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1.
Anticancer Res ; 39(10): 5789-5795, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570483

RESUMO

BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. PATIENTS AND METHODS: We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. RESULTS: The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). CONCLUSION: A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.


Assuntos
Antígeno B7-H1/genética , Carcinoma/genética , Carcinoma/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Oncogenes/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
2.
Medicine (Baltimore) ; 98(38): e17225, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567982

RESUMO

The present study is to analyze the difference of gene methylation in early cervical adenocarcinoma and to find molecular markers for predicting the occurrence and development of cervical adenocarcinoma.A total of 15 cases of primary cervical adenocarcinoma and 10 cases of primary cervical squamous cell carcinoma at stages IB1 or IIA1 were included in the study. Infinium MethylationEPIC BeadChip (850K) was used to screen specifically expressed genes in cervical adenocarcinoma tissues. Bisulfite sequencing polymerase chain reaction (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to verify the methylation levels in cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues.Sex determining region Y-box 1 (SOX1) and cyclin D1 (CCND1) genes participated in multiple signaling pathways, being the central nodes of gene regulatory networks. SOX1 gene, but not CCND1 gene, was a specifically methylated gene in cervical adenocarcinoma according to BSP. According to qRT-PCR, methylation level of SOX1 in cervical adenocarcinoma tissues is significantly different from that in cervical squamous cell carcinoma tissues or normal cervical tissues, and the methylation level of CCND1 in cervical adenocarcinoma tissues or cervical squamous cell carcinoma tissues is significantly different from that in normal cervical tissues.The present study demonstrates that tumor-suppressor gene SOX1 is a methylation-specific expression gene of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma. However, CCND1 gene was not proven to be a specific methylation expression gene in cervical adenocarcinoma in the present study.


Assuntos
Adenocarcinoma/genética , Metilação de DNA/genética , Fatores de Transcrição SOXB1/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Colo do Útero/metabolismo , Ciclina D1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/genética , Marcadores Genéticos/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias do Colo do Útero/metabolismo
3.
Anticancer Res ; 39(9): 4947-4955, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519600

RESUMO

BACKGROUND/AIM: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) plays an important role in the adhesion, invasion, and metastasis of tumor cells. Although emerging evidence suggests that IMP3 promotes tumor progression in several malignancies, the expression of IMP3 and its prognostic implication in adenocarcinoma of the ampulla of Vater (AVAC) has not been clarified to date. MATERIALS AND METHODS: The IMP3 expression status in 87 AVAC tissues was examined using immunostaining, and its association with various clinicopathological features and outcome of patients with AVAC was investigated. RESULTS: The vast majority (87.4%) of AVAC cases displayed at least focal cytoplasmic and membranous IMP3 immunoreactivity in tumor cells, whereas IMP3 expression was consistently absent from normal biliary epithelial cells. Tumor-specific IMP3 expression was associated with submucosal and pancreatic invasion, which were not identified in the corresponding hematoxylin and eosin-stained slides. This finding led to up-staging of the pathological tumor stage in two cases of well-differentiated AVAC. In addition, high IMP3 expression was significantly associated with a poorly differentiated histology (p=0.026). Survival analyses revealed that high IMP3 expression independently predicted shorter recurrence-free (p=0.003) and overall (p=0.029) survival. CONCLUSION: Our study demonstrated tumor-specific IMP3 expression in AVAC, which will be helpful in determining invasion depth and tumor extent in patients with well-differentiated tumors, as well as indicating worse survival of patients with AVAC. Our data highlight IMP3 expression status as a potential diagnostic and prognostic marker for AVAC.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Ampola Hepatopancreática/patologia , Neoplasias do Ducto Colédoco/genética , Neoplasias do Ducto Colédoco/mortalidade , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a RNA/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias do Ducto Colédoco/diagnóstico , Neoplasias do Ducto Colédoco/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Proteínas de Ligação a RNA/genética , Carga Tumoral
4.
JAMA ; 322(5): 445-454, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386140

