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1.
Cancer Treat Rev ; 80: 101895, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31542591

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). MATERIAL AND METHODS: The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. RESULTS: Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). CONCLUSION: Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Humanos , Compostos Organoplatínicos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
DNA Cell Biol ; 38(11): 1207-1222, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483163

RESUMO

Multiple studies have shown that cancer-specific alternative splicing (AS) alterations are associated with clinical outcome. In this study, we aimed to profile prognostic AS signatures for pancreatic ductal adenocarcinoma (PDAC). We integrated the percent-spliced-in (PSI) data of AS in 140 PDAC patients based on the Cancer Genome Atlas (TCGA) dataset. We identified overall survival (OS)-associated AS events using univariate Cox regression analysis. Then, prognostic AS signatures were constructed for OS and chemoresistance prediction using the least absolute shrinkage and selection operator (LASSO) method. We also analyzed splicing factors (SFs) regulatory networks by Pearson's correlation. We detected 677 OS-related AS events in 485 genes by profiling 10,354 AS events obtained from 140 PDAC patients. Gene functional enrichment analysis demonstrated the pathways enriched by survival-associated AS. The AS signatures constructed with significant survival-associated AS events revealed high performance in predicting PDAC survival and gemcitabine chemoresistance. The area under the receiver operator characteristic curve was 0.937 in training cohort and 0.748 in validation cohort at 2000 days of OS. Furthermore, we identified prognostic SFs (e.g., ESRP1 and HNRNPC) to build the AS regulatory network. We constructed AS signatures for OS and gemcitabine chemoresistance in PDAC patients, which may provide clues for further experiment-based mechanism study.


Assuntos
Processamento Alternativo/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Transcriptoma , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Prognóstico , Análise de Sequência de RNA , Análise de Sobrevida
3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 749-756, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413212

RESUMO

OBJECTIVE: To conduct genetic analysis of pancreatic ductal adenocarcinoma tissues and analyze the correlation between targeted microRNA (miRNA) and pathways in pancreatic ductal adenocarcinoma.
 Methods: We collected 19 samples of peripheral venous blood serum from patients with pancreatic ductal adenocarcinoma in Hainan Provincial Hospital of Chinese Medicine, and also collected 21 blood serum samples as a control group of non-pancreatic ductal adenocarcinoma. We used the bioinformatics analysis of literature GCBI data platform for screening and analyzing the genetics of pancreatic ductal adenocarcinoma samples. Through GCBI data platform of hierarchy clustering analysis and the enrichment of gene function analysis, the relevant miRNA was screened as a research object in patients with pancreatic ductal adenocarcinoma. The miRNA was screened by literature analysis and pancreatic cancer gene analysis. Real-time PCR and Western blotting were carried out to study the relationship between the selected miRNA and TGF-ß1 by overexpression and suppression of the gene in pancreatic ductal adenocarcinoma cells.
 Results: MiRNA-21 was screened as a gene associated with pancreatic ductal carcinoma via hierarchy clustering analysis and gene function analysis. MiRNA-21 was highly expressed in the pancreatic ductal carcinoma patients. Expressions of TGF-ß1 were inhibired in miRNA-21 overexpressed PANC-1. While the expression of miRNA-21 was inhibited, TGF-ß1 expression increased obviously.
 Conclusion: MiRNA-21 is highly expressed in patients with pancreatic ductal adenocarcinoma, can regulate the expression of TGF-ß1, which may be a mechanism of miRNA-21 in pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático , MicroRNAs/genética , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Humanos , Neoplasias Pancreáticas/genética , Fator de Crescimento Transformador beta1
4.
JAMA ; 322(5): 438-444, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386141

