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1.
HPB (Oxford) ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32001139

RESUMO

BACKGROUND: Preoperative chemotherapy has shown benefits for locally advanced and borderline resectable pancreatic cancer. Neoadjuvant chemotherapy (NAC) has also been attempted in resectable pancreatic cancer (RPC); however, its role remains controversial. This study aimed to compare the clinical difference between NAC and upfront resection (UR) in RPC. METHODS: Electronic databases including PubMed, Embase, Medline, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials were searched for relevant articles from inception to February 2019 that addressed the overall survival in patients with RPC treated with or without NAC to identify eligible studies. Eleven studies were included in the final meta-analysis. The quality assessment of the included studies was based on the Newcastle-Ottawa quality scale. Data of the unresectable rate, R0 resection rate, and positive lymph node rate were also extracted in each study for further analysis. Pooled hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CIs) were calculated to assess the strength of the association. RESULTS: A total of eleven studies (eight cohort studies and three randomized controlled trials) involving 9773 patients were included. Ten of the eleven studies followed the "intention-to-treat" principle. NAC was found to be significantly associated with a higher R0 resection rate (P < 0.0001; OR = 2.62, 95% CI 1.70-4.03) and increased negative lymph node rate (P < 0.00001; OR = 0.34, 95% CI 0.31-0.37). However, compared with the UR group, NAC was related to a lower surgical resection rate (P = 0.0004; OR = 2.18, 95% CI 1.41-3.37). Overall, the NAC group exhibited no benefits in terms of overall survival compared with that in the UR group (P = 0.10; HR = 0.86, 95% CI 0.73-1.03). In the subgroup analysis, however, patients who received gemcitabine-based regimen as the NAC strategy had more favorable overall survival than that in the UR group (P = 0.04; HR = 0.75, 95% CI 0.57-0.99). CONCLUSIONS: NAC may be associated with a lower resection rate; however, it is associated with an increased R0 resection rate and lymph node negative rate. Although overall survival was similar in patients with or without NAC, gemcitabine-based NAC might provide longer overall survival. Further large-volume, randomized controlled trials are needed to validate the improved prognosis of patients undergoing NAC.

2.
Pancreatology ; 20(1): 95-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31786057

RESUMO

OBJECTIVES: FOLFIRINOX (FFX) or abraxane plus gemcitabine (AG)-based chemotherapy is used widely as firstline treatment for patients with pancreatic cancer. However, their use in the elderly is discouraged because of adverse events. More clinical data about the therapeutic response and tolerability to FFX or AG in elderly patents (over 70 years old) are required. METHODS: Patients with advanced pancreatic cancer (n = 203; 131 metastatic pancreatic cancer patients (MPC) and 72 locally advanced pancreatic cancer patients (LAPC)) were treated using modified-FFX (mFFX) or AG and mFFX sequentially. The patients were grouped according to their age, patients below 70 years old and patients above 70 years old. The objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse events were compared between the groups. RESULTS: The ORRs in the elderly and in patients below 70 were similar (30.0% versus 32.3%). The median OS and PFS were also similar between the groups (mOS 13.3 m vs 12.7 m, p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS mPFS 10.6 m vs 10.3 m, p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293)). However, the elderly patients suffered a higher incidence of severe adverse events (50% vs. 28.3%). CONCLUSIONS: These data could provide guidance for chemotherapy use in elderly patients with advanced pancreatic cancer. Age did not affect treatment outcome; however, supportive treatment is very important for elderly patients receiving chemotherapy.

3.
Br J Cancer ; 121(9): 786-795, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31588122

RESUMO

BACKGROUND: The progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumour microenvironment. Most tumour-associated macrophages (TAMs) are M2 phenotype macrophages, which normally show anti-inflammatory functions in numerous disorders. Previously, we found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation with hepatoma cell-derived debris; however, the molecular mechanism was unclear. METHODS: In vitro and in vivo experiments were employed to investigate the molecular mechanism. Using pancreatic cancer cell lines, mouse models and human tissues, we obtained a general picture of tumour cell-derived debris promoting metastasis of pancreatic cancer by inducing inflammation via TAMs. RESULTS: We showed that M2 macrophage-derived inflammation also exists in PDAC. Debris from PDAC cells induced potent IL-1ß release by M2 macrophages via TLR4/TRIF/NF-κB signalling, and this effect was further boosted by IgG that was also derived from PDAC cells. Increased IL-1ß promoted epithelial-mesenchymal transition and consequent metastasis of PDAC cells. A selective COX-2 inhibitor, celecoxib, enhanced the anti-tumoural efficacy of gemcitabine. CONCLUSIONS: These data revealed a pro-inflammatory mechanism in PDAC, which indicated that IL-1ß and COX-2 could be therapeutic targets of an anti-inflammatory strategy to treat PDAC.