RESUMO

Importance: Pancreatic adenocarcinoma is the third most common cause of cancer death among men and women in the United States. Objective: To systematically review benefits and harms of screening for pancreatic adenocarcinoma to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials, from January 2002 through April 27, 2018; surveillance through March 22, 2019. Study Selection: Studies of adults with or without risk factors for pancreatic adenocarcinoma (eg, family history of pancreatic cancer, personal history of new-onset diabetes) undergoing imaging-based screening; studies of treatment for adults with screen-detected or asymptomatic pancreatic adenocarcinoma. Included study designs were randomized clinical trials, nonrandomized controlled intervention studies, diagnostic accuracy studies with a reference standard, cohort studies, and case-control studies (for evaluation of harms only). Studies consisting entirely of populations with known genetic syndromes associated with pancreatic cancer were excluded. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles and rated included studies for quality; data were quantitatively analyzed to calculate a pooled diagnostic yield and narratively synthesized. Main Outcomes and Measures: Mortality, morbidity, or quality of life; diagnostic accuracy of screening tests; any harm of screening or treatment. Results: Thirteen fair-quality prospective cohort screening studies (N = 1317) conducted predominantly in populations at high familial risk for pancreatic adenocarcinoma were included. No studies reported on the effect of screening on morbidity or mortality or on the effectiveness of treatment for screen-detected pancreatic adenocarcinoma. Although no studies evaluated the diagnostic accuracy of screening tests, all 13 studies reported the diagnostic yield. Yields ranged from 0 to 75 cases per 1000 persons in studies using endoscopic ultrasound, magnetic resonance imaging, and/or computed tomography-based screening. In total, 18 cases of pancreatic adenocarcinoma were detected in 1156 adults at increased familial risk and 0 cases were detected in 161 average-risk adults. In 8 studies (n = 675) assessing procedural harms of screening, no serious harms from initial screening were reported. Two studies (n = 271) found no evidence of psychosocial harms related to screening. Evidence of surgical harms was limited. Conclusions and Relevance: Imaging-based screening in groups at high familial risk can detect pancreatic adenocarcinoma with limited evidence of minimal harms. However, the effect of screening on morbidity and mortality in groups at high familial risk has not been studied, and no data are available in average-risk populations. There is limited evidence to assess benefits or harms of surgical intervention for screen-detected pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Detecção Precoce de Câncer , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Detecção Precoce de Câncer/efeitos adversos , Feminino , Humanos , Masculino , Programas de Rastreamento/efeitos adversos , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias , Qualidade de Vida , Fatores de Risco , Sensibilidade e Especificidade
5.
J Cancer Res Clin Oncol ; 145(10): 2481-2493, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451931

RESUMO

PURPOSE: Pancreatic adenocarcinoma (PAC) represents one of the most fatal types of cancer with an exceptionally poor prognosis, underscoring the need for improved diagnostic and treatment approaches. An over-expression of somatostatin receptors (SST) as well as of the chemokine receptor CXCR4 has been shown for many tumour entities. Respective expression data for PAC, however, are scarce and contradictory. METHODS: Overall, 137 tumour samples from 70 patients, 26 of whom were diagnosed with PAC and 44 with pancreatic neuroendocrine tumour (PanNET), were compared in terms of SST and CXCR4 expression by immunohistochemical analysis using well-characterized rabbit monoclonal antibodies. RESULTS: Only SST1 and CXCR4 expression was detected in PAC tumours, with SST1 present in 42.3% and CXCR4 in 7.7% of cases. However, the overall staining intensity was very weak. In contrast to the tumour cells, in many PAC cases, tumour capillaries exhibited strong SST3, SST5, or CXCR4 expression. In PanNETs, SST2 was the most-prominently expressed receptor, observed in 75.0% of the tumours at medium-strong intensity. SST5, SST1, and CXCR4 expression was detected in 20.5%, 15.9%, and 11.4% of PanNET cases, respectively, but the staining intensity was only weak. SST2 positivity in PanNET, but not in PAC, was associated with favourable patient outcomes. CONCLUSIONS: SST or CXCR4 expression in PAC is clearly of no therapeutic relevance. However, indirect targeting of these tumours via SST3, SST5, or CXCR4 on tumour microvessels may represent a promising additional therapeutic strategy.


