Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Esofagoscopía , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/diagnóstico , Esofagoscopía/métodos , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patologíaRESUMEN
PURPOSE: This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65 years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). RESULTS: A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2 months (95% CI: 5.1-7.3), and the median OS was 15.3 months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. CONCLUSION: The study demonstrated that individuals older than 65 years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Inhibidores de Puntos de Control Inmunológico , Supervivencia sin Progresión , Humanos , Anciano , Masculino , Femenino , Estudios Retrospectivos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Resultado del Tratamiento , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Tasa de SupervivenciaRESUMEN
Less than 15% of patients with esophageal squamous cell carcinoma (ESCC) survive 5 years after diagnosis. A better understanding of the biology of these tumors and the development of clinical biomarkers is needed. Autophagy is a physiological mechanism involved in the turnover of cellular components that plays a key role in cancer. This study evaluated the differential levels of three key regulators of autophagy (SQSTM1, MAP1LC3B, and BECN1) in patients with ESCC, associating autophagy with histopathologic features, including the grade of differentiation, mitotic rate, inflammation score, and the intensity of tumor-infiltrating lymphocytes. Nuclear morphometry of the tumor parenchyma was also assessed, associating it with autophagy and histopathology. All three markers significantly increased in patients with ESCC compared to the control group. Based on the mean expression of each protein in the control group, 57% of patients with ESCC had high levels of all three markers compared to control patients (14%). The most frequent profiles found in ESCC were BECNhigh/MAP1LC3high and BECNhigh/SQSTM1high. According to the TCGA database, we found that the main autophagy genes were upregulated in ESCC. Moreover, high levels of autophagy markers were associated with a poor prognosis. Considering nuclear morphometry, ESCC samples showed a significant reduction in nuclear area, which was strongly negatively correlated with autophagy. Finally, the percentage of normal nuclei was associated with tumor differentiation, while poorly differentiated tumors showed lower SQSTM1 levels. ESCC progression may involve increased autophagy and changes in nuclear structure, associated with clinically relevant histopathological features. KEY MESSAGES: Autophagy markers are co-increased in primary ESCC. Autophagy negatively correlates with nuclear morphometry in ESCC parenchyma. Autophagy and nuclear morphometry are associated with histopathological features. Autophagy is increased in ESCC-TCGA database and associated with poor prognosis.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas/patología , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Biomarcadores de Tumor/genética , AutofagiaRESUMEN
PURPOSE: Esophageal squamous cell carcinoma (ESCC) is characterized by early metastasis and late diagnosis. miR-29c-3p is confirmed to repress angiogenesis in multiple tumor types. Yet, the functions of miR-29c-3p in the mechanism of ESCC angiogenesis, which were not sufficiently explored previously, were exactly what we investigated here at the molecular level. METHODS: The mRNA level of miR-29c-3p and Serpin peptidase inhibitor clade H member 1 (SERPINH1) in ESCC tissues were assessed via bioinformatics analysis. Thereafter, miR-29c-3p and SERPINH1 (HSP47) mRNA level in ESCC cell lines was evaluated via quantitative real-time polymerase chain reaction. The effects of abnormal miR-29c-3p and SERPINH1 expression on ESCC cell viability, proliferation, migration, invasion, and HUVEC angiogenesis were examined via CCK8, colony formation, transwell, and angiogenesis assays, respectively. The protein levels of SERPINH1, vascular endothelial growth factor-A (VEGFA), Wnt-1, ?-catenin, and p-?