4.
Gut ; 68(11): 2019-2031, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31227589

RESUMO

OBJECTIVE: Hepatocellular carcinoma (HCC) is heterogeneous, especially in multifocal tumours, which decreases the efficacy of clinical treatments. Understanding tumour heterogeneity is critical when developing novel treatment strategies. However, a comprehensive investigation of tumour heterogeneity in HCC is lacking, and the available evidence regarding tumour heterogeneity has not led to improvements in clinical practice. DESIGN: We harvested 42 samples from eight HCC patients and evaluated tumour heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions were performed to confirm the expression levels of genes. Three independent cohorts were further used to validate the findings. RESULTS: Tumour heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumours. The immune status of the HCC microenvironment was relatively less heterogenous. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determining the expression levels of CD45 and Foxp3 using immunohistochemistry facilitated the correct classification of HCC patients and the prediction of their prognosis. CONCLUSION: There is comprehensive intratumoral and intertumoral heterogeneity in all dimensions of HCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Antígenos Comuns de Leucócito/metabolismo , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral
5.
Oncogene ; 38(28): 5740-5741, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31068668

RESUMO

Following publication of this article the Authors noted mislabelling in Figure 2k. The label ITGA2 had been duplicated and CDH1 had been omitted. The correct version of the figure is included below.

6.
J Hematol Oncol ; 12(1): 16, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764882

RESUMO

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts' clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

7.
Jpn J Clin Oncol ; 48(12): 1058-1069, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30272196

RESUMO

Background: The effectiveness of combination therapy of transarterial chemoembolization and sorafenib for unresectable hepatocellular carcinoma are controversial in some studies. This meta-analysis aims to compare efficacy and safety, as well as regional disparities, between transarterial chemoembolization plus sorafenib and transarterial chemotherapy alone for hepatocellular carcinoma. Methods: We systematically searched multiple databases to select eligible studies. Studies comparing transarterial chemoembolization plus sorafenib and transarterial chemoembolization alone for unresectable hepatocellular carcinoma were included. Results: Thirteen studies including five randomized clinical trials with 2538 patients (1121 in combination therapy group and 1417 in monotherapy group) were selected. The combination therapy significantly improved time to progression (hazard ratio 0.66; 95% confidence interval 0.48-0.89; P = 0.006) and overall survival (hazard ratio 0.57; 95% confidence interval 0.45-0.72; P < 0.001) in Asian region but not in non-Asian countries (overall survival: hazard ratio 0.96, 95% confidence interval 0.73-1.20; time to progression: hazard ratio 1.08, 95% confidence interval 0.73-1.60). Additionally, disease control rate also favored combination therapy (hazard ratio 1.30; 95% confidence interval 1.00-1.69; P = 0.05), which simultaneously caused higher incidences of adverse events, including hand-foot skin reaction (relative ratio 7.03; 95% confidence interval 4.77-10.37), hematological events (relative ratio 3.14; 95% confidence interval 0.99-10.01), diarrhea (relative ratio 2.75; 95% confidence interval 1.74-4.35), hypertension (relative ratio 2.58; 95% confidence interval 1.33-4.99), rash (relative ratio 2.87; 95% confidence interval 1.86-4.43) and alopecia (relative ratio 4.88; 95% confidence interval 1.67-14.13). Conclusions: The combination of transarterial chemoembolizaiton and sorafenib significantly improves outcomes of unresectable hepatocellular carcinoma compared with transarterial chemoembolization monotherapy, especially in Asian region.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Sorafenibe/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Sorafenibe/administração & dosagem , Sorafenibe/farmacologia , Resultado do Tratamento
8.
Saudi J Biol Sci ; 25(5): 904-908, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30108439