Assuntos
Adenocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Receptores CXCR4/genética , Somatostatina/genética , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Biomarcadores , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Receptores CXCR4/metabolismo , Somatostatina/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
8.
Medicine (Baltimore) ; 98(26): e16207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261569

RESUMO

The cell-surface glycoprotein, mesothelin, is normally present on mesothelial cells. Overexpression of mesothelin has been reported in many tumors and is correlated with poor outcome. We investigated the clinicopathologic significance of mesothelin expression in colorectal adenocarcinoma with microsatellites instability (MSI) status.Mesothelin expression was evaluated immunohistochemically in tissue microarray blocks from 390 colorectal adenocarcinoma samples. Mesothelin expression was interpreted according to the intensity and extent. A score of 2 was considered high expression. We analyzed the correlation between mesothelin expression and clinicopathologic characteristics.High mesothelin expression was observed in 177 (45.4%) out of 390 colorectal adenocarcinoma samples and was significantly associated with high histologic grade (P = .037), lymphatic invasion (P = .028), lymph node metastasis (P = .028), and high AJCC stage (P = .026). Kaplan-Meier survival curves revealed no significant difference between patients with high mesothelin expression and patients with low mesothelin expression in both recurrence-free survival (RFS) and cancer-specific survival (P = .609 and P = .167, respectively). In subgroup survival analyses, high mesothelin expression was associated with poor RFS in the MSI-High group of colorectal adenocarcinoma (P = .004).High mesothelin expression was significantly associated with aggressive phenotypes and poor patient outcome in MSI-High colorectal adenocarcinoma.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteínas Ligadas por GPI/metabolismo , Instabilidade de Microssatélites , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Análise Serial de Tecidos
9.
Anticancer Res ; 39(7): 3609-3614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262886

RESUMO

BACKGROUND/AIM: The novel cytidine analog RX-3117, which is activated by uridine-cytidine kinase 2 (UCK2), shows encouraging activity in pancreatic and bladder cancer Phase IIa studies. In this study we highlight the potential role of UCK2 as a biomarker for selecting patients for RX-3117 treatment. PATIENTS AND METHODS: The online genomics analysis and visualization platform, R2, developed by the Oncogenomics department at the AMC (Amsterdam, The Netherlands) was used for in silico UCK2-mRNA correlation with overall survival of pancreatic cancer patients, while UCK2 protein expression was evaluated by immunohistochemistry on pancreatic tumor formalin-fixed-paraffin-embedded sections from independent pancreatic cancer patients. mRNA expression was also determined for SUIT-2, PANC-1 and PDAC-3. Lastly, the drug sensitivity to RX-3117 was investigated using the Sulforhodamine-B cytotoxicity assay. RESULTS: The in silico data showed that a high UCK2-mRNA expression was correlated with a shorter overall survival in pancreatic cancer patients. Moreover, UCK2 protein expression was high in 21/25 patients, showing a significantly shorter mean. Overall Survival (8.4 versus 34.3 months, p=0.045). Sensitivity to RX-3117 varied between 0.6 and 11 µM. CONCLUSION: Pancreatic cancer cells are sensitive to pharmacologically achievable RX-3117 concentrations and UCK2 might be exploited as a biomarker for patient treatment selection.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Citidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Uridina Quinase/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Citidina/farmacologia , Feminino , Humanos , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/metabolismo , Uridina Quinase/genética
10.
Nat Commun ; 10(1): 3101, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308377

RESUMO

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.


Assuntos
Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica/métodos , Medicina de Precisão/métodos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Progressão da Doença , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Instabilidade Genômica , Humanos , Aprendizado de Máquina , Modelos Genéticos , Família Multigênica/efeitos dos fármacos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único
11.
J Cancer Res Clin Oncol ; 145(8): 1999-2012, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172267

RESUMO

BACKGROUND: The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. METHODS: CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. RESULTS: We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). CONCLUSION: The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa.