-catenin were evaluated via Western blot. Expression of VEGFA secreted by ESCC cells was measured via enzyme-linked immunosorbent assay. Treatment with the Wnt activator BML-284 further revealed the way miR-29c-3p mediated the Wnt signaling pathway and its effects on angiogenesis. RESULTS: Herein, we revealed a decrease of miR-29c-3p expression in ESCC tissues and cells, while the overexpressed miR-29c-3p could remarkably suppress ESCC cell progression, as well as HUVEC angiogenesis. Meanwhile, overexpressed miR-29c-3p notably downregulated VEGFA and repressed the Wnt signaling pathway. Treatment with the Wnt activator BML-284 could reverse the inhibition of HUVEC angiogenesis caused by miR-29c-3p. SERPINH1 was a downstream target of miR-29c-3p. SERPINH1 knockdown suppressed the malignant phenotypes of ESCC cells and impeded the Wnt signaling activation, while such suppression was reversed through miR-29c-3p inhibitor. CONCLUSIONS: We confirmed the mechanism that miR-29c-3p targeted SERPINH1, thus regulating angiogenesis in ESCC through the Wnt signaling pathway. It improves the understanding of angiogenesis in ESCC and offers new ideas for the research of ESCC treatment strategies in the future.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , MicroARNs/genética , MicroARNs/metabolismo , Vía de Señalización Wnt , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Factor A de Crecimiento Endotelial Vascular/genética , Línea Celular Tumoral , Cateninas/metabolismo , ARN Mensajero , Angiogénesis , Proliferación Celular , Proteínas del Choque Térmico HSP47/metabolismoRESUMEN
OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy of the gastrointestinal tract for which therapeutic options are scarce. This study screens for LOXL2, a key gene in ESCC, and explains the molecular mechanism by which it promotes the progression of ESCC. METHODS: Immunohistochemical staining was performed to detect the expression level of LOXL2 in ESCC tissues and paraneoplastic tissues. CCK-8 and Transwell assays were performed to assess the effects of LOXL2 knockdown and overexpression on the proliferation, apoptosis, migration and invasion ability of ESCC cells. High-throughput sequencing analysis screens for molecular mechanisms of action by which LOXL2 promotes ESCC progression. Western blotting and qRT-PCR were used to determine the expression levels of relevant markers. RESULTS: LOXL2 is positively expressed in ESCC and highly correlated with poor prognosis. Silencing LOXL2 significantly inhibited the proliferation, migration and invasive ability of ESCC cells, whereas overexpression showed the opposite phenotype. High-throughput sequencing suggested that LOXL2-associated differentially expressed genes were highly enriched in the PI3K/AKT signaling pathway. In vitro cellular assays confirmed that silencing LOXL2 significantly reduced PI3K, p-AKTThr308 and p-AKTSer473 gene and protein expression levels, while overexpression increased all three gene and protein levels, while AKT gene and protein expression levels were not significantly different. CONCLUSION: This study found that LOXL2 may regulate the PI3K/AKT signaling pathway and exert protumor effects on ESCC cells through phosphorylation of AKT. LOXL2 may be a key clinical warning biomarker or therapeutic target for ESCC.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Esofágicas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína-Lisina 6-Oxidasa/genética , Proteína-Lisina 6-Oxidasa/metabolismo , Fosforilación , Movimiento Celular , Transducción de Señal/genética , Proliferación Celular , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
PURPOSE: To investigate the role and mechanism of ß1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) in esophageal cancer (ESCA). METHODS: The starBase database was used to evaluate the expression of B3GNT3. B3GNT3 function was measured using KYSE-30 and KYSE-410 cells of esophageal squamous cell carcinoma (ESCC) cell lines. The mRNA levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8, clone formation assay and transwell assay were used to detect the changes of proliferation, invasion and migration. RESULTS: B3GNT3 expression was higher in ESCA tissues than in normal tissues. The overall survival rate of ESCA patients with high B3GNT3 expression was lower than that of ESCA patients with low B3GNT3 expression. In vitro functional experiments showed that the proliferation ability, migration and invasion ability of KYSE-30 and KYSE-410 cells with B3GNT3 interference were lower than those of the control, and the overexpression of B3GNT3 had the opposite effect. After silencing B3GNT3 expression in ESCC cell lines, the growth of both cell lines was inhibited and the invasiveness was decreased. Knockdown of B3GNT3 reduced the growth rate and Ki-67 expression level. CONCLUSIONS: B3GNT3, as an oncogene, may promote the growth, invasion and migration of ESCC cell.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Proliferación Celular , Línea Celular Tumoral , Movimiento Celular/genética , Oncogenes , MicroARNs/genética , N-Acetilglucosaminiltransferasas/genéticaRESUMEN