RESUMO

Importance: Pancreatic cancer is an uncommon cancer with an age-adjusted annual incidence of 12.9 cases per 100 000 person-years. However, the death rate is 11.0 deaths per 100 000 person-years because the prognosis of pancreatic cancer is poor. Although its incidence is low, pancreatic cancer is the third most common cause of cancer death in the United States. Because of the increasing incidence of pancreatic cancer, along with improvements in early detection and treatment of other types of cancer, it is estimated that pancreatic cancer may soon become the second-leading cause of cancer death in the United States. Objective: To update the 2004 US Preventive Services Task Force (USPSTF) recommendation on screening for pancreatic cancer. Evidence Review: The USPSTF reviewed the evidence on the benefits and harms of screening for pancreatic cancer, the diagnostic accuracy of screening tests for pancreatic cancer, and the benefits and harms of treatment of screen-detected or asymptomatic pancreatic cancer. Findings: The USPSTF found no evidence that screening for pancreatic cancer or treatment of screen-detected pancreatic cancer improves disease-specific morbidity or mortality, or all-cause mortality. The USPSTF found adequate evidence that the magnitude of the benefits of screening for pancreatic cancer in asymptomatic adults can be bounded as no greater than small. The USPSTF found adequate evidence that the magnitude of the harms of screening for pancreatic cancer and treatment of screen-detected pancreatic cancer can be bounded as at least moderate. The USPSTF reaffirms its previous conclusion that the potential benefits of screening for pancreatic cancer in asymptomatic adults do not outweigh the potential harms. Conclusions and Recommendation: The USPSTF recommends against screening for pancreatic cancer in asymptomatic adults. (D recommendation).


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Detecção Precoce de Câncer/normas , Neoplasias Pancreáticas/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Efeitos Psicossociais da Doença , Detecção Precoce de Câncer/efeitos adversos , Feminino , Humanos , Masculino , Programas de Rastreamento/normas , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade
5.
Nat Commun ; 10(1): 3055, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296870

RESUMO

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Técnicas de Inativação de Genes , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/genética , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Sci ; 110(9): 2760-2772, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325400

RESUMO

Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. TP53TG1 is a recently identified lncRNA and several studies have shown that TP53TG1 may play the role of tumor suppressor gene or oncogene in different tumors. Nevertheless, the involvement of TP53TG1 in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has not been characterized. In our studies, we identified that TP53TG1 was highly expressed in PDAC and was a novel regulator of PDAC development. Knockdown of TP53TG1 inhibited proliferation, induced apoptosis, and decreased migration and invasion in PDAC cells, whereas enhanced expression of TP53TG1 had the opposite effects. Mechanistically, TP53TG1 could directly bind to microRNA (miR)-96 and effectively function as a sponge for miR-96, thus antagonizing the functions of miR-96 and leading to derepression of its endogenous target KRAS, which is a core oncogene in the initiation and maintenance of PDAC. Taken together, these observations imply that TP53TG1 contributes to the growth and progression of PDAC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR-96 and regulate KRAS expression, which highlights the importance of the complicated miRNA-lncRNA network in modulating the progression of PDAC.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteínas de Ligação a DNA/metabolismo , MicroRNAs/antagonistas & inibidores , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Longo não Codificante/metabolismo , Carcinogênese/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Longo não Codificante/genética
7.
Gastroenterology ; 157(3): 838-850.e6, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31163177

RESUMO

BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.


Assuntos
Anexina A2/metabolismo , Orientação de Axônios , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular , Gânglios Espinais/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Pancreáticas/metabolismo , Semaforinas/metabolismo , Animais , Anexina A2/deficiência , Anexina A2/genética , Orientação de Axônios/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundário , Comunicação Celular , Gânglios Espinais/patologia , Regulação Neoplásica da Expressão Gênica , Genes p53 , Genes ras , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Crescimento Neuronal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Semaforinas/genética , Transdução de Sinais , Transativadores/genética , Células Tumorais Cultivadas
8.
Cancer Sci ; 110(8): 2442-2455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148345

RESUMO

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease-free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer-driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer-driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
9.
Int J Med Sci ; 16(4): 583-592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171910

