RESUMEN
Hypoxia and angiogenesis play key roles in the pathogenesis of esophageal squamous cell carcinoma (ESCC), but regulators linking these two pathways to drive tumor progression remain elusive. Here we provide evidence of ADAM9's novel function in ESCC progression. Increasing expression of ADAM9 was correlated with poor clinical outcomes in ESCC patients. Suppression of ADAM9 function diminished ESCC cell migration and in vivo metastasis in ESCC xenograft mouse models. Using cellular fractionation and imaging, we found a fraction of ADAM9 was present in the nucleus and was uniquely associated with gene loci known to be linked to the angiogenesis pathway demonstrated by genome-wide ChIP-seq. Mechanistically, nuclear ADAM9, triggered by hypoxia-induced translocation, functions as a transcriptional repressor by binding to promoters of genes involved in the negative regulation of angiogenesis, and thereby promotes tumor angiogenesis in plasminogen/plasmin pathway. Moreover, ADAM9 suppresses plasminogen activator inhibitor-1 gene transcription by interacting with its transcription factors at the promoter. Our findings uncover a novel regulatory mechanism of ADAM9 as a transcriptional regulator in angiogenesis and highlight ADAM9 as a promising therapeutic target for ESCC treatment.
Asunto(s)
Proteínas ADAM/fisiología , Neoplasias Esofágicas/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Proteínas de la Membrana/fisiología , Neovascularización Patológica/fisiopatología , Factores de Transcripción/fisiología , Animales , Movimiento Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Ratones , Ratones SCID , Neovascularización Patológica/genética , Inhibidor 1 de Activador Plasminogénico/genética , Pronóstico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Angiogenesis produced by tumor microenvironment is play an important role in development of esophageal squamous cell carcinoma (ESCC). As a quantitative index of angiogenesis, literature has emerged contradictory results about the prognostic role of microvessel density (MVD) in ESCC. The aim of the study was to explore the impact of the correlation between MVD and the prognosis of ESCC based the published evidence. METHODS: Pubmed and Web of science database were screened for the relationship of MVD with prognostic feature in ESCC up to March, 2021. 11 relevant articles were used for meta-analysis. The following data were extracted from the literature: author, year, country, the patients number of high/low MVD, tumor-node-metastasis (TNM) classification, clinical stage, lymphoid infiltrates, vessel invasion, invasive depth, differential degree and survival rate. The hazard ratio (HR) and odds ratios (OR) with 95% CI were used to assess the associations between MVD and overall survival (OS). Chi-squared test and I2 statistics were completed to evaluate the heterogeneity in our study. A random-effects model was used when significant heterogeneity existed (I2>50% and p < 0.05). Egger test was used to calculate the publication bias. Subgroup analysis was stratified by antibody, region, sample capacity to explore the source of heterogeneity. RESULTS: 11 studies with 1055 patients were analyzed. Our results suggested that high MVD is an important factor to advanced TNM classification and clinical stage, and the high MVD is positive correlation with the lymph node invasion and vascular invasion(p < 0.05) in ESCC, but irrelevant to poor differential and invasive depth(p > 0.05). The result also indicated that low MVD is a benefit factor to prolong the survival rate (p < 0.05). And the source of the heterogeneity maybe is that the antibody used to detect the MVD was not consistent, patient number was not large enough and the count method on MVD. CONCLUSION: Across multiple studies, high MVD is correlated with clinicopathological criteria of poor prognosis and survival in ESCC. MVD could be the quantitative index to reactive angiogenesis and may play a pivotal role in ESCC development and progression. MVD may represent a valuable addition to current pathologic analysis and help to guide prognosis and treatment.