PURPOSE: Tumor-associated macrophages (TAMs), are crucial for the survival and development of tumor cells. Heat shock factor 1 (HSF1) is a potent, complex carcinogenesis modulator, and esophageal cancer (EC) patients have a bad prognosis when HSF1 is highly expressed. HSF1's clinical importance and biological role in TAMs are still unknown. METHODS: The HSF1 expression profile and patient survival information were analyzed from the TCGA database. The infiltration of different types of immune cells in EC was evaluated based on HSF1 gene expression by Sangerbox 3.0. Immunochemistry was employed to assess HSF1 protein expression in 134 individuals with esophageal squamous cell carcinoma (ESCC), proceeded by association with clinicopathological variables. The role of macrophage-driven HSF1 were observed using HSF1-knockdown THP1 cells. RESULTS: High level of HSF1 have a poorer prognosis in individuals with EC. The expressing level of HSF1 was positively related to infiltration of M2 macrophages (P < 0.05). The expression of HSF1 in macrophages was an independent factor for DFS (P = 0.002) and OS (P = 0.002) in ESCC cases. HSF1 was up-regulated in IL-4 stimulation THP1 cells in a time-dependent manner. Under the heat stimulation condition, THP1-derived macrophages were more sensitive than tumor cells. Compared to IL-4 induced-THP1 cells control, the HSF1 knockdown in THP1 cell inhibited the growth and proliferation of ESCC cells. CONCLUSIONS: The up-regulation of HSF1 was more rapid and could affect the proliferation of tumor cells in IL4-induced macrophages. The expression of HSF1 in TAMs can also serve as a marker for ESCC prognosis.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas/patología , Macrófagos Asociados a Tumores/metabolismo , Interleucina-4 , Línea Celular Tumoral , Pronóstico , Proliferación CelularRESUMEN
Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer (EC) in Asia. It is a malignant digestive tract tumor with abundant gene mutations. Due to the lack of specific diagnostic markers and early cancer screening markers, most patients are diagnosed at an advanced stage. Genetic and epigenetic changes are closely related to the occurrence and development of ESCC. Here, We review the activation of proto-oncogenes into oncogenes through gene mutation and gene amplification in ESCC from a genetic and epigenetic genome perspective, We also discuss the specific regulatory mechanisms through which these oncogenes mainly affect the biological function and occurrence and development of ESCC through specific regulatory mechanisms. In addition, we summarize the clinical application value of these oncogenes is summarized, and it provides a feasible direction for clinical use as potential therapeutic and diagnostic markers.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/metabolismo , Oncogenes , Mutación , Epigénesis Genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
PURPOSE: Esophageal squamous cell carcinoma is associated with high morbidity and mortality rate for which radiotherapy is the main treatment modality. Niraparib, a Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) was previously reported to confer radiosensitivity in different malignancies including non-small cell lung cancer. In this study, we assessed the in vivo ability of niraparib in conferring radiosensitivity to esophageal squamous cell carcinoma cells. MATERIALS AND METHODS: In this study, KYSE-30 and KYSE-150 cell lines were selected as in vivo esophageal squamous cell carcinoma models. The experimental groups were: niraparib tosylate alone, radiotherapy alone, control (no intervention), and combination therapy (radiotherapy + niraparib tosylate). Cell cytotoxicity assay, colony formation assay, flow cytometry, immunofluorescence, Western blotting, immunohistochemistry, lentivirus transfection analysis, and xenograft models were used for confirming radiosensitizing ability of niraparib and to investigate the possible cellular mechanism involved in radiosensitization. RESULTS: The colony formation efficiency of the combination group was significantly much lower than that of the single radiation group (P < 0.01). Cell cytotoxicity assay demonstrated a significant reduction in proliferation of irradiated cells after treatment with niraparib tosylate compared to niraparib tosylate alone (P < 0.01). Cell apoptosis significantly increased in the combination group compared to either niraparib tosylate or radiotherapy alone (P < 0.01). Rate of tumor suppression rate was significantly high in the combined treatment group (P < 0.01) but, significantly decreased in nude mice. Western blot and lentivirus infection model suggested overexpression of FANCG genes to confer radiosensitivity. CONCLUSION: These results suggest that the synergistic effect of niraparib tosylate and radiation may be related to the down-regulation of FANCG.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Pulmonares , Fármacos Sensibilizantes a Radiaciones , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/radioterapia , Humanos , Indazoles , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Desnudos , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Tolerancia a Radiación , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéuticoRESUMEN
PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor with high heterogeneity. Research on molecular mechanisms involved in the process of tumor origination and progression is extremely limited to investigating mechanisms of molecular typing for ESCC. METHODS: After comprehensively analyzing the gene expression profiles in The Cancer Genome Atlas and Gene Expression Omnibus databases, we identified four immunotypes of ESCC (referred to as C1-C4) based on the gene sets of 28 immune cell subpopulations. The discrepancies in prognostic value, clinical features, drug sensitivity, and tumor components between the immunotypes were individually analyzed. RESULTS: The ranking of immune infiltration is C1 > C4 > C3 > C2. These subtypes are characterized by high and low expression of immune checkpoint proteins, enrichment and insufficiency of immune-related pathways, and differential distribution of immune cell subgroups. Poorer survival was observed in the C1 subtype, which we hypothesized could be caused by an immunosuppressive cell population. Fortunately, C1's susceptibility to anti-PD-1 therapy offers hope for patients with poor prognosis in advanced stages. On the other hand, C4 is sensitive to docetaxel, which may offer novel treatment strategies for ESCC in the future. It is worth noting that immunophenotyping is tightly bound to the abundance of stromal components and stem cells, which could explain the tumor immune escape to some extent. Ultimately, determination of hub genes based on the C1 subtypes provides a reference for the discovery of immunotarget drugs against ESCC. CONCLUSION: The identification of immunophenotypes in our study provides new therapeutic strategies for patients with ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Biomarcadores de Tumor/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunofenotipificación , Pronóstico , Microambiente TumoralRESUMEN
Background: Esophageal neoplasms are rarely reported in cats. The frequency rate is less than 0.5% and those neoplasms are usually malignant. Esophageal squamous cell carcinoma (SCC) is an idiopathic epithelial neoplasm, invasive and metastatic that can induce partial or complete obstruction of the esophageal lumen. There is no breed or sex predisposition, and it is more common in cats over 8-years-old. Esophageal SCC is more frequent in the middle third of the esophagus. The prognosis is poor, as the cats are usually diagnosed at an advanced stage. This report aims to describe clinical, endoscopic, radiographic, and pathological features of two cases of esophageal squamous cell carcinoma in cats. Cases: A 11-year-old neutered male cat presenting regurgitation, weight loss, anorexia and dyspnea was referred to veterinary internal medicine care. Simple and contrast-enhanced radiographic images of the cervical and thoracic regions showed an alveolar pattern in the cranial lung lobes and signs of esophageal lumen irregularity and dilatation in the mediastinum topography. The upper digestive endoscopy showed a dilated esophageal lumen, and an irregular mass was observed in the thoracic esophagus involving the entire esophageal circumference. Biopsy fragments were collected, and the histopathological result was compatible with squamous cell carcinoma. The second case was a 10-year-old neutered male cat presenting hyporexia, regurgitation, dyspnea, tachypnea, and abnormal breath sounds. The ultrasound of the chest showed 3 amorphous hypoechogenic and heterogeneous areas in the right and left hemithorax between parietal and visceral pleura. The cytological examination was compatible with a malignant epithelial tumor. The patient died 3 months after the onset of clinical signs. At gross exam, it was observed a friable, irregular, and ulcerated mass of 5.0 x 3.0 cm in the middle third of the esophagus...