RESUMO

Aims: Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are members of the glycosylphosphatidylinositol (GPI)-linked immunoglobulin (Ig) superfamily and take part in regulation of cell adhesion, tumor suppression and angiogenesis. Overexpression of CEACAM 1, 5 and 6 is widely described in several gastrointestinal epithelial tumors. The aim of study was to evaluate the expression of CEACAM 1, CEACAM 5 and CEACAM 6 in the most common precursor lesions of pancreatic ductal adenocarcinoma -pancreatic intraepithelial neoplasia (PanIN). Methods and results: The study group consisted of 32 patients treated for chronic pancreatitis and 38 patients with pancreatic ductal adenocarcinoma who also had pancreatic intraepithelial neoplasia. The expression of CEACAM was performed by immunohistochemical method and evaluated using 3-point scale: 0 - lack of positive reaction in pancreatic intraepithelial neoplasia, 1 (weak and moderate) - reaction present in 1-30% epithelial cells in PanIN and 2 (strong) - reaction present in >30% epithelial cells in PanIN. Expression of CEACAM 1, 5 and 6 increased with increasing degree of advancement of PanIN. Differences in expression of CEACAM 1, 5 and 6 between normal pancreatic ducts and different degrees of PanIN were statistically significant (p<0.001). We observed relationship between CEACAM1 expression and localization of PanIN in different parts of the pancreas. Conclusions: CEACAM 1, CEACAM 5 and CEACAM 6 expression appears to be an early event in pancreatic carcinogenesis. Moreover, expression of CEACAM 1, 5 and 6 may represent a useful biomarker that may aid in the identification of precancerous lesions in the pancreas.


Assuntos
Adenocarcinoma/genética , Antígenos CD/genética , Antígeno Carcinoembrionário/genética , Carcinoma Ductal Pancreático/genética , Moléculas de Adesão Celular/genética , Adenocarcinoma/complicações , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinoma in Situ/complicações , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite Crônica/complicações , Pancreatite Crônica/genética , Pancreatite Crônica/patologia
10.
Clin Cancer Res ; 25(15): 4589-4591, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164372

RESUMO

Approximately 8%-10% of pancreatic ductal adenocarcinoma cases are KRAS wild type. In a subset of these tumors, NRG1 gene fusions have been identified as targetable oncogenic drivers, a discovery that highlights the importance of deep molecular characterization for KRAS wild-type pancreatic cancers and provides a novel treatment strategy in this disease.See related article by Jones et al., p. 4674.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Carcinogênese , Humanos , Neuregulina-1/genética , Oncogenes , Proteínas Proto-Oncogênicas p21(ras)/genética
11.
Expert Opin Drug Metab Toxicol ; 15(6): 437-447, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31100206

RESUMO

Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors' and patients' features. Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making. Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Farmacogenética/métodos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Seleção de Pacientes , Prognóstico
12.
Cancer Sci ; 110(7): 2296-2308, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074083

RESUMO

Vasohibin-2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL-KrasG12D ; LSL-Trp53R172H ; Pdx-1-Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2-knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2-deficient mice, metastasis was significantly decreased in Vash2-deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2-induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2-deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.


Assuntos
Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Tubulina (Proteína)/metabolismo , Microambiente Tumoral
13.
Gastroenterology ; 157(3): 823-837, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078621

RESUMO

BACKGROUND & AIMS: Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. METHODS: We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. RESULTS: Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. CONCLUSIONS: In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Neoplasias Pancreáticas/enzimologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral , Animais , Antígenos de Neoplasias/genética , Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/genética , Inibidores da Anidrase Carbônica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Glicólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Compostos de Fenilureia/farmacologia , Transdução de Sinais , Sulfonamidas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
World J Gastroenterol ; 25(15): 1797-1816, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057295

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pancreáticas/genética , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Reposicionamento de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Metformina/farmacologia , Metformina/uso terapêutico , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Fosfoproteínas/antagonistas & inibidores , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética
15.
Klin Onkol ; 32(Suppl 1): 174-176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31064193

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of pancreas, characterized by extremely poor prognosis largely due to problem with early diagnosis and lack of progress in personalization of therapy. Of all available treatment strategies, radical surgical resection of the tumour in its early stage remains the only possibility how to reach long-term survival. However, even a technically perfect surgical resection may still not provide a survival benefit for all PDAC patients. Appropriate selection of patients for surgical resection is one the important medical needs in management of PDAC patients. MATERIAL AND METHODS: To this study we enrolled 24 PDAC patients who underwent surgical resection and preoperatively collected their blood plasma specimends. Patients were divided into to two prognostic groups according to their overall survival - 12 patients with poor prognosis (median overall survival 10 months) and 12 patients with good prognosis (median overall survival 25 months). Small RNA sequencing technology was applied to screen for microRNAs (miRNA) with differential levels between both PDAC patients group. cDNA libraries were prepared using QIAseq miRNA Library Kit (Qiaqen) and sequencing by NextSeq500 instrument (Illumina). RESULTS: When miRNA expression profiles of the PDAC patients from good and poor prognostic groups were compared, 61 miRNAs were identified to have significantly different plasma levels between the two groups (p < 0.05). A total of 21 miRNAs showed increased expression and 40 miRNAs showed decreased expression in a group of patients with poor prognosis compared to patients with good prognosis. CONCLUSION: This study demonstrated differences in miRNA expression profiles in preoperative plasma specimens of PDAC patients with short and long overall survival. Our observations indicate that after independent validations plasma miRNAs might become useful biomarkers for identification of PDAC patients having clinical benefit from surgical resection of the tumour. This work was supported by Czech Ministry of Health, grant No. 16-31314A. All rights reserved. The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 8. 3. 2019 Accepted: 9. 3. 2019.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/patologia , MicroRNAs/sangue , Neoplasias Pancreáticas/patologia , Cuidados Pré-Operatórios , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Prognóstico , Taxa de Sobrevida
17.
BMC Cancer ; 19(1): 452, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088413

