Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Gut ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31611300

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive type of GI tumour, and it possesses deregulated cellular energetics. Although recent advances in PDAC biology have led to the discovery of recurrent genetic mutations in Kras, TP53 and SMAD4, which are related to this disease, clinical application of the molecular phenotype of PDAC remains challenging. DESIGN: We combined molecular imaging technology (positron emission tomography/CT) and immunohistochemistry to evaluate the correlation between the maximum standardised uptake value and SMAD4 expression and examined the effect of SMAD4 on glycolysis through in vitro and in vivo experiments. Furthermore, we identified the effect of SMAD4 on metabolic reprogramming by metabolomics and glucose metabolism gene expression analyses. Dual luciferase reporter assays and chromatin immunoprecipitation were performed to identify whether SMAD4 functioned as a transcription factor for phosphoglycerate kinase 1 (PGK1) in PDAC cells. Proliferative and metastatic assays were performed to examine the effect of PGK1 on the malignant behaviour of PDAC. RESULTS: We provide compelling evidence that the glycolytic enzyme PGK1 is repressed by transforming growth factor-ß/SMAD4. Loss of SMAD4 induces PGK1 upregulation in PDAC, which enhances glycolysis and aggressive tumour behaviour. Notably, in SMAD4-negative PDAC, nuclear PGK1 preferentially drives cell metastasis via mitochondrial oxidative phosphorylation induction, whereas cytoplasmic PGK1 preferentially supports proliferation by functioning as a glycolytic enzyme. The PDAC progression pattern and distinct PGK1 localisation combine to predict overall survival and disease-free survival. CONCLUSION: PGK1 is a decisive oncogene in patients with SMAD4-negative PDAC and can be a target for the development of a therapeutic strategy for SMAD4-negative PDAC.

4.
Biochim Biophys Acta Rev Cancer ; 1872(2): 188311, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442475

RESUMO

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.

5.
Cancer Med ; 8(11): 5000-5011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31293053

RESUMO

PURPOSE: This study aimed to investigate the characteristics of colonic neuroendocrine neoplasms (NENs) and to validate the prognostic value of the European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) 8th staging systems. METHODS: A total of 167 and 1248 patients with colonic NENs from 12 medical centers across China and from the Surveillance, Epidemiology, and End Results (SEER) cancer registry in the United States, respectively, were reviewed. Patients were staged according to the ENETS and AJCC 8th staging systems. RESULTS: Clinicopathological features of colonic NENs in the Chinese cohort and SEER cohort were significantly distinct. In both the Chinese cohort and the SEER cohort, colonic neuroendocrine carcinoma (NEC) and mixed adeno-neuroendocrine carcinoma (MANEC) were more frequent in the midgut than in the hindgut. Tumors originating from the midgut tended to be larger and at a more advanced stage than those from the hindgut. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC. CONCLUSIONS: Our study revealed that tumors originating from the midgut and the hindgut shared different clinicopathological features. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC.

6.
Cancer Lett ; 459: 100-111, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31158430

RESUMO

The mixed lineage kinase domain-like protein (MLKL) has emerged as a critical mediator of necroptosis, which results in the release of cellular damage-associated molecular patterns (DAMPs). However, its physiological role in regulating inflammation is not fully understood. We herein showed that Mlkl-/- mice were highly susceptible to colitis and colitis-associated tumorigenesis (CAT), which was associated with massive leukocyte infiltration and increased inflammatory responses. Moreover, we used bone marrow transplantation to reveal that MLKL in inflammatory cells is crucial for its role on colitis. Intestinal mucosal tissue and polyps isolated from Mlkl-/- mice exhibited increased ERK activation and elevated expression of genes associated with inflammation and cancer. Mechanistically, enhanced inflammation in Mlkl-/- mice was due to MEK/ERK activation particularly in dendritic cells (DCs). Our results demonstrate the role of MLKL in maintaining intestinal homeostasis and protecting against colitis and tumorigenesis.

7.
Mol Cancer ; 18(1): 97, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109338

RESUMO

Microbiota is just beginning to be recognized as an important player in carcinogenesis and the interplay among microbes is greater than expected. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease for which mortality closely parallels incidence. Early detection would provide the best opportunity to increase survival rates. Specific well-studied oral, gastrointestinal, and intrapancreatic microbes and some kinds of hepatotropic viruses and bactibilia may have potential etiological roles in pancreatic carcinogenesis, or modulating individual responses to oncotherapy. Concrete mechanisms mainly involve perpetuating inflammation, regulating the immune system-microbe-tumor axis, affecting metabolism, and altering the tumor microenvironment. The revolutionary technology of omics has generated insight into cancer microbiomes. A better understanding of the microbiota in PDAC might lead to the establishment of screening or early-stage diagnosis methods, implementation of cancer bacteriotherapy, adjustment of therapeutic efficacy even alleviating the adverse effects, creating new opportunities and fostering hope for desperate PDAC patients.