Assuntos
Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Catepsina K/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Inibidores de Proteases/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Neoplasias Ósseas/genética , Catepsina K/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos SCID , Células PC-3 , Neoplasias da Próstata/genética , Inibidores de Proteases/farmacologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
BMC Complement Altern Med ; 19(1): 151, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242894

RESUMO

BACKGROUND: Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS: The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS: Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS: Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/fisiopatologia
13.
N Engl J Med ; 381(4): 317-327, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31157963

RESUMO

BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Quimioterapia de Manutenção , Neoplasias Pancreáticas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Intervalo Livre de Progressão
14.
Biochim Biophys Acta Rev Cancer ; 1872(1): 37-48, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152823

RESUMO

Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett's esophagus to esophageal adenocarcinoma are also discussed.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Neoplasias Esofágicas/genética , Refluxo Gastroesofágico/genética , Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Dano ao DNA/genética , Neoplasias Esofágicas/patologia , Refluxo Gastroesofágico/patologia , Humanos , Fatores de Risco , Transdução de Sinais/genética
15.
Gastroenterology ; 157(3): 744-759.e4, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31154022

RESUMO

BACKGROUND & AIMS: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. METHODS: Colon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry. RESULTS: Levels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues. CONCLUSIONS: Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.


Assuntos
Adenocarcinoma/prevenção & controle , Colo/enzimologia , Neoplasias do Colo/prevenção & controle , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Proteínas Nucleares/metabolismo , PPAR alfa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Anticarcinógenos/farmacologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Colo/patologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Bases de Dados Genéticas , Modelos Animais de Doenças , Fenofibrato/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , PPAR alfa/agonistas , PPAR alfa/deficiência , PPAR alfa/genética , Proteína-Arginina N-Metiltransferases/genética , Transdução de Sinais
16.
Surg Clin North Am ; 99(3): 403-418, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047032

RESUMO

Esophageal cancer and gastric cancer are leading causes of cancer-related mortality worldwide. In this article, the authors discuss the molecular biology of esophageal and gastric cancer with a focus on esophageal adenocarcinoma. They review data from The Cancer Genome Atlas project and advances in the molecular stratification and classification of esophageal carcinoma and gastric cancer. They also summarize advances in microRNA, molecular staging, gene expression profiling, tumor microenvironment, and detection of circulating tumor DNA. Finally, the authors summarize some of the implications of understanding the molecular basis of esophageal cancer and future directions in the management of esophageal cancer.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Neoplasias Gástricas/genética , Adenocarcinoma/epidemiologia , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/genética , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Neoplasias Esofágicas/epidemiologia , Previsões , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Metástase Linfática , MicroRNAs , Mutação/genética , Estadiamento de Neoplasias , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Microambiente Tumoral
17.
Surg Clin North Am ; 99(3): 511-527, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047039

RESUMO

Next-generation sequencing has enabled genome-wide molecular profiling of gastric and esophageal malignancies at single-nucleotide resolution. The resultant genomic profiles provide information about the specific oncogenic pathways that are the likely driving forces behind tumorigenesis and progression. The abundance of available genomic data has immense potential to redefine management paradigms for these difficult disease processes. The ability to capitalize on the information provided through high-throughput sequencing technologies will define cancer care in the coming decades and could shift the paradigm from current stage-based, organ-specific treatments toward tailored regimens that target the specific culprit pathways driving individual tumors.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Gástricas/genética , Adenocarcinoma/classificação , Adenocarcinoma/terapia , Neoplasias Esofágicas/classificação , Neoplasias Esofágicas/terapia , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Instabilidade de Microssatélites , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Neoplasias Gástricas/classificação , Neoplasias Gástricas/terapia , Terminologia como Assunto
18.
Cell Physiol Biochem ; 52(6): 1517-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120230

