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1.
Adv Exp Med Biol ; 1287: 59-68, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034026

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Receptores Notch/metabolismo , Carcinogênese , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Transdução de Sinais
2.
Anticancer Res ; 40(10): 5343-5349, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988852

RESUMO

BACKGROUND/AIM: The present study aimed to examine the association of the controlling nutritional status (CONUT) score with outcomes in patients undergoing esophagectomy for esophageal cancer (EC). MATERIALS AND METHODS: A systematic literature review was carried out to investigate the impact of the CONUT score in EC. Next, meta-analysis of long-term outcomes was performed. RESULTS: The search found six eligible retrospective studies, and five studies with 952 patients were included in the meta-analysis. Meta-analysis found a significant association of the CONUT score with outcomes including overall survival [hazard ratio (HR)=2.51, 95% confidence interval (CI)=1.75-3.60, p<0.001], cancer-specific survival (HR=2.60, 95%CI=1.53-4.41, p<0.001), and recurrence free survival (HR=2.08, 95%CI=1.39-3.12, p<0.001). CONCLUSION: The CONUT score may be an independent predictor associated with prognosis in patients undergoing esophagectomy for EC. However, further studies are needed to clarify the association of the CONUT score with postoperative outcomes in EC patients.


Assuntos
Neoplasias Esofágicas/metabolismo , Estado Nutricional/fisiologia , Complicações Pós-Operatórias/metabolismo , Intervalo Livre de Doença , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Humanos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/patologia , Modelos de Riscos Proporcionais
3.
PLoS Biol ; 18(9): e3000825, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886690

RESUMO

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.


Assuntos
Infecções por Bacteroidaceae/complicações , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Porphyromonas gingivalis/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Animais , Infecções por Bacteroidaceae/metabolismo , Infecções por Bacteroidaceae/mortalidade , Infecções por Bacteroidaceae/patologia , Células Cultivadas , Progressão da Doença , Drosophila , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/microbiologia , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/microbiologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Feminino , Seguimentos , Células HCT116 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo
4.
Clin Nucl Med ; 45(10): 741-746, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32796247

RESUMO

PURPOSE: Esophagectomy with extended lymph node (LN) dissection is a standard treatment for resectable esophageal cancer to prevent recurrence, but severe, potentially life-threatening postoperative complications are still important issues. Accurate diagnosis of LN metastases would enable the decision to dissect or leave the LNs in regions with high risk of complications. Advancements in intraoperative gamma probe and radioactivity detectors have made intraoperative navigation surgery possible using a radiotracer as a marker. F-FDG is one such candidate markers, and the diagnostic power of FDG through counting the radioactivity close to each LN should be elucidated. MATERIALS AND METHODS: In 20 patients, 1073 LNs including 38 metastatic LNs were prospectively investigated. Preoperative FDG PET was performed on the same day before esophagectomy and visually surveyed in each LN station to identify abnormal uptake. The FDG radioactivity of each individual dissected LN was measured by a well-type counter, and the pathological diagnosis was compared with LN radioactivity on a one-by-one basis and with the preoperative FDG PET findings for each LN station. RESULTS: Lymph node station-based analysis showed a sensitivity and specificity of 28.6% and 96.7%, respectively. One-by-one LN-based analysis using a cutoff value obtained from the receiver operating characteristic curve showed a sensitivity and specificity of 94.7% and 78.7%, respectively, demonstrating higher accuracy compared with the use of LN weight or the shortest diameter. CONCLUSIONS: The FDG uptake by each LN is a potentially useful marker for navigation surgery in esophageal cancer and has higher accuracy than LN weight or diameter.