8.
Biochim Biophys Acta Rev Cancer ; 1871(2): 267-272, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30738097

RESUMO

Pancreatic cancer characteristically has an extremely dense stroma, which facilitates chemoresistance by creating physical and biological barriers to therapeutic agents. Thus, stroma-depleting agents may enhance the delivery and efficacy of chemotherapy drugs. However, stroma-targeting therapy for pancreatic cancer is a double-edged sword, as the stroma can also inhibit tumor metastasis and malignancy. In-depth understanding of the critical role of the stroma in cancer metastasis may improve therapeutic approaches by allowing them to harness specific features of the stroma to treat pancreatic cancer.


Assuntos
Fibroblastos Associados a Câncer/patologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico
10.
World J Gastroenterol ; 24(43): 4893-4905, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30487699

RESUMO

AIM: To uncover the roles of tumor-promoting gene ZEB1 in aerobic glycolysis regulation and shed light on the underlying molecular mechanism. METHODS: Endogenous zinc finger E-box binding homeobox-1 (ZEB1) was silenced using a lentivirus-mediated method, and the impact of ZEB1 and methyl-CpG binding domain protein 1 (MBD1) on aerobic glycolysis was measured using seahorse cellular flux analyzers, reactive oxygen species quantification, and mitochondrial membrane potential measurement. The interaction between ZEB1 and MBD1 was assessed by co-immunoprecipitation and immunofluorescence assays. The impact of ZEB1 and MBD1 interaction on sirtuin 3 (SIRT3) expression was confirmed by quantitative polymerase chain reaction, western blotting, and dual-luciferase and chromatin-immunoprecipitation assays. RESULTS: ZEB1 was a positive regulator of aerobic glycolysis in pancreatic cancer. ZEB1 transcriptionally silenced expression of SIRT3, a mitochondrial-localized tumor suppressor, through interaction with MBD1. CONCLUSION: ZEB1 silenced SIRT3 expression via interaction with MBD1 to promote aerobic glycolysis in pancreatic cancer.

11.
Eur J Surg Oncol ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30416079

RESUMO

INTRODUCTION: Arpin (Arp2/3 complex inhibitor), a novel protein found in 2013, plays a pivotal role in cell motility and migration. However, the prognostic value of Arpin in pancreatic ductal adenocarcinoma (PDAC) remains unknown. MATERIALS AND METHODS: We analyzed the gene expression of ARPIN using the GEO dataset (GSE71989) and validated the results by immunohistochemistry (IHC) and Western blot in our clinical database. Tissue microarray specimens from 214 patients who underwent curative pancreatectomy for PDAC were used. The tumors that expressed high and low levels of Arpin were compared with patient outcome using Kaplan-Meier curves and the multivariate Cox proportional hazard regression model. IHC was then used in 43 paired primary tumor tissues and metastasis tissues to detect the expression of Arpin. RESULTS: Arpin had low expression in the tumor tissue compared with the paracancerous tissue in PDAC. Patients with low intratumoral Arpin expression had worse overall survival (OS) and recurrence-free survival (RFS) than patients with high expression in the training set (p < 0.001, p < 0.001) and validation set (p < 0.001, p < 0.001). The multivariate analysis revealed that the 8th edition TNM stage and Arpin expression were independent prognostic factors associated with OS and RFS in the training and validation sets, respectively. Arpin had lower expression in the metastasis tissues than in the primary tumors of patients with PDAC (p = 0.048). CONCLUSION: The Arpin level is an independent prognostic factor that can be a potential predictor to aid in the management of PDAC.

12.
Ann Surg Oncol ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374923

RESUMO

BACKGROUND: Tumor-infiltrating neutrophils (TINs) indicate poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). Activated neutrophils can generate neutrophil extracellular traps (NETs). Little is known about the presence and prognostic significance of tumor-infiltrating NETs in PDAC. METHODS: This study enrolled 317 patients, in two independent sets (training and validation), who underwent curative pancreatectomy for PDAC in Shanghai Cancer Center. TINs and NETs were identified by immunohistochemical staining for CD15 and citrullinated histone H3, respectively. The relationship between clinicopathological features and outcomes was analyzed. Accuracy of prognostic prediction models was evaluated using concordance index (C-index) and Akaike information criterion (AIC). RESULTS: NETs were associated with OS (both, P < 0.001) and RFS (both, P < 0.001) in the training and validation sets. Tumor-infiltrating NETs predicted poor postsurgical survival of patients with PDAC. Moreover, multivariate analysis identified NETs and AJCC TNM stage as two independent prognostic factors for OS and RFS. Combination of NETs with the 8th edition TNM staging system (C-index, 0.6994 and 0.6669, respectively; AIC, 1067 and 1126, respectively) generated a novel model that improved the predictive accuracy for survival in both sets (C-index, 0.7254 and 0.7117, respectively; AIC, 1047 and 1102, respectively). The model combining presence of NETs with the 7th edition AJCC TNM staging system also had improved predictive accuracy. CONCLUSIONS: NETs were an independent prognostic factor in PDAC and incorporation of NETs along with the standard TNM stating system refined risk-stratification and predicted survival in PDAC with improved accuracy.