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Animales , Gatos , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/veterinaria , Esófago/patología , Metástasis de la NeoplasiaRESUMEN
OBJECTIVES: High-risk human papillomavirus (HR-HPV) is an important risk factor for esophageal cancer. Macrophages constitute a crucial immune medium for regulating HPV-related tumors; however, the specific regulatory mechanisms remain unknown. Therefore, the purpose of our current study was to investigate the mechanism by which HPV16E6 regulates macrophages to promote the invasion and metastasis of esophageal cancer. METHODS: HPV16E6 infection was detected by polymerase chain reaction. Immunohistochemistry was used to verify the distribution of tumor-associated macrophages (TAMs) and MMP-9 expression in esophageal squamous cell carcinoma tissues (ESCCs), and cancer adjacent normal tissues (CANs) from Kazakh patients. ESCC cells were transfected with a plasmid over-expressing HPV16E6 and non-contact cocultured with macrophages. RESULTS: The infection rate of HPV16E6 in Kazakh ESCCs was clearly higher than that in CANs (P < 0.05). The density of CD163-positive TAMs was significantly positively correlated with HPV16E6 infection in ESCCs (P < 0.05). After coculturing macrophages and EC9706 cells transfected with the HPV16E6 plasmid, the phenotype of macrophages transformed into M2 macrophages. The migration and invasion ability of ESCC cells were higher in the HPV16E6-transfected and coculture group than in the HPV16E6 empty vector-transfected and non-cocultured HPV16E6-transfected groups (all P < 0.05). The density of M2-like TAMs in ESCCs was positively correlated with the level of MMP-9 expression. MMP-9 expression in the HPV16E6-ESCC coculture macrophages group was substantially higher than that in controls (all P < 0.05). CONCLUSIONS: HPV16 infection mediates tumor-associated macrophages to promote ESCC invasion and migration.
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Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Papillomavirus Humano 16 , Proteínas Oncogénicas Virales/metabolismo , Infecciones por Papillomavirus/complicaciones , Proteínas Represoras/metabolismo , Macrófagos Asociados a Tumores/patología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Diferenciación Celular , China/etnología , Técnicas de Cocultivo , Neoplasias Esofágicas/etnología , Neoplasias Esofágicas/virología , Carcinoma de Células Escamosas de Esófago/etnología , Carcinoma de Células Escamosas de Esófago/virología , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/etnología , Fenotipo , Receptores de Superficie Celular/metabolismo , Proteínas Represoras/genética , Microambiente Tumoral , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/virologíaRESUMEN
Esophageal cancer (EC) is an aggressive disease, presenting two main histological subtypes: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). The two EC subtypes widely differ concerning virtually all factors. ESCC development is mainly associated with tobacco and alcohol abuse, whereas obesity and chronic gastroesophageal reflux disease (GERD) are important risk factors not only for EAC, but also for for Barrett's esophagus (BE), an intestinal metaplasia that precedes EAC. Obesity triggers ectopic lipid droplets (LD) accumulation in non-adipose tissues. LD are organelles involved in cell metabolism, signaling, proliferation and production of inflammatory mediators. Therefore, the aim of this work was to investigate LD occurrence and role in EC. This study shows progressive LD levels increase along EAC development, in esophageal samples from non-obese through obese individuals, as well as BE, and EAC patients, whereas no significant changes were observed in ESCC samples, when compared to non-tumor samples. Additionally, in order to mimic BE and EAC risk factors exposure, a non-tumor esophageal cell line was incubated with oleic acid (OA) and acidified medium and/or deoxycholic acid (DCA), revealing a significant increment in LD amount as well as in COX-2 and CXCL-8 expression, and in IL-8 secretion. Further, COX-2 expression and LD amount presented a significant positive correlation and were detected co-localized in EAC, but not in ESCC, suggesting that LD may be the site for eicosanoid production in EAC. In conclusion, this study shows that obesity, and BE- and EAC-associated inflammatory stimuli result in a gradual increase of LD, that may be responsible for orchestrating inflammatory mediators' production and/or action, thus contributing to BE and EAC genesis and progression.
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Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Ciclooxigenasa 2/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Gotas Lipídicas/metabolismo , Transducción de Señal/fisiología , Adenocarcinoma/patología , Esófago de Barrett/patología , Línea Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Esófago/metabolismo , Esófago/patología , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Factores de RiesgoRESUMEN
BACKGROUND: The identification of prognostic factors of esophageal cancer has allowed to predict the evolution of patients. AIM: Assess different prognostic factors of long-term survival of esophageal cancer and evaluate a new prognostic factor of long-term survival called lymphoparietal index (N+/T). METHOD: Prospective study of the Universidad de Chile Clinical Hospital, between January 2004 and December 2013. Included all esophageal cancer surgeries with curative intent and cervical anastomosis. Exclusion criteria included: stage 4 cancers, R1 resections, palliative procedures and emergency surgeries. RESULTS: Fifty-eight patients were included, 62.1% were men, the average age was 63.3 years. A total of 48.3% were squamous, 88% were advanced cancers, the average lymph node harvest was 17.1. Post-operative surgical morbidity was 75%, with a 17.2% of reoperations and 3.4% of mortality. The average overall survival was 41.3 months, the 3-year survival was 31%. Multivariate analysis of the prognostic factors showed that significant variables were anterior mediastinal ascent (p=0.01, OR: 6.7 [1.43-31.6]), anastomotic fistula (p=0.03, OR: 0.21 [0.05-0.87]), N classification (p=0.02, OR: 3.8 [1.16-12.73]), TNM stage (p=0.04, OR: 2.8 [1.01-9.26]), and lymphoparietal index (p=0.04, RR: 3.9 [1.01-15.17]. The ROC curves of lymphoparietal index, N classification and TNM stage have areas under the curve of 0.71, 0.63 and 0.64 respectively, with significant statistical difference (p=0.01). CONCLUSION: The independent prognostic factors of long-term survival in esophageal cancer are anterior mediastinal ascent, anastomotic fistula, N classification, TNM stage and lymphoparietal index. In esophageal cancer the new lymphoparietal index is stronger than TNM stage in long-term survival prognosis.
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Supervivientes de Cáncer/estadística & datos numéricos , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Esofagectomía/métodos , Ganglios Linfáticos/patología , Chile/epidemiología , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Esófago/patología , Femenino , Humanos , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , SobrevivientesRESUMEN
Esophageal squamous cell carcinoma (ESCA) exhibits high intratumoral molecular heterogeneity posing a challenge to cancer therapy. Immune checkpoint blockade therapy has been approved for this disease, but with modest results. RNA-Seq data from paired tumor and surrounding nonmalignant tissue from 14 patients diagnosed with ESCA without previous treatment and from The Cancer Genome Atlas-ESCA cohort were analyzed. Herein, we investigated ESCA immune landscape including mutation-derived neoantigens and immune cell subpopulations. Tumor-associated antigen expression was determined by in silico analyses and confirmed by immunohistochemistry showing that PRAME, CEACAM4, and MAGEA11 proteins are expressed on tumors. Immune checkpoint molecules gene expression was higher in the tumor compared with surrounding nonmalignant tissue, but its expression varies greatly among patients. TCR repertoire and BCR transcripts analysis evidenced low clonal diversity with one TCR clone predicted to be specific for a MAGEA11-derived peptide. A high number of B-cell clones infiltrating the tumors and the abundance of these cells in tertiary lymphoid structures observed in ESCA tumors support B cells as a potential immune modulator in this tumor.
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Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Neoplasias Esofágicas/inmunología , Carcinoma de Células Escamosas de Esófago/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Estructuras Linfoides Terciarias/inmunología , Microambiente Tumoral/inmunología , Linfocitos B/patología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/patología , Masculino , RNA-Seq , Estructuras Linfoides Terciarias/patologíaRESUMEN
BACKGROUND: Fibrinogen (Fib) to albumin (ALB) fibrinogen-to-albumin ratio as a prognostic index for esophageal cancer has been confirmed. A novel prognostic index was initially proposed with fibrinogen to prealbumin ratio (FPR) in patients with resectable esophageal squamous cell carcinoma (ESCC). OBJECTIVE: The objective of the study was to study the prognostic role of the novel prognostic index (FPR) in patients with resectable ESCC without any neoadjuvant treatment. METHODS: In this retrospective study, a total of 372 resectable ESCC patients without any neoadjuvant treatment were included. The best cutoff values were selected by the receiver operating characteristic curves. Two Cox regression analyses with forward stepwise (one for categorical variables and the other for continuous variables) were used to evaluate the overall survival (OS) and cancer-specific survival (CSS). RESULTS: The best cutoff point was 0.014 for FPR. Patients with lower levels of FPR (≤0.014) had better CSS (50.7% vs. 18.0%, p < 0.001) and OS (48.0% vs. 17.6%, p < 0.001) than patients with higher levels of FPR (> 0.014). Multivariate Cox analyses (categorical and continuous) demonstrated that FPR was an independent prognostic factor in CSS (categorical: hazard ratio [HR]: 2.014, 95% confidence interval [CI]: 1.504-2.697, p < 0.001; continuous per 0.01: HR: 1.438, 95% CI: 1.154-1.793, p = 0.001) and OS (categorical: HR: 1.964, 95% CI: 1.475-2.617, p < 0.001; continuous per 0.01: HR: 1.429, 95% CI: 1.146-1.781, p = 0.002). CONCLUSIONS: Our study indicated that FPR served as an independent prognostic factor in patients with resectable ESCC.
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Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Fibrinógeno/metabolismo , Prealbúmina/metabolismo , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
PURPOSE: To investigate the role of PRDX2 in esophageal carcinoma (ESCA). METHODS: The expression of PRDX2 was detected in ESCA tissues. And PRDX2 expression in two ESCA cell lines was knocked down. Cell proliferation, metastasis and invasion were detected in these cells. RESULTS: Here, we found that PRDX2 expression was significantly increased in ESCA tissues and was associated with a poor prognosis in ESCA patients. In addition, PRDX2 expression was significantly associated with pathological grading, infiltration degree and 5-year survival time in ESCA patients. Next, we knocked down PRDX2 expression by PRDX2-shRNA transfection in two ESCA cell lines, Eca-109 and TE-1. Proliferation analysis indicated that in vitro PRDX2 knockdown decreased growth and clone formation of ESCA cells. Scratch and transwell assays indicated that cell migration and invasion were significantly inhibited by PRDX2 knockdown. In addition, PRDX2 knockdown inhibited cell cycle of ESCA cells and down-regulated Cyclin D1-CDK4/6. Moreover, PRDX2 knockdown regulated proteins involved in mitochondrial-dependent apoptosis, including increased Bax and Caspase9/3 and decreased Bcl2. Mechanism investigation indicated that PRDX2 knockdown led to inactivation of Wnt/ß-catenin and AKT pathways. CONCLUSIONS: Our data suggest that PRDX2 may function as an oncogene in the development of ESCA via regulating Wnt/ß-catenin and AKT pathways. Our study fills a gap in the understanding of the role of PRDX2 in ESCA and provides a potential target for ESCA treatment.
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Neoplasias Esofágicas/etiología , Carcinoma de Células Escamosas de Esófago/etiología , Peroxirredoxinas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Vía de Señalización Wnt/fisiología , Apoptosis , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Humanos , Peroxirredoxinas/análisisRESUMEN
PURPOSE: Esophageal squamous cell cancer (ESCC) has high rates of recurrence and mortality. Small nucleolar RNA host gene 12 (SNHG12) is known to promote the progression of several cancers. Therefore, we aimed to investigate the expression and role of SNHG12 in ESCC. METHODS: The expression and clinical value of SNHG12 in esophageal cancer were explored using data from The Cancer Genome Atlas (TCGA) and the online server GEPIA. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify the expression levels of SNHG12 in ESCC tissues and cell lines. Furthermore, loss-of-function assays were performed to examine the effect of SNHG12 on ESCC cells in vitro and in vivo. The potential competing endogenous RNA networks of SNHG12 in ESCC were explored. RESULTS: SNHG12 was downregulated in human ESCA tissues compared to control tissues. The expression of SNHG12 was strongly associated with T stage, N stage, and TNM stage. Low SNHG12 expression in esophageal tumor tissues was significantly correlated with poor prognosis. Furthermore, knockdown of SNHG12 not only promoted proliferation, colony formation, migration, and invasion and inhibited apoptosis in ESCC cells in vitro, but also increased tumor growth in vivo. Additionally, this proves that the SNHG12/miRNA-195-5p/BCL9 network might be involved in ESCC. CONCLUSION: This is the first study to reveal that SNHG12 is downregulated in ESCC tissues and could be used as a prognostic tool. SNHG12 suppressed tumor progression in ESCC cells, serving as a potential biomarker. The SNHG12/miRNA-195-5p/BCL9 network is proposed to be the mechanism leading to ESCC progression.
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Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , ARN Largo no Codificante/fisiología , Animales , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Redes Reguladoras de Genes , Masculino , Ratones , Ratones Endogámicos BALB C , MicroARNs/fisiología , Pronóstico , ARN/genética , Factores de Transcripción/fisiologíaRESUMEN
ABSTRACT Background: Fibrinogen (Fib) to albumin (ALB) fibrinogen-to-albumin ratio as a prognostic index for esophageal cancer has been confirmed. A novel prognostic index was initially proposed with fibrinogen to prealbumin ratio (FPR) in patients with resectable esophageal squamous cell carcinoma (ESCC). Objective: The objective of the study was to study the prognostic role of the novel prognostic index (FPR) in patients with resectable ESCC without any neoadjuvant treatment. Methods: In this retrospective study, a total of 372 resectable ESCC patients without any neoadjuvant treatment were included. The best cutoff values were selected by the receiver operating characteristic curves. Two Cox regression analyses with forward stepwise (one for categorical variables and the other for continuous variables) were used to evaluate the overall survival (OS) and cancer-specific survival (CSS). Results: The best cutoff point was 0.014 for FPR. Patients with lower levels of FPR (≤0.014) had better CSS (50.7% vs. 18.0%, p < 0.001) and OS (48.0% vs. 17.6%, p < 0.001) than patients with higher levels of FPR (> 0.014). Multivariate Cox analyses (categorical and continuous) demonstrated that FPR was an independent prognostic factor in CSS (categorical: hazard ratio [HR]: 2.014, 95% confidence interval [CI]: 1.504-2.697, p < 0.001; continuous per 0.01: HR: 1.438, 95% CI: 1.154-1.793, p = 0.001) and OS (categorical: HR: 1.964, 95% CI: 1.475-2.617, p < 0.001; continuous per 0.01: HR: 1.429, 95% CI: 1.146-1.781, p = 0.002). Conclusions: Our study indicated that FPR served as an independent prognostic factor in patients with resectable ESCC.
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Fibrinógeno/metabolismo , Prealbúmina/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Pronóstico , Neoplasias Esofágicas/cirugía , Estudios Retrospectivos , Estudios de Seguimiento , Carcinoma de Células Escamosas de Esófago/cirugíaRESUMEN
PURPOSE: Esophageal squamous cell carcinoma (ESCC) is one of the most important causes of mortality in the developing world. Although hereditary forms arise from germ-line mutations in TP53, Rb, and the mismatch repair genes, many familial cases present with an unknown inherited cause. The new theory of rare, high-penetrance mutations in less known genes is a likely explanation for the underlying predisposition in some of these familial cases. METHODS: Exome sequencing was performed in 9 patients with esophageal squamous cancer from 9 families with strong disease aggregation without mutations in known hereditary esophageal cancer genes. Data analysis was limited to only really rare variants (0-0.01%), producing a putative loss of function and located in genes with a role compatible with carcinogenesis. RESULTS: Twenty-two final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDK11A, ARID1A, JMJD6, MAML3, CDKN2AIP, and PHLDA1. CONCLUSION: Together, we identified new potential esophageal squamous cancer predisposition variants in genes which may have a role in cancer and are involved in chromatin remodeling and cell-cycle pathway, which could increase the risk of ESCC.