Assuntos
Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/metabolismo , Fluordesoxiglucose F18/metabolismo , Linfonodos/metabolismo , Idoso , Neoplasias Esofágicas/patologia , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Sensibilidade e Especificidade
5.
Hum Cell ; 33(4): 1294-1301, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32710259

RESUMO

Carcinostatic effects of combined use of hydrogen nano-bubbles (nano-H) and platinum-povidone (PVP--Pt) were examined. Hydrogen-dissolved medium was prepared by hydrogen-gas bubbling with a microporous gas-emittance-terminal into a medium in the absence or presence of PVP-Pt (nano-H, nano-H/PVP-Pt). Human esophagus-derived carcinoma cells KYSE70 were repressed for cell proliferation with nano-H/PVP-Pt more markedly than with nano-H, indicating the hydrogen-intensification for PVP-Pt-alone-carcinostasis. However, the intensified carcinostasis required co-administration of nano-H and PVP-Pt, and no intensified carcinostasis was shown in two-step separate administration of nano-H and PVP-Pt. Furthermore, hydrogen bubbling into PVP-Pt-containing medium achieved more appreciable carcinostasis than mere addition of PVP-Pt into nano-H-containing medium, indicating the potent interaction of hydrogen and PVP-Pt. The nano-H/PVP-Pt-administered human tongue-derived carcinoma cells HSC-4 were repressed for cell proliferation more markedly than pre-malignant human tongue-derived epitheliocytes DOK, concurrently with more abundant intracellular Pt-intake into HSC-4 cells than DOK as analyzed by ICP-MS. Thus, PVP-Pt is able to adsorb hydrogen nano-bubbles on Pt and applicable for cancer therapy by diminishing the side-effects to normal cells.


Assuntos
Antineoplásicos , Carcinoma/patologia , Proliferação de Células/efeitos dos fármacos , Interações Medicamentosas , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Hidrogênio/farmacologia , Nanopartículas , Compostos de Platina/efeitos adversos , Compostos de Platina/metabolismo , Compostos de Platina/farmacologia , Povidona/efeitos adversos , Povidona/farmacologia , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia , Carcinoma/metabolismo , Linhagem Celular Tumoral , Coloides , Meios de Cultura , Combinação de Medicamentos , Neoplasias Esofágicas/tratamento farmacológico , Gases , Humanos , Hidrogênio/administração & dosagem , Povidona/metabolismo , Neoplasias da Língua/tratamento farmacológico
6.
Am Surg ; 86(6): 615-620, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32683954

RESUMO

BACKGROUND: Enhanced recovery protocols after esophagectomy aim to discharge patients by day 7. A small risk of delayed complications exists. We aimed to assess whether C-reactive protein (CRP) levels on day 7 could help predict delayed complications and assist safe discharge. METHODS: All consecutive esophagectomies over 3 years were retrospectively reviewed. Patients were categorized on day 7 into (1) those clinically unsafe for discharge; (2) those clinically safe for discharge; and (3) those considered safe for discharge but develop a delayed complication. CRP level on day 7 and the trend in CRP levels between days 3 and 7 were compared. RESULTS: A total of 140 patients underwent esophagectomy, of which 64 patients (46%) had at least one complication. On day 7, 62 (44%) patients were considered clinically unsafe for discharge; 74 (53%) were considered safe for discharge; and 4 (3%) were safe but developed a delayed complication. No patient with delayed complication had a day 7 CRP level < 84 mg/L. CRP trend did not help predict delayed complications. CONCLUSIONS: The actual CRP level on day 7 after esophagectomy, rather than the trend, can predict delayed complications. Early discharge after esophagectomy should be desisted if the clinical picture is better than the actual blood results.


Assuntos
Proteína C-Reativa/metabolismo , Neoplasias Esofágicas/cirurgia , Esofagectomia , Alta do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/diagnóstico , Adulto , Idoso , Biomarcadores/metabolismo , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos
7.
Nat Commun ; 11(1): 3715, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709844

RESUMO

Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8+ response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.


Assuntos
Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Análise de Célula Única/métodos , Transcriptoma , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Células Epiteliais/patologia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T , Fatores de Transcrição , Microambiente Tumoral
8.
Life Sci ; 257: 118104, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679143

RESUMO

Halofuginone (HF) from Dichroa febrifuga has shown therapeutic potential in hepatocellular, lung and colorectal cancer cell models. Evidence has also indicated that HF plays roles in caustic induced esophageal strictures and oxidative injury. However, the role of HF in esophageal squamous carcinoma (ESCC) remains unclear. In this study, we investigated HF actions and mechanisms during ESCC cell apoptosis. We observed different HF concentrations (5, 10 and 20 nM) inhibited ESCC cell survival in a time and dose-dependent manner. HF treatment markedly induced KYSE-30 and TE-1 cell apoptosis, and caspase-3 activity. Apoptosis related protein Bax expression was dramatically increased, whereas Bcl-2 levels were reduced in KYSE-30 and TE-1 cells, after HF exposure. Also, we showed that HF treatment induced DNA damage by promoting γH2AX, pATM and pATR expression. HF treatment also reduced hypoxia-inducible factor-1α (HIF-1α) and forkhead box class O 3a (FOXO3a) expression in KYSE-30 and TE-1 cells. We also showed that HF inhibited FOXO3a expression, but this was dependent on HIF-1α inhibition. Finally, FOXO3a overexpression reversed HF induced cell survival inhibition, cell apoptosis and DNA damage. FOXO3a knockdown enhanced the effects of HF on cell survival, cell apoptosis and DNA damage. In summary, HF plays inhibitory roles in ESCC cell apoptosis, via HIF-1α-FOXO3a-dependent signaling. These data support the notion that HF could act as an effective therapeutic reagent towards ESCC.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteína Forkhead Box O3/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Piperidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/metabolismo , Humanos
9.
J Cancer Res Clin Oncol ; 146(9): 2319-2327, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592066

RESUMO

PURPOSE: Lymphocyte activation gene-3 (LAG3) is an immunosuppressive checkpoint molecule expressed on T cells. The frequency and distribution of LAG3 expression in oesophageal adenocarcinoma (EAC) is unknown. Aim of the study was the evaluation and distribution of LAG3 on tumour infiltrating lymphocytes (TILs) and correlation with clinico-pathological and molecular data. METHODS: We analysed tumor tissue samples using immunohistochemistry, multi-colour immunofluorescence and mRNA in-situ technology. The analyses were performed on a multi-spot tissue microarray (TMA) with 165 samples, followed by an evaluation on a single-spot TMA with 477 samples. These results were correlated with clinical and molecular tumour data. RESULTS: LAG3 expression on TILs was detectable in 10.5% on the multi-spot TMA and 11.4% on the single-spot TMA. There was a strong correlation between protein expression and mRNA expression (p < 0.001) in TILs. LAG 3 expression was correlated with CD4+ and CD8+ T-cells within the tumor (p < 0.001). LAG3 expression showed an improved overall survival (OS) compared to patients without LAG3 expression (median OS 70.2 vs. 26.9 months; p = 0.046). The effect was even clearer in the group of patients with tumour stages > pT2 (70.2 vs 25.0 months; p = 0.037). CONCLUSION: This is the first description of LAG3 expression on TILs in EAC, underscoring the importance of immunomodulation in EAC. Our data suggest an impact of LAG3 in a relevant subset of EAC. Therapeutic studies investigating the efficacy of LAG3 inhibition in EAC will also provide predictive evidence and relevance of the immunohistochemical determination of LAG3 expression.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Neoplasias Esofágicas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , RNA Mensageiro/metabolismo , Adenocarcinoma/patologia , Idoso , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Ativação Linfocitária/fisiologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Estadiamento de Neoplasias/métodos
10.
Cancer Sci ; 111(9): 3132-3141, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579769

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD-L1 expression on tumors, tumor-infiltrating lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Imunomodulação/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Mutação , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
11.
J Cancer Res Ther ; 16(2): 269-275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474512

RESUMO

Background: Hypoxia-inducible factor 1α (HIF-1α), p53, and vascular endothelial growth factor (VEGF) are important factors that facilitate tumor progression. The aims of our study were to investigate the expression of HIF-1α, p53, and VEGF in esophageal squamous cell carcinoma (ESCC) treated by curative surgery and to analyze their association with clinicopathological parameters and clinical outcome. Materials and Methods: The surgical specimens from 120 patients who had undergone potentially curative resection for ESCC were immunohistochemically assessed using monoclonal antibodies against HIF-1α, p53, and VEGF. Results: Positive rates of HIF-1α, p53, and VEGF expression were 61.7%, 56.7%, and 78.3%, respectively. No significant relationship was found between HIF-1α, p53, VEGF expression, and the analyzed clinicopathological parameters. There was no significant correlation between the expression of HIF-1α, p53, and VEGF. Univariate analysis revealed that overexpression of HIF-1α was associated with poor disease-free and overall survival (P = 0.023 and 0.01, respectively). Multivariate analysis demonstrated that upregulation of HIF-1α is an independent predictor for poor overall survival (P = 0.044). Conclusions: HIF-1α was a useful independent prognostic factor for surgically treated ESCC. Further studies with larger sample size are required to determine the relationship between the expression of HIF-1α, p53, VEGF, and clinicopathological parameters.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/cirurgia , Feminino , Humanos , Hipóxia/patologia , Metástase Linfática , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Taxa de Sobrevida
12.
Am J Pathol ; 190(9): 1921-1930, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479822

RESUMO

Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were analyzed by immunohistochemistry in a cohort of 260 esophageal cancers, including 40 matched lymph node metastases and 137 normal adjacent esophageal tissues. Nerves were detected in 38% of esophageal cancers and were more associated with squamous cell carcinomas (P = 0.04). The surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with reduced survival (P = 0.04). Nerves were found to express the following receptors for nerve growth factor (NGF): neurotrophic receptor tyrosine kinase 1 and nerve growth factor receptor. An association was suggested between high production of NGF by cancer cells and the presence of nerves (P = 0.02). In vitro, NGF production in esophageal cancer cells was shown by Western blot, and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. The neurotrophic activity of esophageal cancer cells was inhibited by anti-NGF blocking antibodies. Together, these data suggest that innervation is a feature in esophageal cancers that may be driven by cancer cell-released NGF.


Assuntos
Neoplasias Esofágicas/patologia , Invasividade Neoplásica/patologia , Fator de Crescimento Neural/metabolismo , Nervos Periféricos/patologia , Adulto , Idoso , Neoplasias Esofágicas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral
13.
Lab Invest ; 100(9): 1140-1157, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32457351

RESUMO

Tumor-associated macrophages (TAMs) contribute to the progression and mortality of various malignancies. We reported that high numbers of infiltrating TAMs were significantly associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma (ESCC). In our previous investigation of TAMs' actions in ESCC, we compared gene expression profiles between peripheral blood monocyte (PBMo)-derived macrophages and TAM-like macrophages stimulated with conditioned media of ESCC cell lines. Among the upregulated genes in the TAM-like macrophages, we focused on CC chemokine ligand 3 (CCL3), which was reported to contribute to tumor progression in several malignancies. Herein, we observed that not only TAMs but also ESCC cell lines expressed CCL3. A CCL3 receptor, CC chemokine receptor 5 (CCR5) was expressed in the ESCC cell lines. Treating the ESCC cell lines with recombinant human (rh)CCL3 induced the phosphorylations of Akt and ERK, which were suppressed by CCR5 knockdown. Migration and invasion of ESCC cells were promoted by treatment with rhCCL3 and co-culture with TAMs. TAMs/rhCCL3-promoted cell migration and invasion were suppressed by inhibition of the CCL3-CCR5 axis, PI3K/Akt, and MEK/ERK pathways. Treatment with rhCCL3 upregulated MMP2 and VEGFA expressions in ESCC cell lines. Our immunohistochemical analysis of 68 resected ESCC cases showed that high expression of CCL3 and/or CCR5 in ESCC tissues was associated with poor prognosis. High CCR5 expression was associated with deeper invasion, presence of vascular invasion, higher pathological stage, higher numbers of infiltrating CD204+ TAMs, and higher microvascular density. High expression of both CCL3 and CCR5 was an independent prognostic factor for disease-free survival. These results suggest that CCL3 derived from both TAMs and cancer cells contributes to the progression and poor prognosis of ESCC by promoting cell migration and invasion via the binding of CCR5 and the phosphorylations of Akt and ERK. The CCL3-CCR5 axis could become the target of new therapies against ESCC.


Assuntos
Carcinoma de Células Escamosas/genética , Quimiocina CCL3/genética , Neoplasias Esofágicas/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Receptores CCR5/genética , Idoso , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Quimiocina CCL3/metabolismo , Progressão da Doença , Neoplasias Esofágicas/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CCR5/metabolismo
14.
Mol Carcinog ; 59(8): 940-954, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32367570

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with poor prognosis. And different individuals respond to the same drug differently. Increasing evidence has confirmed that metabolism reprogramming was involved in the drug sensitivity of tumor cells. However, the potential molecular mechanism of 5-fluorouracil (5-FU) sensitivity remains to be elucidated in ESCC cells. In this study, we found that the 5-FU sensitivity of TE1 cells was lower than that of EC1 and Eca109 cells. Gas chromatography-mass spectrometry analysis results showed that nicotinate and nicotinamide metabolism and tricarboxylic acid cycle were significantly different in these three cell lines. Nicotinamide N-methyltransferase (NNMT), a key enzyme of nicotinate and nicotinamide metabolism, was significantly higher expressed in TE1 cells than that in EC1 and Eca109 cells. Therefore, the function of NNMT on 5-FU sensitivity was analyzed in vitro and in vivo. NNMT downregulation significantly increased 5-FU sensitivity in TE1 cells. Meanwhile, the glucose consumption and lactate production were decreased, and the expression of glycolysis-related enzymes hexokinase 2, lactate dehydrogenase A, and phosphoglycerate mutase 1 were downregulated in NNMT knockdown TE1 cells. Besides, overexpression of NNMT in EC1 and Eca109 cells caused the opposite effects. Moreover, when glycolysis was inhibited by 2-deoxyglucose, the roles of NNMT on 5-FU sensitivity was weakened. In vivo experiments showed that NNMT knockdown significantly increased the sensitivity of xenografts to 5-FU and suppressed the Warburg effect. Overall, these results demonstrated that NNMT decreases 5-FU sensitivity in human ESCC cells through promoting the Warburg effect, suggesting that NNMT may contribute to predict the treatment effects of the clinical chemotherapy in ESCC.


Assuntos
Reprogramação Celular , Resistencia a Medicamentos Antineoplásicos , Carcinoma de Células Escamosas do Esôfago/patologia , Fluoruracila/farmacologia , Glicólise/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Nicotinamida N-Metiltransferase/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais , Proliferação de Células , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nicotinamida N-Metiltransferase/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Zhonghua Zhong Liu Za Zhi ; 42(3): 197-202, 2020 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-32252197

RESUMO

Objective: To investigate the effects of metastasis associated gene 1 (MTA1) expression on the proliferation and apoptosis of human esophageal cancer Eca109 cells. Methods: MTA1 siRNA was transfected into human esophageal cancer Eca109 cells, and the control group and blank group were set up. The expression of MTA1 in Eca109 cells with different treatment was detected by real-time fluorescent quantitative PCR (RT-PCR) and western blot. The proliferation of Eca109 cells was detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. The cloning formation ability of Eca109 cells was detected by plate cloning assay. The apoptosis of Eca109 cells were detected by flow cytometry. The expression of proliferating cell nuclear antigen (PCNA) and apoptosis-related proteins, including cleaved caspase-3 and total caspase-3 protein in Eca109 cells were detected by western blot. Results: After 48 hours of transfection, RT-PCR result showed that the relative expression levels of MTA1 mRNA in Eca109 cells in the blank group, control group, and siRNA group were 1.00±0.10, 0.98±0.09 and 0.21±0.03, respectively. The expression of MTA1 mRNA in siRNA group was significantly inhibited (P<0.05), while no significant difference of MTA1 mRNA expression between the blank group and the control group has been found (P>0.05). Western blot results were consistent with those of RT-PCR. MTT array results showed that, compared with the blank group and transfection group, the absorbance values of Eca109 cells in siRNA group were dramatically reduced at 48, 72, and 96 h (all P<0.05). There were no significant differences of absorbance values between the blank group and the control group at 48, 72, and 96 h (all P>0.05). The results of the plate colony formation test showed that the number of colony formation in the blank group and control group were 58.64±6.86 and 60.02±7.04, respectively, significantly higher than 18.10±3.16 in siRNA group (P<0.05), while there was no significant difference between the blank group and control group (P>0.05). Flow cytometry results showed that the apoptosis rates in the blank group and control group were (2.13±0.54)% and (2.27±0.61)%, respectively, significantly lower than (32.61±5.28)% in siRNA group (P<0.05), while there was no significant difference between blank group and control group (P>0.05). Western blot results showed that the expression of PCNA protein was down-regulated while cleaved caspase-3 protein expression was upregulated in siRNA group, compared to the control group and blank group (P<0.05). Conclusions: Inhibition of MTA1 expression can inhibit the proliferation of Eca109 cells and induce apoptosis. This process may be related to the down-regulation of PCNA protein expression and activation of caspase-3 protein expression.


Assuntos
Apoptose , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/fisiologia , Proteínas Repressoras/fisiologia , Transativadores/metabolismo , Apoptose/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Histona Desacetilases/genética , Humanos , Antígeno Nuclear de Célula em Proliferação , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transativadores/genética , Transfecção
16.
Cancer Sci ; 111(6): 1969-1978, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32302443

RESUMO

The relationship between the local immune status and cancer metabolism regarding 18 F-FDG and 18 F-FAMT uptake in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study examined the correlations between tumor immune status, clinicopathological factors, and positron emission tomography (PET) tracer uptake in ESCC. Forty-one ESCC patients who underwent 18 F-FDG PET and 18 F-FAMT PET before surgery were enrolled in the study. Immunohistochemistry was conducted for programmed death 1 (PD-1), CD8, Ki-67, CD34, GLUT1 (18 F-FDG transporter) and LAT1 (18 F-FAMT transporter). ESCC specimens with high tumoral PD-L1 and high CD8-positive lymphocytes were considered to have "hot tumor immune status." High PD-L1 expression (53.7%) was significantly associated with tumor/lymphatic/venous invasion (P = 0.028, 0.032 and 0.018), stage (P = 0.041), CD8-positive lymphocytes (P < 0.001), GLUT1 (P < 0.001), LAT1 expression (P = 0.006), Ki-67 labelling index (P = 0.009) and CD34-positive vessel counts (P < 0.001). SUVmax of 18 F-FDG was significantly higher in high PD-L1 cases than in low PD-L1 cases (P = 0.009). SUVmax of 18 F-FAMT was significantly higher in high PD-L1 (P < 0.001), high CD8 (P = 0.012) and hot tumor groups (P = 0.028) than in other groups. High SUVmax of 18 F-FAMT (≥4.15) was identified as the only predictor of hot tumor immune status. High PET tracer uptake was significantly associated with cancer aggressiveness and hot tumor immune status in ESCC. PET imaging may be an effective tool to predict tumor immune status in ESCC with respect to immune checkpoint inhibitor sensitivity.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Tomografia por Emissão de Pósitrons/métodos , Adulto , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , alfa-Metiltirosina
17.
Cancer Res ; 80(13): 2764-2774, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32345674

RESUMO

The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging (MSI) can support objective diagnosis in minutes using a routine frozen tissue section. However, whether MSI can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here, we used desorption electrospray ionization-MSI (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariate models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (AUC = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in premalignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of premalignant tissues and unveils mechanisms of phospholipidomic reprogramming. SIGNIFICANCE: These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Lipidômica , Lipogênese , Fosfolipídeos/análise , Adenocarcinoma/metabolismo , Estudos de Coortes , Neoplasias Esofágicas/metabolismo , Humanos , Espectrometria de Massas em Tandem , Células Tumorais Cultivadas
18.
Arch Biochem Biophys ; 686: 108371, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32325088

RESUMO

Understanding the role of Long non-coding RNAs (lncRNAs) in tumorigenesis in diverse human malignancies would helpful for targeted therapies, containing esophageal squamous cell carcinoma (ESCC). However, the specific role and molecular mechanisms of LINC01980 in ESCC remain unclarified. In this study, we investigated the expression level, function role, and molecular mechanisms of LINC01980 in esophageal cancer cells and ESCC tissues. The high expression of LINC01980 was detected in ESCC tissues and cells, and predicted poor prognosis. LINC01980 promoted the cell proliferation, migration, invasion ability and epithelial-mesenchymal transition (EMT) progress in ESCC cells. In addition, a negative correlation between LINC01980 and miR-190a-5p or miR-190a-5p and MYO5A was observed in ESCC. We found that miR-190a-5p could directly bind with the mRNA of LINC01980 and MYO5A, and it was detected low expression in ESCC. We further demonstrated that the downregulation of MYO5A caused by overexpressing miR-190a-5p was released via upregulation of LINC01980. Functionally, LINC01980 acted as a competitively endogenous RNA (ceRNA) to impact the expression of MYO5A by sponging miR-190a-5p in ESCC. Therefore, these findings suggest that LINC01980 may act as an oncogenic lncRNA in ESCC and LINC01980/miR-190a-5p/MYO5A pathway contributes to the development of ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , MicroRNAs/metabolismo , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos
19.
Cancer Immunol Immunother ; 69(8): 1493-1504, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32285170

RESUMO

Though therapy that promotes anti-tumor response about CD8+ tumor-infiltrating lymphocytes (TILs) has shown great potential, clinical responses to CD8+ TILs immunotherapy vary considerably, largely because of different subpopulation of CD8+ TILs exhibiting different biological characters. To define the relationship between subpopulation of CD8+ TILs and the outcome of antitumor reaction, the phenotype and function of CD103+ CD8+ TILs in esophageal squamous cell carcinoma (ESCC) were investigated. CD103+ CD8+ TILs were presented in ESCC, which displayed phenotype of tissue-resident memory T cells and exhibited high expression of immune checkpoints (PD-1, TIM-3). CD103+ CD8+ TILs were positively associated with the overall survivals of ESCC patients. This population of cells elicited potent proliferation and cytotoxic cytokine secretion potential. In addition, CD103+ CD8+ TILs were elicited potent anti-tumor immunity after anti-PD-1 blockade and were not affected by chemotherapy. This study emphasized the feature of CD103+ CD8+ TILs in immune response and identified potentially new targets in ESCC patients.


Assuntos
Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/metabolismo , Cadeias alfa de Integrinas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , 4-Nitroquinolina-1-Óxido/toxicidade , Adulto , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Biomarcadores Tumorais , Carcinógenos/toxicidade , Estudos de Coortes , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/imunologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Seguimentos , Humanos , Cadeias alfa de Integrinas/imunologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Taxa de Sobrevida , Células Tumorais Cultivadas
20.
Nucleic Acids Res ; 48(9): 4858-4876, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32313942

RESUMO

High-mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that plays essential roles in embryonic development and cancer progression. However, the mechanism of HMGA2 regulation remains largely uncharacterized. Here, we demonstrate that HMGA2 can be modulated by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, in esophageal squamous cell carcinoma (ESCC). HMGA2 expression was positively associated with HBXIP expression in clinical ESCC tissues, and their high levels were associated with advanced tumor stage and reduced overall and disease-free survival. We found that oncogenic HBXIP could posttranslationally upregulate HMGA2 protein level in ESCC cells. HBXIP induced HMGA2 acetylation at the lysine 26 (K26), resulting in HMGA2 protein accumulation. In this process, HBXIP increased the acetyltransferase p300/CBP-associated factor (PCAF) phosphorylation and activation via the Akt pathway, then PCAF directly interacted with HMGA2, leading to HMGA2 acetylation in the cells. HMGA2 K26 acetylation enhanced its DNA binding capacity and blocked its ubiquitination and then inhibited proteasome-dependent degradation. Functionally, HBXIP-stabilized HMGA2 could promote ESCC cell growth in vitro and in vivo. Strikingly, aspirin suppressed ESCC growth by inhibiting HBXIP and HMGA2. Collectively, our findings disclose a new mechanism for the posttranslational regulation of HMGA2 mediated by HBXIP in ESCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteína HMGA2/metabolismo , Acetilação , Animais , Aspirina/farmacologia , Linhagem Celular Tumoral , DNA/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/química , Humanos , Lisina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Ligação Proteica , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ubiquitinação , Fatores de Transcrição de p300-CBP/metabolismo
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