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies and the fifth leading cause of cancer-related death worldwide. Novel prognostic biomarkers are urgently needed for patients with HCC. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) overexpression may promote tumor metastasis in HCC. However, few studies investigate the prognosis predictive role of LGR5 in patients with HCC. Herein, we aimed to examine the expression level of LGR5 in tumors and its correlation with clinical characteristics and survivals of patients with HCC. LGR5 expression in tumor specimens and adjacent tissue resected from 66 patients were detected by immunohistochemistry. The results showed that the expression of LGR5 was markedly higher in HCC than in normal adjacent tissues (P = .006). High expression of LGR5 was significantly correlated with later disease stage (P = .009). In addition, high LGR5 expression was remarkably correlated with short overall survival than those with low LGR5 expression (P < .05). The median overall survival of patients with high LGR5 expression was 12 months, whereas that of patients with low LGR5 expression was still not reached (longer than 70 months). Notably, in our limited cases, we did not detect any difference in tumor size, lymphatic invasion, or metastasis in patients with high or low expression of LGR5. In conclusion, high protein level of LGR5 was associated with poor prognosis of these patients. LGR5 appears to be a valuable prognostic predictor clinically and a potential target in HCC therapy.

9.
Oncogene ; 37(47): 6105-6118, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29991801

RESUMO

Hepatocellular carcinoma (HCC) is a fatal disease and patients with HCC frequently die from metastasis. The mechanisms of HCC metastasis are not completely understood. In the present study, in vitro and in vivo data showed that HCC cells promoted cancer cell proliferation and lung metastases formation in a paracrinal/endocrinal way. We found that HCC-derived exosomes mediated this phenomenon and observed enhanced cell adhesion in the presence of these malignant exosomes. We further identified that reactive oxygen species (ROS) regulated the adhesive molecules. Intriguingly, attached HCC cells released exosomes containing both SMAD Family Member 3 (SMAD3) protein and mRNA, which were delivered to detached HCC cells and facilitated their adhesion. These exosomes induced enhanced SMAD3 signaling in the recipient HCC cells and increased their adhesive ability. In addition, we showed that SMAD3-abundant exosomes existed in the peripheral blood of patients with HCC, and their levels correlated with disease stage and the SMAD3 expression of primary tumors. Our study suggested a possible mechanism by which primary HCC supported metastases formation and revealed the role of SMAD3 in the exosomes-mediated crosstalk between primary and circulating HCC cells.


Assuntos
Exossomos/metabolismo , Neoplasias Hepáticas/metabolismo , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes/metabolismo , Proteína Smad3/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Células Neoplásicas Circulantes/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
10.
Hepatology ; 67(5): 1872-1889, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29171040

RESUMO

The development and progression of hepatocellular carcinoma (HCC) are dependent on its local microenvironment. Hypoxia and inflammation are two critical factors that shape the HCC microenvironment; however, the interplay between the two factors and the involvement of cancer cells under such conditions remain poorly understood. We found that tumor-associated macrophages, the primary proinflammatory cells within tumors, secreted more interleukin 1ß (IL-1ß) under moderate hypoxic conditions due to increased stability of hypoxia inducible factor 1α (HIF-1α). Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL-1ß release by tumor-associated macrophages with an M2 phenotype. We further confirmed that the necrotic debris-induced IL-1ß secretion was mediated through Toll-like receptor 4/TIR domain-containing adapter-inducing interferon-ß/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in a similar, but not identical, fashion to lipopolysaccharide-induced inflammation. Using mass spectrometry, we identified a group of proteins with O-linked glycosylation to be responsible for the necrotic debris-induced IL-1ß secretion. Following the increase of IL-1ß in the local microenvironment, the synthesis of HIF-1α was up-regulated by IL-1ß in HCC cells through cyclooxygenase-2. The epithelial-mesenchymal transition of HCC cells was enhanced by overexpression of HIF-1α. We further showed that IL-1ß promoted HCC metastasis in mouse models and was predictive of poor prognosis in HCC patients. CONCLUSION: Our findings revealed an HIF-1α/IL-1ß signaling loop between cancer cells and tumor-associated macrophages in a hypoxic microenvironment, resulting in cancer cell epithelial-mesenchymal transition and metastasis; more importantly, our results suggest a potential role of an anti-inflammatory strategy in HCC treatment. (Hepatology 2018;67:1872-1889).


Assuntos
Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/metabolismo , Immunoblotting , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Microambiente Tumoral/genética
11.
Mol Cancer ; 16(1): 119, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28705232

RESUMO

BACKGROUND: Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood. METHODS: Herein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function. Using several cell lines, mouse models, and human tissues, we obtained a general picture of hif-2α in pancreatic cancer progression. RESULTS: Functional assays revealed that hif-2α promotes epithelial-to-mesenchymal transition, enhances tumor proliferation and invasion, increases stemness, facilitates angiogenesis, and up-regulates aerobic glycolysis. We identified an interaction between hif-2α and ß-catenin, and found that hif-2α/ß-catenin complex formation increased the activity of ß-catenin and the protein stability of hif-2α. In vivo study confirmed the pro-oncogenic role of hif-2α, whose expression correlated with those of E-cadherin, vimentin, Ki-67, and CD31, but not hif-1α. A human tissue study showed that hif-2α was associated with lymph node metastasis, pathological grade, stroma abundance, vascularization and patient survival. High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer. CONCLUSIONS: Our systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Progressão da Doença , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Via de Sinalização Wnt , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise Multivariada , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , Prognóstico , Proteólise , Transcrição Genética , Regulação para Cima/genética , beta Catenina/metabolismo
12.
Tumour Biol ; 39(7): 1010428317711098, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28718370

RESUMO

Hook1 is a member of the hook family of coiled-coil proteins, which is recently found to be associated with malignant tumors. However, its biological function in hepatocellular carcinoma is yet unknown. Here, we evaluated the Hook1 levels in human hepatocellular carcinoma samples and matched peritumoral tissues by real-time polymerase chain reaction. Small interfering RNA knockdown and a transforming growth factor-ß-induced epithelial-mesenchymal transition model were employed to investigate the biological effects of Hook1 in hepatocellular carcinoma. Our results indicated that Hook1 levels were significantly lower in hepatocellular carcinoma tissues than in the peritumoral tissues. In addition, Hook1 expression was significantly associated with hepatocellular carcinoma malignancy. Hook1 was downregulated after transforming growth factor-ß-induced epithelial-mesenchymal transition. Moreover, Hook1 knockdown promoted epithelial-mesenchymal transition and attenuated the sensitivity of hepatocellular carcinoma cells to doxorubicin. In summary, our results indicate that downregulation of Hook1 plays a pivotal role in hepatocellular carcinoma progression via epithelial-mesenchymal transition. Hook1 may be used as a novel marker and therapeutic molecular target in hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , Proteínas Associadas aos Microtúbulos/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/patologia , Proteínas Associadas aos Microtúbulos/biossíntese , RNA Interferente Pequeno , Fator de Crescimento Transformador beta/genética
13.
Int J Surg ; 36(Pt A): 240-247, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27826046

RESUMO

OBJECTIVE: Duct-to-mucosa and invagination are two commonly used techniques of pancreaticojejunostomy (PJ) after pancreaticoduodenectomy. Previously, we conducted a systematic review comparing the safety and efficacy of the two PJ techniques. Here, we added new evidence and updated our previous conclusion. METHODS: We systematically searched multiple databases and included randomized controlled trials (RCTs) comparing duct-to-mucosa and invagination techniques of PJ. The quality of evidence was assessed using Jadad score, and reporting bias was evaluated using funnel plots. Meta-analysis was performed using a random-effects model. Risk ratio (RR) and 95% confidence interval (CI) were calculated. The primary outcome was pancreatic fistula, and the secondary outcomes included mortality, reoperation, morbidity and postoperative hospital stay. Trial sequential analysis was performed to calculate the required information size. RESULTS: Seven RCTs with 850 participants were included. No significant difference was detected in the rates of pancreatic fistula (RR 0.98, 95% CI 0.63 to 1.53), mortality (RR 0.94, 95% CI 0.40 to 2.18), reoperation (RR 1.23, 95% CI 0.69 to 2.20) and morbidity (RR 0.98, 95% CI 0.82 to 1.16) between the two groups. However, patients who underwent duct-to-mucosa PJ had a significantly shorter postoperative hospital stay (mean difference -2.80, 95% CI -5.08 to -0.52). Trial sequential analysis showed that another 279 participants were needed for conclusive results. CONCLUSIONS: Given the current evidence, duct-to-mucosa PJ did not decrease the rates of pancreatic fistula and other adverse events as compared to invagination PJ; however, it did reduce postoperative hospital stay. Further RCTs are needed.