Asunto(s)
Neoplasias Esofágicas/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Densidad Microvascular , Microvasos/patología , Neovascularización Patológica , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago/mortalidad , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Factores de RiesgoRESUMEN
Dysregulated expression of S100A7 is found in several cancers and plays an important role in tumor progression; however, its carcinogenic role in esophageal squamous carcinoma (ESCC) is still poorly understood. Here, we identified that the levels of S100A7 were remarkably upregulated in 341 tumor tissues (P < .001) and 274 serum samples (P < .001) of ESCC patients compared with normal control. It was an independent prognostic factor (P = .026). Furthermore, a new diagnostic model for ESCC based on serum S100A7, SCC, and crfra21-1 was established with area under curve (AUC) up to 0.863 (95% CI: 0.802-0.925). Mechanically, we found upregulated S100A7 could promote cell migration and proliferation through intracellular binding to JAB1 and paracrine interaction with RAGE receptors and then activates the downstream signaling pathways. In addition, exocrine S100A7 could promote M2 macrophage infiltration and polarization by up-regulating M2 macrophage associated proteins, and tumor angiogenesis by enhancing the activation of p-ErK and p-FAK pathways. Further animal experiments confirmed the role of S100A7 in promoting M2 macrophage infiltration and angiogenesis in ESCC. In conclusion, these findings highlighted the potential diagnostic and prognostic value of S100A7 in patients with ESCC. Meanwhile, our results reveal that S100A7 promotes tumor progression by activating oncogenic pathways and remodeling tumor microenvironment, which paving the way for the progress of S100A7 as a therapeutic target for cancer treatment.
Asunto(s)
Neoplasias Esofágicas/diagnóstico , Carcinoma de Células Escamosas de Esófago/diagnóstico , Macrófagos/inmunología , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Animales , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Complejo del Señalosoma COP9/metabolismo , Proliferación Celular , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neovascularización Patológica , Péptido Hidrolasas/metabolismo , Pronóstico , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100/antagonistas & inhibidores , Proteína A7 de Unión a Calcio de la Familia S100/sangre , Proteína A7 de Unión a Calcio de la Familia S100/genética , Transducción de SeñalRESUMEN
Non-muscle myosin heavy chain 9 (MYH9) is one novel low frequency mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinical relevance, potential function and mechanisms remain elusive. Methods: Genomic sequencing datas from 104 esophageal squamous cell carcinoma (ESCC) cases were screened a series of low frequency mutant genes. MYH9 was selected to further analyze its clinical significance, function and PCR-array was performed to explore its potential mechanism. Results: MHY9 is a low frequency mutant gene with a mutation frequency of 2.88% in ESCC. Immunohistochemical analysis showed that MYH9 expression was significantly higher in ESCC tumor tissues, and the expression levels were associated with lymph node metastasis of ESCC patients. Moreover, we found that MYH9 knock-down led to inhibition of cell migration and invasion. PCR-array showed MYH9 knockdown led to a significant change of genes expression associated with angiogenesis and epithelial-to-mesenchymal transition (EMT). This observation is further confirmed in TCGA database of LUSC (lung squamous cell carcinoma), CESC (cervical squamous cell carcinomas) and HNSC (head and neck squamous cell carcinoma). Conclusions: Collectively, our study identifies a novel role and mechanism of MYH9, highlights a significance of MYH9 as a metastatic biomarker, and offers potential therapeutic targets for ESCC patients harboring MYH9 mutations.
Asunto(s)
Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Cadenas Pesadas de Miosina/genética , Neovascularización Patológica/genética , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal/fisiología , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mutación , Cadenas Pesadas de Miosina/metabolismo , Neovascularización Patológica/patología , PronósticoAsunto(s)
Carcinoma Hepatocelular/diagnóstico , Neoplasias Esofágicas/diagnóstico , Várices Esofágicas y Gástricas/diagnóstico , Cirrosis Hepática/patología , Neoplasias Hepáticas/diagnóstico , Biopsia , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/secundario , Mucosa Esofágica/irrigación sanguínea , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/secundario , Várices Esofágicas y Gástricas/etiología , Humanos , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Vena Porta/diagnóstico por imagen , Vena Porta/patología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND Protocadherin 8 (PCDH8) functions as a tumor-suppressor gene in many types of cancer. This study aimed to investigate the role of PCDH8 in esophageal squamous cell carcinoma (ESCC). MATERIAL AND METHODS Cell proliferation, apoptosis, transwell assay, tube formation assays, and tumor xenograft experiment were performed to explore the role of PCDH8 in the progression of ESCC. RESULTS PCDH8 was found to be downregulated in ESCC cells. Ectopic expression of PCDH8 blocked proliferation, invasion, and migration and induced apoptosis in ESCC cells. Furthermore, vascular endothelial growth factor A (VEGFA) secretion and the AKT signaling pathway were also inhibited when PCDH8 was upregulated. PCDH8 overexpression suppressed epithelial-mesenchymal transition (EMT) and pro-angiogenic activity of ESCC cells. In a mouse model of ESCC xenograft tumors, PCDH8 overexpression remarkably restrained tumor cell growth, with the tumor inhibition rate of 75.2%. PCDH8 was the target of miR-200c and had a negative correlation with miR-200c. CONCLUSIONS PCDH8 exerts a tumor-suppressive effect against ESCC cells. However, further studies are required to elucidate the exact molecular mechanism underlying the antitumor activity of PCDH8 in ESCC.
Asunto(s)
Cadherinas/biosíntesis , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/metabolismo , Regiones no Traducidas 3' , Animales , Apoptosis/fisiología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Transición Epitelial-Mesenquimal , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Invasividad Neoplásica , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Protocadherinas , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Early stage of esophageal squamous cell carcinoma (ESCC) is known to be accompanied by angiogenesis and morphological changes of microvessels. Transcription factor Sox2 is amplified in various cancers including ESCC, but the role of Sox2 in the carcinogenesis and angiogenesis has not been determined. Hence, we aimed to investigate the role of Sox2 in the early stage of ESCC. We found that the expression of Sox2 was significantly higher in early-stage ESCC tissues than that in their adjacent normal tissues. We then established Sox2-inducible normal human esophageal squamous cell line (HetSox2) to investigate the role of Sox2 in esophageal carcinogenesis and angiogenesis in vitro. Sox2 overexpression led to increased cell proliferation and spheroid formation. The culture supernatant of Sox2-overexpressing HetSox2 induced migration and sprouting of endothelial cell line HUVEC (human umbilical vein endothelial cell). As for the mechanism, we found that the expression of secreted protein Suprabasin was directly induced by Sox2. Suprabasin enhanced proliferation of normal human esophageal squamous cells when added to the culture. Moreover, Suprabasin enhanced migration and sprouting of HUVEC cells, which were observed with the culture supernatant of Sox2-overexpressing HetSox2. This angiogenic effect of Suprabasin was abolished by inhibiting AKT phosphorylation, which suggested its dependence on AKT signaling. Finally, we showed that Suprabasin expression and the density of microvessels were significantly higher in ESCC tissues with high Sox2 expression. Our study suggested that increased Sox2 expression in esophageal squamous cells induced Suprabasin expression, and as a result initiated the carcinogenesis via increased cell proliferation and angiogenesis.
Asunto(s)
Antígenos de Diferenciación/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/patología , Factores de Transcripción SOXB1/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Movimiento Celular , Proliferación Celular , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Humanos , Neovascularización Patológica/metabolismo , Fosforilación , Pronóstico , Factores de Transcripción SOXB1/genética , Transducción de Señal , Células Tumorales CultivadasRESUMEN
OBJECTIVES: Accurate diagnosis of invasion depth is important for reliable treatment of esophageal squamous cell carcinoma (ESCC), but it is limited to the muscularis mucosae to slight submucosal invasion (MM/SM1). The diagnostic accuracy of invasion depth is unsatisfactory and remains to be improved. We aimed to investigate the association between the color of the superficial ESCC and invasion depth using linked color imaging (LCI) under light-emitting diode (LED) light sources. METHODS: Lesions diagnosed as superficial ESCC were observed using white light imaging and then by LCI. The color values were calculated using Commission Internationale de l'Eclariage - L*a*b* color space, and the color difference was calculated according to invasion depth. The vascular diameters and vascular angles of the intrapapillary capillary loops were pathologically analyzed. Their correlation with mucosal color was also investigated by LCI. RESULTS: In all, 52 lesions from 48 patients were analyzed. On the basis of invasion depth, the color difference between the normal mucosa and the lesion was larger in the MM/SM1 or deeper group than in the epithelium and the lamina propria mucosa (EP/LPM) group using LCI (P = 0.025). The vascular diameter was positively correlated with the b* color value (correlation coefficient = 0.302, P = 0.033). CONCLUSION: Observation using LCI under LED light sources may improve the endoscopic diagnosis of the invasion depth of superficial ESCC. Further research is needed to validate its usefulness. (UMIN000024615).
Asunto(s)
Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/patología , Anciano , Anciano de 80 o más Años , Color , Resección Endoscópica de la Mucosa , Endoscopía Gastrointestinal , Mucosa Esofágica/irrigación sanguínea , Mucosa Esofágica/cirugía , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Femenino , Humanos , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estudios RetrospectivosRESUMEN
Anti-angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient-derived xenograft (PDX) models of EAC were subjected to long-term and short-term treatment with anti-VEGFR2 therapy followed by chemotherapy injection or multi-agent dynamic contrast-enhanced (DCE-) MRI and vascular casting. Long-term anti-VEGFR2-treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short-term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short-term anti-angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long-term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti-angiogenic therapy combined with chemotherapy in EAC patients.
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Adenocarcinoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/metabolismo , Animales , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/metabolismo , Femenino , Humanos , Ratones Desnudos , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/metabolismo , Células Tumorales Cultivadas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Cyclin E and hepatocyte growth factor (HGF) have been observed as a multifaceted factor in many cancers, and the assessment of microvascular density (MVD) and micro-lymphatic vessel density (MLVD) has been used to quantify tumor angiogenesis and lymphangiogenesis. The aim of this study was to explore the association between expression of cyclin E, HGF, MVD, and MLVD, and clinicopathologic parameters in esophageal squamous cell carcinoma (ESCC). The expression of cyclin E, HGF, MVD, and MLVD were detected using immunohistochemically anticyclin E, HGF, CD34, and lymphatic vessel endothelial hyaluronan receptor 1 in 168 surgically resected ESCC cases and 30 normal esophageal mucosal samples. The expression levels of cyclin E, HGF, MVD, and MLVD were higher compared to controls. High cyclin E and HGF expression was found more frequently in the tumors larger than 5 cm (P < .001), with poorer differentiation (P = .034) and higher tumor node metastasis (TNM) staging (P = .009) compared to their counterparts. Both MVD and MLVD values were found to be higher in the tumors larger than 5 cm (P < .001), with poorer differentiation (P < .001) and higher TNM staging (P < .001) compared to their counterparts. Furthermore, the expression of MVD and MLVD in both the high cyclin E and high HGF expression groups was significantly higher compared to the low cyclin E and HGF expression groups (P < .001). This study demonstrated that high cyclin E and HGF expression is closely correlated with tumor size, tumor differentiation degree, and TNM stage in patients with ESCC. These findings proposed that cyclin E and HGF could serve as novel molecular markers for preoperational evaluation of ESCC.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Carcinoma de Células Escamosas/metabolismo , Ciclina E/biosíntesis , Neoplasias Esofágicas/metabolismo , Factor de Crecimiento de Hepatocito/biosíntesis , Vasos Linfáticos/metabolismo , Neovascularización Patológica/metabolismo , Anciano , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/patología , Femenino , Humanos , Inmunohistoquímica , Vasos Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/patología , PronósticoRESUMEN
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, and serves as a conduit for migration. Targeting oncogenes involved in angiogenesis is needed to treat organ-confined and locally advanced ESCC. Although the phospholipase C epsilon-1 (PLCE1) gene was originally identified as a susceptibility gene for ESCC, how PLCE1 is involved in ESCC is unclear. METHODS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to measure the methylation status of the PLCE1 promoter region. To validate the underlying mechanism for PLCE1 in constitutive activation of the NF-κB signaling pathway, we performed studies using in vitro and in vivo assays and samples from 368 formalin-fixed esophageal cancer tissues and 215 normal tissues with IHC using tissue microarrays and the Cancer Genome Atlas dataset. RESULTS: We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts. PLCE1 can activate NF-κB through phosphoinositide-phospholipase C-ε (PI-PLCε) signaling pathway. Furthermore, PLCE1 can bind p65 and IκBα proteins, promoting IκBα-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IκBα promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro. Moreover, xenograft tumors in nude mice proved that PLCE1 can induce angiogenesis, inhibit apoptosis, and increase tumor aggressiveness via the NF-κB signaling pathway in vivo. CONCLUSIONS: Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCε-NF-κB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC.
Asunto(s)
Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago/genética , Fosfoinositido Fosfolipasa C/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Apoptosis/fisiología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/fisiología , Epigénesis Genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , FN-kappa B/genética , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Fosfoinositido Fosfolipasa C/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Angiogenesis is crucial for the progression of esophageal squamous cell carcinoma (ESCC). Antiangiogenesis by targeting important molecules has been considered as one of the most promising and efficient strategy for cancer therapy. Recent studies have demonstrated that the IQdomain GTPase activating protein 1 (IQGAP1) plays critical roles in tumorigenesis and cancer progression. We previously reported that IQGAP1 is overexpressed in ESCC, and IQGAP1 knockdown can decrease cell proliferation and metastasis ability in vitro and in vivo. However, the effects of IQGAP1 on the angiogenesis of ESCC and its underlying mechanisms remain unknown. In the present study, we found that IQGAP1 overexpression promoted tumor angiogenesis confirmed by human umbilical vascular endothelial cell (HUVEC) tube formation in vitro and chicken embryo chorioallantoic membrane (CAM) assay in vivo. Moreover, IQGAP1 overexpression in ESCC cells increased expression of vascular endothelial growth factor (VEGF) and phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). Meanwhile, we found that levels of AKT and ERK phosphorylation were upregulated in IQGAP1overexpressing cells. Importantly, IQGAP1knockdown cells showed the opposing results. Furthermore, AKT and ERK inhibitors not only significantly decreased VEGF expression and VEGFR2 phosphorylation in IQGAP1overexpressing cells, but also abolished the proangiogenic effect of IQGAP1 overexpression on angiogenesis in the HUVEC tube formation and chicken embryo CAM assay. Taken together, this evidence confirms that IQGAP1 overexpression promotes tumor angiogenesis via the AKT and ERKmediated VEGFVEGFR2 signaling pathway in ESCC, and IQGAP1 may be an attractive therapeutic target for cancer antiangiogenesis treatment.
Asunto(s)
Neoplasias Esofágicas/irrigación sanguínea , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neovascularización Patológica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo , Apoptosis , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proliferación Celular , Membrana Corioalantoides/metabolismo , Membrana Corioalantoides/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Humanos , Fosforilación , Células Tumorales CultivadasRESUMEN
BACKGROUND: The relationship between thymidine phosphorylase (TP) and angiogenesis at the early stage of esophageal squamous cell carcinoma has been unclear. METHODS: Using 14 samples of normal squamous epithelium, 11 samples of low-grade intraepithelial neoplasia, and 64 samples of superficial esophageal cancer, microvessel density (MVD) was estimated using immunostaining for CD34 and CD105. TP expression was also evaluated in both cancer cells and stromal monocytic cells (SMCs). We then investigated the correlation between MVD and TP expression in both cancer cells and SMCs. RESULTS: On the basis of the above parameters, MVD was significantly higher in cancerous lesions than in normal squamous epithelium. In terms of CD34 and CD105 expression, MVD showed a gradual increase from normal squamous epithelium, to low-grade intraepithelial neoplasia, and then to M1 and M2 cancer, and M3 or deeper cancer. M1 and M2 cancer showed overexpression of TP in both cancer cells and SMCs. There was no significant correlation between TP expression in cancer cells and MVD estimated from CD34 (rS = 0.16, P = 0.21) or CD105 (rS = 0.05, P = 0.68) expression. Significant correlations were found between TP expression in SMCs and CD34-related (rS = 0.46, P < 0.001) and CD105-related (rS = 0.34, P < 0.01) MVD. In M3 or deeper cancers, there were no significant correlations between TP expression in cancer cells or SMCs and venous invasion, lymphatic invasion, and lymph node metastasis. CONCLUSION: TP expression is activated in both cancer cells and stromal monocytic cells at the very early stage of ESCC progression. TP expression in SMCs, rather than in cancer cells, is significantly correlated with angiogenesis.
Asunto(s)
Carcinoma de Células Escamosas/enzimología , Neoplasias Esofágicas/enzimología , Neovascularización Patológica/enzimología , Timidina Fosforilasa/fisiología , Antígenos CD34/metabolismo , Carcinoma de Células Escamosas/irrigación sanguínea , Progresión de la Enfermedad , Endoglina/metabolismo , Epitelio/irrigación sanguínea , Epitelio/enzimología , Neoplasias Esofágicas/irrigación sanguínea , Carcinoma de Células Escamosas de Esófago , Esófago/irrigación sanguínea , Esófago/enzimología , Humanos , Microvasos/patología , Lesiones Precancerosas/enzimología , Células del Estroma/enzimología , Timidina Fosforilasa/metabolismoRESUMEN
Aidi injection, a proprietary Chinese medicine, has been widely used for the treatment of cancer. However, its effects and potential mechanism in esophageal squamous cell carcinoma (ESCC) have not yet been characterized. The aim of the present study was to identify the mechanism underlying the antimetastatic effects of treatment with Aidi. To test the effects and mechanism, EC9706 and KYSE70 cells were selected for in vitro experiments. In vivo, the antimetastatic effects of Aidi injection on a nude mouse peritoneal metastasis model were examined, and the mechanisms were assessed with immunohistochemical staining. A cell proliferation assay demonstrated that treatment with more than 3 mg/ml Aidi for 24 or 48 h significantly inhibited the proliferation of EC9706 (P<0.01) and KYSE70 cells (P<0.05, P<0.01). Subsequent experiments assessed cell migration, invasion and vasculogenic mimicry (VM) formation, with 5fluorouracil serving as a positive control. It was observed that treatment with Aidi inhibited cell migration, invasion and VM formation. Furthermore, it was identified that treatment with Aidi inhibited epithelialmesenchymal transition (EMT) signaling and the expression of vascular endothelial growth factor A (VEGFA) in EC9706 and KYSE70 cells, using western blotting. In the in vivo experiments, Aidi injection effectively suppressed tumor metastasis in the mouse tumor model. Additionally, the expression of vimentin and vascular endothelial growth factor was decreased, and the expression of cadherin1 was increased in the tumor tissue. The present results suggested that treatment with Aidi may inhibit tumor metastasis in ESCC through the inhibition of EMT signaling and angiogenesis.
Asunto(s)
Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Animales , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patologíaRESUMEN
Observation of the microvasculature using narrow band imaging (NBI) with magnifying endoscopy is useful for diagnosing superficial squamous cell carcinoma. Increased vascular density is indicative of cancer, but not many studies have reported differences between cancerous and noncancerous areas based on an objective comparison. We observed specimens of endoscopic submucosal dissection (ESD) using NBI magnification, and determined the vascular density of cancerous and noncancerous areas. A total of 25 lesions of esophageal squamous cell carcinoma that were dissected en bloc by ESD between July 2013 and December 2013 were subjected to NBI magnification. We constructed a device that holds an endoscope and precisely controls the movement along the vertical axis in order to observe submerged specimens by NBI magnification. NBI image files of both cancerous (pathologically determined invasion depth, m1/2) and surrounding noncancerous areas were created and subjected to vascular density assessment by two endoscopists who were blinded to clinical information. The invasion depth was m1/2 in 20, m3/sm1 in four and sm2 in one esophageal cancer lesion. Mean vascular density was significantly increased in cancerous areas (37.6 ± 16.3 vessels/mm2) compared with noncancerous areas (17.6 ± 10.0 vessels/mm2) (P < 0.05). The correlation coefficients between vascular density determined by two endoscopists were 0.86 and 0.81 in cancerous and noncancerous areas, respectively. Receiver operating curve (ROC) analysis revealed that the area under the curve (AUC) of vascular density was 0.895 (95% CI, 0.804-0.986). For this ROC curve, sensitivity was 78.3% and specificity was 87.0% when the cutoff value of vascular density was 26 vessels/mm2. NBI magnification confirmed significant increases in vascular density in cancerous areas compared with noncancerous areas in esophageal squamous cell carcinoma. The rates of agreement between vascular density values determined by two independent operators were high.
Asunto(s)
Carcinoma de Células Escamosas/irrigación sanguínea , Neoplasias Esofágicas/irrigación sanguínea , Esofagoscopía/métodos , Esófago/irrigación sanguínea , Microvasos/patología , Imagen de Banda Estrecha/métodos , Anciano , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Esófago/patología , Femenino , Humanos , Aumento de la Imagen/métodos , Masculino , Microvasos/diagnóstico por imagen , Persona de Mediana Edad , Curva ROC , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: To date, literature has emerged that shows contradictory results about the prognostic role of microvessel density (MVD) in esophageal squamous cell cancer (ESCC). The aim of the study set out to evaluate the correlation between MVD and the prognosis of ESCC. METHODS: Identified publications from various databases were obtained and reviewed. A meta-analysis was performed to evaluate the prognostic role of MVD among ESCC patients. RESULTS: A total of 11 eligible studies containing 891 ESCC cases were included in the meta-analysis. The pooled hazard ratio for overall survival was 2.39 (95% confidence interval 1.92-2.96, Pâ<â.001). Heterogeneity among the studies was not significant, and publication bias was not found. Subgroup analyses were also performed on different issues, such as districts, antibodies, and median age. CONCLUSION: High MVD is a prognostic factor among ESCC that indicated worse prognosis in these patients. More studies are needed, and through abundant evidence, the topic could be re-evaluated by then.
Asunto(s)
Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/diagnóstico , Microvasos , Carcinoma de Células Escamosas de Esófago , Humanos , PronósticoRESUMEN
Antiangiogenesis therapy is one of only 2 biologically targeted approaches shown to improve overall survival over standard of care in advanced adenocarcinoma of the stomach or gastroesophageal junction (GEJ). Therapeutic targeting of vascular endothelial growth factor receptor 2 improves overall survival in patients with previously treated advanced gastric/GEJ adenocarcinoma. No antiangiogenesis therapy has demonstrated an overall survival benefit in patients with chemo-naïve or resectable esophagogastric cancer or in patients whose tumors arise from the esophagus. Promising ongoing clinical investigations include the combination of antiangiogenesis therapy with immune checkpoint inhibition and anti-human epidermal growth factor receptor 2 therapy.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/irrigación sanguínea , Neoplasias Esofágicas/irrigación sanguínea , Unión Esofagogástrica/irrigación sanguínea , Humanos , Neoplasias Gástricas/irrigación sanguíneaRESUMEN
The aims of this study were to investigate intrapapillary capillary loops (IPCLs) of superficial esophageal lesions changes in different types classified by the Japan Esophageal Society classification. The calibers, areas, and densities of IPCLs were detected in 34 cases of esophageal lesions using immunohistochemical analysis. Statistically significant differences in calibers, areas, and densities of IPCLs were observed between type A, type B1/B2, and type B3 area (P < 0.001). In conclusion, the results of this observation showed the Japan Esophageal Society classification of IPCL would help endoscopists to diagnose the type and the invasion depth of lesion in esophagus, and decide the treatment strategy.
Asunto(s)
Capilares/patología , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Anciano , Carcinoma de Células Escamosas/irrigación sanguínea , Carcinoma de Células Escamosas/cirugía , Resección Endoscópica de la Mucosa , Neoplasias Esofágicas/irrigación sanguínea , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago , Esofagoscopía , Esófago/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Imagen de Banda Estrecha , Estudios RetrospectivosRESUMEN
PURPOSE: To reveal the patterns of the mediastinal course of the bronchial arteries (BAs). METHODS: The BAs were dissected to determine the positional relationships of their mediastinal courses with the tracheobronchus and the esophagus in 72 adult cadavers. RESULTS: The mediastinal courses of the 227 BAs found in this study were classified into 4 types. There were 61 and 163 BAs passing the right side (Type I) and the left side (Type II reaching dorsal surface (n = 98), or Type III reaching ventral surface (n = 65) of the tracheobronchus) of the esophagus, respectively. Three BAs originated from the subclavian artery (Type IV). All Type I BAs were right BAs, whereas 91.8% of the Type II BAs were left BAs. However, 43.1 and 56.9% of the Type III BAs were the right and left BAs, respectively. CONCLUSION: The classification of the mediastinal course of the BAs determined by the spatial relationships to the tracheobronchus and the esophagus may be clinically useful, because each category of this classification can be determined during esophagectomy and indicates whether the BA is a right or left BA.