RESUMO

BACKGROUND/AIMS: Cadmium (Cd) is a heavy metal contaminant whose toxicity is associated with colorectal cancer (CRC). However, the underlying molecular mechanisms of Cd-induced CRC malignancy remain obscure. METHODS: A monolayer scratch assay was employed to assess the migration of HT-29 human adenocarcinoma cells. Luciferase reporter assay was used to determine cyclooxygenase-2 (COX-2) transcriptional activity, and Western blotting was used to detect p38 Mitogen Activated Protein Kinase (MAPK) and Akt phosphorylation as well as COX-2 expression. Prostaglandin E2 (PGE2) levels were measured using Enzyme Linked Immunosorbent Assay (ELISA) and reactive oxygen species (ROS) formation was assessed using dihydroethidium (DHE) stain. RESULTS: Here, we show that Cd potentiates the migratory capacity of HT-29 CRC cells. Cd caused a time-dependent increase in COX-2 expression. Celecoxib, a COX-2 selective inhibitor, significantly reduced Cd-induced migration. Cd also increased levels of ROS and phosphorylated p38. Importantly, Cd-induced COX-2 expression and migration were significantly abolished by N-Acetyl-Cysteine (NAC), a ROS scavenger, or SB202190, a specific p38 inhibitor. Furthermore, Cd-induced p38 phosphorylation was inhibited by NAC. Cd (100 nM) also increased PGE2 levels, which was abrogated by NAC, SB202190, or celecoxib. Exogenous PGE2 significantly potentiated cell migration. Cd caused a significant increase in Akt phosphorylation in a ROS-mediated pathway. Moreover, Cd-induced migration was significantly attenuated by LY294 002, a phosphatidylinositol-3-kinase inhibitor. CONCLUSION: Taken together, our results suggest that exposure to low levels of Cd promotes a more migratory cancer phenotype in a ROS-p38-COX-2-PGE2 pathway as well as ROS-Akt pathway. Therefore, COX-2, PGE2 receptors or Akt represent potential targets in the treatment of CRC, particularly in patients exposed to Cd.


Assuntos
Adenocarcinoma/induzido quimicamente , Cádmio/toxicidade , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ativação Enzimática/efeitos dos fármacos , Células HT29 , Humanos , Ativação Transcricional/efeitos dos fármacos
19.
BMC Bioinformatics ; 20(Suppl 7): 197, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074380

RESUMO

BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, with high mortality worldwide. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, DNA methylation, and miRNA quantification. However, the hub genes, which can be served as bio-markers for discriminating cancer and healthy individuals, are not well screened. RESULT: Here we present a new method for extracting gene predictors, aiming to obtain the least predictors without losing the efficiency. We firstly analyzed three different expression microarrays and constructed multi-interaction network, since the individual expression dataset is not enough for describing biological behaviors dynamically and systematically. Then, we transformed the undirected interaction network to directed network by employing Granger causality test, followed by the predictors screened with the use of the stepwise character selection algorithm. Six predictors, including TOP2A, GRK5, SIRT7, MCM7, EGFR, and COL1A2, were ultimately identified. All the predictors are the cancer-related, and the number is very small fascinating diagnosis. Finally, the validation of this approach was verified by robustness analyses applied to six independent datasets; the precision is up to 95.3% ∼ 100%. CONCLUSION: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new, robust, and effective method for extracting gene predictors. We identified as low as 6 genes which can be taken as predictors for diagnosing lung adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico , Algoritmos , Biologia Computacional/métodos , Metilação de DNA , Redes Reguladoras de Genes , Neoplasias Pulmonares/diagnóstico , MicroRNAs/genética , Adenocarcinoma/genética , Idoso , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade
20.
Braz J Med Biol Res ; 52(5): e8379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31116314

RESUMO

Gastric cancer (GC) is the third most lethal type of cancer worldwide. Single nucleotide polymorphisms (SNPs) in regulatory sites or coding regions can modify the expression of genes involved in gastric carcinogenesis, as ERBB2, which encodes for the tyrosine-kinase receptor HER-2. The aim of this work was to analyze the association of the polymorphisms: rs2643194, rs2517951, rs2643195, rs2934971, and rs1058808 with GC, as they have not yet been analyzed in GC patients, as well as to report their frequency in the general Mexican population (GMP). We studied genomic DNA from subjects with GC (n=74), gastric inflammatory diseases (GID, n=76 control subjects), and GMP (n=102). Genotypes were obtained by means of real-time PCR and DNA-sequencing. The risks for GC were estimated through odds ratio (OR) using the Cochran-Armitage trend test and multinomial logistic regression. Increased risk for GC was observed under the dominant inheritance model for the rs2643194 TT or CT genotypes with an OR of 2.75 (95%CI 1.12-6.75, P=0.023); the rs2934971 TT or GT genotypes with an OR of 2.41 (95%CI 1.01-5.76, P=0.043), and the rs1058808 GG or CG genotypes with an OR of 2.21 (95%CI 1.00-4.87, P=0.046). The SNPs rs2643194, rs2934971, and rs1058808 of the ERBB2 gene were associated with increased risk for GC.


Assuntos
Adenocarcinoma/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Adulto Jovem
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