Assuntos
Mucosa Intestinal/cirurgia , Ductos Pancreáticos/cirurgia , Fístula Pancreática/epidemiologia , Pancreaticoduodenectomia , Pancreaticojejunostomia/métodos , Complicações Pós-Operatórias/epidemiologia , Anastomose Cirúrgica/métodos , Humanos , Tempo de Internação , Mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Reoperação , Segurança
14.
Biomaterials ; 104: 192-200, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27459325

RESUMO

Lack of efficient adjuvant therapy contributes to a high incidence of recurrence and metastasis of hepatocellular carcinoma (HCC). A novel therapeutic is required for adjuvant treatment of HCC. We developed a polymer-based nanosystem (ROSE) for functional gene therapy by synthesizing a supramolecular complex self-assembled from polycations and functional adamantyl modules. The ROSE system condensing tumor suppressor microRNA-34a (miR-34a) therapeutics becomes ROSE/miR-34a nanoparticles that could facilitate gene transfection in HCC cells with satisfied stability and efficiency, possibly due to proton sponge effect by polycations, PEGlyation protection, and controlled release by breakdown of disulfide bonds. Meanwhile, modification with a targeting oligopeptide SP94 in ROSE/miR-34a enables approximately higher affinity for LM3 HCC cells than hepatocytes in vitro and greater HCC specificity in vivo. Furthermore, ROSE/miR-34a nanoparticles significantly inhibits HCC cell proliferation and in vivo tumor growth, representing a notable effect improvement over conventional gene delivery strategies. ROSE/miR-34a, featuring redox-responsiveness, oligopeptide-guided specificity, self-assembly, and enhanced transfection, is therefore a potential therapeutic agent in future adjuvant therapy for HCC treatment.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , MicroRNAs/uso terapêutico , Nanocápsulas/química , Oligopeptídeos/farmacocinética , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Cristalização/métodos , Sinergismo Farmacológico , Camundongos , MicroRNAs/genética , Nanocápsulas/ultraestrutura , Oligopeptídeos/química , Oxirredução , Resultado do Tratamento
15.
Cancer Lett ; 380(1): 98-105, 2016 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-27339327

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer, with poor outcomes. Infection with the hepatitis B virus (HBV) may be associated as a worse prognosis for PDAC patients; however, the mechanisms involved in this process are unclear. We evaluated whether HBV infection leads to PDAC with a more aggressive phenotype, and attempted to elucidate the mechanisms involved. Clinicopathological data and outcomes from 64 patients with PDAC were collected and compared between serum HBsAg+ and HBsAg- patients. Furthermore, we examined the effects of the HBV X protein (HBx) on proliferation and migration of the pancreatic cancer cell lines PANC-1 and SW1990. We investigated expression changes of over 500 proteins by protein array analysis and identified several HBV- and PDAC-related candidates, which were further validated by immunoblotting and enzyme-linked immunosorbent assay. No differences in clinicopathological features were observed between HBsAg+ and HBsAg- patients; however, HBsAg+ patients had a shorter median survival time (8 vs. 13 months), although the differences were not significant. HBV DNA was detected in clinical specimens, even in PDAC patients considered "HBV-free", potentially due to occult infection. HBx expression significantly enhanced cellular proliferation and migration and induced an epithelial-mesenchymal transition phenotype. Expression of ErbB4 and TGF-α was increased in parallel with HBx expression, and several downstream pathways including PI3K/AKT, MAPK, and ERK were upregulated. Inhibition of the PI3K/AKT pathway reversed the effects of HBx in PDAC cell lines. HBx may, therefore, contribute to the progression of PDAC through modulation of these pathways.


Assuntos
Carcinoma Ductal Pancreático/enzimologia , Transformação Celular Viral , Vírus da Hepatite B/metabolismo , Hepatite B/metabolismo , Neoplasias Pancreáticas/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/virologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hepatite B/complicações , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/virologia , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptor ErbB-4/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transativadores/genética , Transfecção , Fator de Necrose Tumoral alfa/metabolismo
16.
Cancer Res ; 76(4): 818-30, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26837767

RESUMO

Portal vein tumor thrombosis (PVTT) is a significant risk factor for metastasis in hepatocellular carcinoma (HCC) patients and is therefore associated with poor prognosis. The presence of PVTT frequently accompanies substantial hypoxia within the tumor microenvironment, which is suggested to accelerate tumor metastasis, but it is unclear how this occurs. Recent evidence has shown that the hypoxia-inducible factor HIF-1α induces epithelial-to-mesenchymal transition (EMT) in tumor cells to facilitate metastasis. In this study, we investigated whether hypoxia-induced EMT in cancer cells also affects immune cells in the tumor microenvironment to promote immunosuppression. We found that hypoxia-induced EMT increased the expression of the CCL20 cytokine in hepatoma cells. Furthermore, coculture of monocyte-derived macrophages with hypoxic hepatoma cells revealed that the expression of indoleamine 2, 3-dioxygenase (IDO) was induced in monocyte-derived macrophages in a CCL20-dependent manner. In turn, these IDO-expressing monocyte-derived macrophages suppressed T-cell proliferation and promoted the expansion of immunosuppressive regulatory T cells. Moreover, high CCL20 expression in HCC specimens was associated with PVTT and poor patient survival. Collectively, our findings suggest that the HIF-1α/CCL20/IDO axis in hepatocellular carcinoma is important for accelerating tumor metastasis through both the induction of EMT and the establishment of an immunosuppressive tumor microenvironment, warranting further investigation into the therapeutic effects of blocking specific nodes of this signaling network.


Assuntos
Carcinoma Hepatocelular/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/mortalidade , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Hepáticas/mortalidade , Metástase Neoplásica , Transdução de Sinais , Microambiente Tumoral
17.
Tumour Biol ; 37(6): 7277-86, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26666823

RESUMO

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The multikinase inhibitor sorafenib is the only clinically proved systematic treatment for HCC. However, few patients respond to sorafenib. Hypoxic microenvironments contribute to sorafenib resistance. LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor was previously found to be a chemosensitizer in HCC. Here, we tested whether LB-100 could sensitize HCC to the effects of sorafenib. Intriguingly, LB-100 enhanced the effects of sorafenib in HCC cells only during hypoxic environments. LB-100 dramatically increased intracellular p-Smad3 level, which was responsible for the effect of LB-100 as a sensitizer. LB-100 downregulated Bcl-2 expression and enhanced sorafenib-induced apoptosis in HCC cells. We further proved that PP2A mediated LB-100-induced p-Smad3 overexpression. In addition, p38 mitogen-activated protein kinase pathway was activated in hypoxic conditions, and enhanced p-Smad3-dependent Bcl-2 inhibition and consequent apoptosis. In conclusion, LB-100 sensitized HCC cells to sorafenib in hypoxic environments. This effect was mediated by inactivation of PP2A, resulting in enhanced level of p-Smad3. Increased p-Smad3 downregulated Bcl-2, causing increased apoptosis of HCC cells.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Hepatocelular/patologia , Hipóxia Celular/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Smad3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes bcl-2 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Niacinamida/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/antagonistas & inibidores , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Distribuição Aleatória , Proteína Smad3/genética , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Mol Cancer Ther ; 13(8): 2062-72, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24867249

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common and therapeutically challenging malignancies worldwide. For patients ineligible for "curative resection" or liver transplantation, chemotherapy is an important minimally effective option. Strategies for chemosensitization are urgently needed. Here, we report that LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor, enhances the cytotoxicity of chemotherapy for HCC in vitro and in vivo. We found that LB-100 significantly enhanced inhibition of HCC by doxorubicin and cisplatin in vitro and in vivo in a PP2A-dependent way, while having little inhibitory activity when used alone. LB-100 promoted vascular endothelial growth factor secretion and vasculogenic mimicry, associated with increased microvessel density and blood perfusion of tumor cell xenografts. LB-100 also enhanced paracellular endothelial permeability to Evans Blue dye and doxorubicin in vivo and in vitro, presumably by altering vascular endothelial-cadherin contact between cells. Changes in permeability and perfusion were accompanied by increased accumulation of doxorubicin in HCC xenografts but not in normal liver tissue. In conclusion, LB-100 enhances chemotherapy by interfering with DNA damage-induced defense mechanisms and by increasing angiogenesis and drug penetration into tumor cells. The induction of angiogenesis and vascular permeability of tumor xenografts by inhibition of PP2A may be a novel approach for enhancing the cytotoxic treatment of HCC and potentially other cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Proteína Fosfatase 2/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Permeabilidade Capilar/efeitos dos fármacos , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas Experimentais/irrigação sanguínea , Neoplasias Hepáticas Experimentais/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Piperazinas/administração & dosagem , Proteína Fosfatase 2/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Cancer Res Clin Oncol ; 140(8): 1429-40, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24770582

RESUMO

BACKGROUND AND AIM: Combination therapy of sorafenib and transarterial chemoembolization (TACE) showed benefits for hepatocellular carcinoma (HCC). This systematic review aims for evaluation of efficacy and safety between sorafenib plus TACE and TACE alone for HCC. METHODS: We systematically searched multi-databases to identify eligible studies. Studies comparing sorafenib combined with TACE and TACE alone for HCC were included. RESULTS: Nine studies with 900 patients (sorafenib + TACE = 446, TACE = 454) were finally included. Sorafenib combined with TACE significantly reduced 6-month mortality [OR 0.24, 95 % confidential interval (CI) 0.09-0.68, P = 0.007] and 1-year mortality (OR 0.35, 95 % CI 0.21-0.56, P < 0.0001), but did not decrease 2-year mortality (OR 0.58, 95 % CI 0.14-2.46, P = 0.46). Although combination therapy tend to reduce 3-month (OR 0.76, 95 % CI 0.52-1.10, P = 0.15) and 6-month progression free rate (OR 0.27, 95 % CI 0.07-1.05, P = 0.06), the changes were not significant. Additionally, objective response ratio (OR 0.39, 95 % CI 0.19-0.78, P = 0.008) and clinical benefit ratio (OR 0.27, 95 % CI 0.15-0.50, P < 0.0001) also favored for combination therapy, which, however, caused higher morbidity, especially hand-foot skin reaction (OR 53.71, 95 % CI 28.86-99.93, P < 0.00001), hematological events (OR 14.8, 95 % CI 6.07-36.07, P < 0.00001), diarrhea (OR 6.62, 95 % CI 3.82-11.45, P < 0.00001), hypertension (OR 5.03, 95 % CI 3.02-8.38, P < 0.00001), rash/desquamation (OR 5.67, 95 % CI 3.58-8.99, P < 0.00001), and fatigue (OR 2.5, 95 % CI 1.09-5.72, P = 0.03). CONCLUSION: Combination of sorafenib and TACE showed survival and clinical benefits in patients with HCC, though enhanced morbidity.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Neoplasias Hepáticas/terapia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/mortalidade , Terapia Combinada , Humanos , Neoplasias Hepáticas/mortalidade , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe , Análise de Sobrevida , Resultado do Tratamento
20.
World J Gastroenterol ; 18(45): 6686-9, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23236247

RESUMO

Sister Mary Joseph's nodule (SMJN) refers to a metastatic tumor of the umbilicus. It is a rare entity which arises from a malignancy in the intra-abdominal cavity. We herein describe a patient who presented with SMJN as his first sign of pancreatic cancer. It is an even more unusual case of SMJN. We therefore, suggest that pancreatic cancer should be included in the differential diagnosis when an umbilical mass is found. With the progress made in surgical procedures and other modalities, an early diagnosis will dramatically improve the prognosis of the patients.


Assuntos
Neoplasias Pancreáticas/diagnóstico , Nódulo da Irmã Maria José/diagnóstico , Neoplasias Cutâneas/diagnóstico , Umbigo/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Biópsia , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Neoplasias Pancreáticas/patologia , Prognóstico , Nódulo da Irmã Maria José/patologia , Neoplasias Cutâneas/patologia , Resultado do Tratamento
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