14.
J Cancer ; 9(18): 3417-3426, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271504

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer. The 5-year survival rate for PDAC remains low because it is always diagnosed at an advanced stage and it is resistant to therapy. A biomarker, which could detect asymptomatic premalignant or early malignant tumors and predict the response to treatment, will benefit patients with PDAC. However, traditional biopsy has its limitations. There is an urgent need for a tumor biomarker that could easily and repeatedly sample and monitor, in real time, the progress of tumor development. Liquid biopsy could be a tool to assess potential biomarkers. In this review, we focused on the latest discoveries and advancements of liquid biopsy technology in pancreatic cancer research and demonstrated how this technology is being used in clinical applications.

16.
World J Gastroenterol ; 24(33): 3677-3680, 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30197474

RESUMO

Pancreatic cancer remains a lethal disease and is associated with poor prognosis, particularly for patients with distant metastasis at diagnosis. Recently, Oweira reported a retrospective study that included 13233 metastatic pancreatic cancer patients from the Surveillance, Epidemiology and End Results database. They demonstrated that pancreatic cancer patients with isolated liver metastases had worse outcomes than patients with isolated lung metastases or distant nodal metastases. At present, the standard treatment for metastatic pancreatic cancer is chemotherapy. However, improvement in the safety of pancreatic surgery has led to the consideration of more aggressive surgical approaches. Schneitler reported two cases of hepatic metastatic pancreatic cancer in which negative margin (R0) resection and long survival were achieved after effective preoperative chemotherapy. In general, these two studies indicate that although pancreatic cancer patients with liver metastasis have a poor prognosis, surgical approaches may prolong survival for a few of these patients. A strategy to select hepatic metastatic pancreatic cancer patients who may benefit from surgical intervention is urgently needed.


Assuntos
Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Seleção de Pacientes , Hepatectomia/efeitos adversos , Hepatectomia/normas , Hepatectomia/tendências , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Pancreatectomia/efeitos adversos , Pancreatectomia/normas , Pancreatectomia/tendências , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Angiogenesis ; 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30168025

RESUMO

Pancreatic cancer is one of the most lethal malignancies worldwide. Although the standard of care in pancreatic cancer has improved, prognoses for patients remain poor with a 5-year survival rate of < 5%. Angiogenesis, namely, the formation of new blood vessels from pre-existing vessels, is an important event in tumor growth and hematogenous metastasis. It is a dynamic and complex process involving multiple mechanisms and is regulated by various molecules. Inhibition of angiogenesis has been an established therapeutic strategy for many solid tumors. However, clinical outcomes are far from satisfying for pancreatic cancer patients receiving anti-angiogenic therapies. In this review, we summarize the current status of angiogenesis in pancreatic cancer research and explore the reasons for the poor efficacy of anti-angiogenic therapies, aiming to identify some potential therapeutic targets that may enhance the effectiveness of anti-angiogenic treatments.

18.
Ann Surg Oncol ; 25(13): 3984-3993, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30171511

RESUMO

BACKGROUND: Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown. METHODS: A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015). CONCLUSION: TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.

19.
Pancreatology ; 18(6): 671-677, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30153903

RESUMO

OBJECTIVE: To evaluate the prediction of benefits from adjuvant chemoradiotherapy by postoperative serum CA19-9, CA125 and CEA. METHODS: The relations between benefits from adjuvant chemoradiotherapy and levels of postoperative serum CA19-9, CA125 and CEA were investigated in 804 pancreatic adenocarcinoma patients who received radical resection. RESULTS: Adjuvant chemoradiotherapy was an independent factor for late recurrence [12.2 vs. 8.5 months, P = 0.001 for recurrence free survival (RFS)] and long survival [23.7 vs. 17.0 months, P < 0.001 for overall survival (OS)] in resected pancreatic adenocarcinoma. Postoperative serum CA19-9, CA125 and CEA were independent risk predictors for poor surgical outcome in pancreatic adenocarcinoma (P < 0.001 for all). Adjuvant chemradiotherapy (hazard ratio: 0.359, 95% confidence interval: 0.253-0.510, P < 0.001 for OS; hazard ratio: 0.522, 95% confidence interval: 0.387-0.705, P < 0.001 for RFS) were confirmed to improve the surgical outcome in patients with abnormal levels of any one of the three postoperative markers, but not in patients with normal levels of the three postoperative markers. In the subgroup of patients with negative lymph node, its improvement of surgical outcome was also significant in patients with abnormal levels of any one of postoperative serum CA19-9, CA125 and CEA (hazard ratio: 0.412, 95% confidence interval: 0.244-0.698, P = 0.001 for OS; hazard ratio: 0.546, 95% confidence interval: 0.352-0.847, P = 0.007 for RFS). CONCLUSION: Postoperative serum CA19-9, CA125 and CEA could serve as predictors of response for adjuvant chemoradiotherapy even if the status of lymph nodes is negative.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA