ESCC patients.Herein, we report for the first time that the high expression of the CAM 5.2 is an independent predictor of poor prognosis in patients with ESCC.


Assuntos
Biomarcadores/análise , Neoplasias Esofágicas/classificação , Carcinoma de Células Escamosas do Esôfago/complicações , Queratinas/análise , Queratinas/genética , Adulto , Idoso , Biópsia/métodos , Biópsia/estatística & dados numéricos , China , Estudos de Coortes , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Imuno-Histoquímica/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transcriptoma
11.
J Radiol Case Rep ; 13(7): 14-20, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31558963

RESUMO

Intramedullary spinal cord metastases are rarely encountered in patients suffering from extra - central nervous system primary cancer, with only 2 described cases reported in the literature deriving from esophageal cancer. Intramedullary spinal cord metastases may occur at any level of the spinal cord but cervical location is the most frequent. We report the first case of intramedullary metastasis affecting the thoracic spinal cord from esophageal squamous cell carcinoma in a 35-year-old patient.


Assuntos
Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Segunda Neoplasia Primária/diagnóstico por imagem , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/secundário , Adulto , Evolução Fatal , Feminino , Humanos , Medula Espinal/diagnóstico por imagem
12.
J Exp Clin Cancer Res ; 38(1): 389, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488217

RESUMO

BACKGROUND: In cancer progression, hypoxia, or low oxygen tension, is a major regulator of tumor aggressiveness and metastasis. However, how cancer cells adapt to the hypoxia and communicate with other mesenchymal cells in microenvironment during tumor development remains to be elucidated. Here, we investigated the involvement of exosomes in modulating angiogenesis and enhancing metastasis in esophageal squamous cell carcinoma (ESCC). METHODS: Differential centrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to isolate and characterize exosomes. Colony formation and transwell assay were performed to assess the proliferation, migration and invasion of human umbilical vein endothelial cells (HUVECs). The tube formation assay and matrigel plug assay were used to evaluate the vascular formation ability of HUVECs in vitro and in vivo respectively. An in vivo nude mice model was established to detect the regulatory role of exosomes in ESCC progression. Microarray analysis was performed to analyze the transcriptome profiles in HUVECs. RESULTS: Exosomes derived from ESCC cells cultured under hypoxia played a better role in promoting proliferation, migration, invasion and tube formation of HUVECs in vitro and in vivo than exosomes from ESCC cells cultured under normoxia. Moreover, hypoxic exosomes significantly enhanced the tumor growth and lung metastasis compared with normoxic exosomes in nude mice models. Interestingly, endothelial cells were programmed by hypoxic and normoxic exosomes from ESCC cells which altered the transcriptome profile of HUVECs. CONCLUSIONS: Taken together, our data identified an angiogenic role of exosomes from ESCC cells which shed light on the further application of exosomes as valuable therapeutic target for ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Exossomos/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transcriptoma , Animais , Ciclo Celular , Linhagem Celular Tumoral , Biologia Computacional/métodos , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais , Carcinoma de Células Escamosas do Esôfago/patologia , Perfilação da Expressão Gênica , Humanos , Camundongos , Anotação de Sequência Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Fenótipo
13.
Biol Pharm Bull ; 42(9): 1500-1509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474710

RESUMO

Cinobufagin isolated from traditional Chinese herbs has antitumour, anaesthetic, analgesic and anti-inflammatory effects. Recently, the antitumour activity of cinobufagin has attracted increasing attention from researchers. However, the anticancer activity of this drug on esophageal cancer cells and the precise mechanism are unclear. In this study, we determined the inhibitory effect of cinobufagin on the growth of three esophageal squamous cell carcinoma cell lines and explored its underlying mechanism. EC-109, Kyse-150, and Kyse-520 cells were treated with different concentrations of cinobufagin. The results of the Cell Counting Kit-8 (CCK-8) and clone formation assays showed that cinobufagin significantly reduced cell proliferation in a dose- and time-dependent manner. Also, flow cytometry and Hoechst 33342 staining indicated that the inhibition of growth induced by cinobufagin was mediated by G2/M cell cycle arrest and apoptosis. In addition, the expression of proteins related to cell cycle arrest and apoptosis was assessed by real-time quantitative (q)RT-PCR and Western blot. The results showed that cinobufagin caused G2/M arrest via upregulation of p21 and Wee1 and downregulation of cyclin B1 and Cdc2 at the mRNA and protein levels and induced apoptosis via upregulation of cleaved caspase-3, Puma and Noxa expression and an increased Bax/Bcl-2 ratio. Other data further showed that cinobufagin increased p73 expression and decreased Mdm2 expression, whereas p53 expression was not significantly changed. Taken together, these results suggest that growth inhibition of cinobufagin in esophageal cancer cells might act through the p73 pathway and its downstream molecules.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteína Tumoral p73/metabolismo , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Transdução de Sinais , Fatores de Tempo , Proteína Tumoral p73/genética
14.
EBioMedicine ; 46: 66-78, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383552

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are involved in oncogenesis of esophageal squamous cell carcinoma (ESCC). miR-134 is reported to have a tumour-suppressive role but its role in ESCC is not known. The present study was designed to examine whether miR-134 inhibits ESCC development and further explored relevant underlying mechanisms. METHODS: Differentially expressed genes related to ESCC were identified from microarray gene expression profiles. Immunohistochemical staining and RT-qRCR assays identified elevated PLXNA1 expression levels and low miR-134. The relationship between miR-134 and PLXNA1 was predicted and further verified by a dual-luciferase reporter assay. The expression levels of miR-134 and PLXNA1 in ESCC cells were modified by miR-134 mimic/inhibitor and siRNA against PLXNA1, respectively. Thereafter, the expression of MAPK signalling pathway-related proteins, as well as the viability, migration, invasion, cell cycle and cell apoptosis of ESCC cells was investigated. FINDINGS: The results showed that miR-134 could block the MAPK signalling pathway by downregulating PLXNA1. When miR-134 was overexpressed or PLXNA1 was silenced, cell apoptosis was enhanced, the cell cycle was retarded, and the cell proliferation, migration and invasion were suppressed. In vivo experiments confirmed that miR-134 overexpression or PLXNA1 silencing restrained tumour growth and lymph node metastasis. INTERPRETATION: These findings demonstrate that cancer cell proliferation, migration, invasion, and tumour metastasis of ESCC can be suppressed by overexpression of miR-134 through downregulating PLXNA1, which subsequently blocks the MAPK signalling pathway. These results provide new potential targets and strategies for the treatment of ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular/metabolismo , Idoso , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional/métodos , Progressão da Doença , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Interferência de RNA
15.
Med Sci Monit ; 25: 5850-5855, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31385574

RESUMO

BACKGROUND The aim of this study was to detect the expression levels of chemokines (CX3CL1, CXCL-11, CXCL-12, CCL3, CCL4, and CCL20) in the serum of esophageal cancer patients and a normal control group, and to explore the correlations of those expression levels with the pathological type, progression, and metastasis of esophageal cancer. MATERIAL AND METHODS A total of 50 normal people and 50 untreated patients initially diagnosed with esophageal cancer (including 17 cases of non-metastatic esophageal cancer, 33 cases of metastatic esophageal cancer, 36 cases of esophageal squamous cell carcinoma and 14 cases of esophageal adenocarcinoma) were collected. The liquid chip (Luminex) technology was applied to detect the expression levels of the above-mentioned serum chemokines in the two groups. The results were analyzed using Statistical Product and Service Solution 20.0 software. RESULTS The expression levels of CX3CL1, CXCL-12, and CCL20 in esophageal cancer group were evidently higher than those in normal control group (P<0.001, P<0.001 and P=0.003, respectively). There were no statistically significant differences in chemokine expressions between metastatic esophageal cancer group and non-metastatic esophageal cancer group (P>0.05). The expression level of serum CCL4 in esophageal adenocarcinoma group was remarkably higher than that in esophageal squamous cell carcinoma group [18.45 (11.94) versus 13.37 (9.29), Z=-2.039, P=0.031]. In esophageal cancer group and normal control group, the serum CX3CL1 was positively correlated with CCL20 (r=0.649, P<0.001, r=0.758, P<0.001). CONCLUSIONS The expressions of serum CX3CL1, CXCL-12, and CCL20 are increased markedly in the patients, which may promote the occurrence, development and metastasis of esophageal cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Esofágicas/patologia , Soro/química , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Quimiocinas/sangue , China , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Oncology ; 97(6): 348-355, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31461716

RESUMO

BACKGROUND: Preoperative therapy followed by surgery has become the clinical standard for resectable advanced esophageal cancer. Several studies showed that neoadjuvant docetaxel/cisplatin/5-fluorouracil (DCF) resulted in a high response rate and prolonged relapse-free survival, but what constitutes appropriate additional therapy is unknown. METHODS: A total of 101 consecutive patients with cStage I B-III esophageal cancer were treated with preoperative DCF between April 2011 and December 2015. After completing 2 cycles of DCF neoadjuvant chemotherapy (NAC), esophagectomy was performed. We investigated prognostic factors and recurrence patterns in patients with resectable esophageal cancer who underwent DCF NAC followed by surgery. RESULTS: Univariate analysis showed that performance status (hazard ratio, HR 2.85; p = 0.033), clinical response (HR 2.16; p = 0.048), pT stage (HR 2.20; p = 0.047), pN stage (HR 5.83; p< 0.001), pathological curability (HR 5.64; p = 0.038), and histological grade (HR 1.92; p = 0.048) were significant factors. Multivariate prognostic analysis revealed that pN stage and pathological curability were significant prognostic factors (HR 11.20; p < 0.001, and HR 27.41; p = 0.007, respectively). In addition, based on the number of metastatic lymph nodes (LNs), the difference in overall survival was the largest between patients with ≤2 and ≥3 metastatic LNs (HR 5.83; p< 0.001). Distant metastatic recurrence increased significantly in patients with 3 or more pathologically confirmed metastatic LNs (p = 0.008). CONCLUSION: Distant recurrence occurred more frequently and prognosis was poorer in patients with 3 or more pathologically confirmed metastatic LNs; they might need additional systemic therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Idoso , Cisplatino/administração & dosagem , Terapia Combinada , Docetaxel/administração & dosagem , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Feminino , Fluoruracila/administração & dosagem , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico
17.
Anticancer Res ; 39(8): 4539-4548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366557

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Idoso , Antígeno B7-H1/sangue , Linfócitos T CD8-Positivos/efeitos dos fármacos , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Receptor de Morte Celular Programada 1/sangue , Microambiente Tumoral/efeitos dos fármacos
18.
Oncol Rep ; 42(4): 1497-1506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364751

RESUMO

Intrinsic and acquired resistance of cancer to radio­and chemotherapy is one of the major challenges in the treatment of esophageal squamous cell carcinoma (ESCC). Elevated reactive oxygen species (ROS) play an important role in the resistance to cisplatin in ESCCs. Super dismutase [Mn], mitochondrial (SOD­2), an important primary antioxidant enzyme located in mitochondria, could regulate ROS production. Our previous study showed that tumor necrosis factor­α (TNF­α)­mediated SOD­2 through NF­κB was involved in epithelial­mesenchymal transition and migration in A549 cells. Therefore, the present study aimed to identify if TNF­α mediated SOD­2 upregulation is involved in cisplatin resistance in ESCC. It was identified that a higher expression of SOD­2 in human ESCC samples was associated with TNF­α expression and poor overall survival in patients with ESCC, suggesting that SOD­2 may act as an oncogene in ESCC. To further confirm if TNF­α could upregulate SOD­2 to contribute to cell proliferation, the human ESCC cell line Eca­109 was treated with TNF­α in vitro. TNF­α could upregulate SOD­2 and induce cell proliferation in Eca109 cells, while blocking SOD­2 using small interfering RNA (siRNA) inhibited TNF­α­induced cell proliferation. Upregulation of SOD­2 by TNF­α was inhibited by blocking the NF­κB pathway, which suggested that SOD­2 by TNF­α/NF­κB contributes to cell proliferation in Eca109 cells. Furthermore, it was observed that TNF­α could induce cisplatin resistance in Eca109 cells, while transfection with SOD­2 siRNA could significantly increase the chemosensitivity of ESCC to cisplatin. Therefore, the present results suggested that SOD­2 may serve as an oncogene, and the upregulation of SOD­2 by TNF­α/NF­κB may contribute to cisplatin resistance in ESCC.


Assuntos
Cisplatino/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Superóxido Dismutase/genética , Fator de Necrose Tumoral alfa/farmacologia , Idoso , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , NF-kappa B/metabolismo , Oncogenes , Superóxido Dismutase/biossíntese , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
J Exp Clin Cancer Res ; 38(1): 304, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296250

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor. METHODS: In this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs. RESULTS: We found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-ß signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples. CONCLUSION: Our results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-ß signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.


Assuntos
Transformação Celular Neoplásica/metabolismo , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Diferenciação/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Exp Clin Cancer Res ; 38(1): 321, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324197

RESUMO

BACKGROUND: Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown. METHODS: Single cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 µm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics. RESULTS: The percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively. CONCLUSIONS: Tumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Interleucina-6/genética , Interleucina-8/genética , Fator de Transcrição STAT3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Transdução de Sinais/genética , Análise de Célula Única , Ensaios Antitumorais Modelo de Xenoenxerto
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