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is not a clinically homogeneous disease, but subsets of patients with distinct prognosis and response to therapy can be identified by genome-wide analyses. Mutations in major PDAC driver genes were associated with poor survival. By bioinformatics analysis, we identified protocadherins among the most frequently mutated genes in PDAC suggesting an important role of these genes in the biology of this tumor. Promoter methylation of protocadherins has been suggested as a prognostic marker in different tumors, but in PDAC this epigenetic modification has not been extensively studied. Thus, we evaluated whether promoter methylation of three frequently mutated protocadherins, PCDHAC2, PCDHGC5 and PCDH10 could be used as survival predictors in PDAC patients. METHODS: DNA extracted from 23 PDACs and adjacent non-neoplastic pancreatic tissues were bisulfite treated. Combined Bisulfite Restriction Analysis (COBRA) coupled to denaturing high-performance liquid chromatography (dHPLC) detection and bisulfite genomic sequencing (BGS) were used to determine the presence of methylated CpG dinucleotides in the promoter amplicons analyzed. RESULTS: In an exploratory analysis, two protocadherins showed the same pattern of CpG methylation in PDAC and adjacent non-neoplastic pancreatic tissues: lack of methylation for PCDHAC2, complete methylation for PCDHGC5. Conversely, the third protocadherin analyzed, PCDH10, showed a variable degree of CpG methylation in PDAC and absence of methylation in adjacent non-neoplastic pancreatic tissues. At Kaplan-Meier analysis, high levels of PCDH10 methylation defined according to the receiver operating characteristic (ROC) curve analysis were significantly associated with worse progression-free survival (PFS) rates (P = 0.008), but not with overall survival (OS). High levels of PCDH10 methylation were a prognostic factor influencing PFS (HR = 4.0: 95% CI, 1.3-12.3; P = 0.016), but not the OS. CONCLUSIONS: In this study, we show for the first time that the methylation status of PCDH10 can predict prognosis in PDAC patients with a significant impact on the outcome in terms of progression-free survival. High levels of PCDH10 promoter methylation could be useful to identify patients at high risk of disease progression, contributing to a more accurate stratification of PDAC patients for personalized clinical management.


Assuntos
Caderinas/genética , Carcinoma Ductal Pancreático/genética , Metilação de DNA , Neoplasias Pancreáticas/genética , Adulto , Idoso , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Curva ROC , Análise de Sequência de DNA , Análise de Sobrevida
18.
Surg Oncol ; 28: 121-127, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30851885

RESUMO

Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained almost unchanged for many decades. Pancreatic cancer has few prevalent genetic mutations. Available data on dMMR pancreatic cancer is limited and heterogeneous with regard to its prevalence and prognostic implications. Discordant results are mainly due to differences in detection methods and sample sizes. Interest in dMMR is growing since initial reports on immune checkpoint inhibition therapy for pancreatic cancer has shown it to be effective, generating impressive and durable responses. However, it has been accompanied by several questions regarding the appropriate screening, detection tools, patient selection, timing and modality of testing. Herein, we provide an extensive literature review and outline recommendations for testing.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Reparo de Erro de Pareamento de DNA , Imunoterapia , Instabilidade de Microssatélites , Neoplasias Pancreáticas/tratamento farmacológico , Medicina de Precisão , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Testes Genéticos , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia
19.
BMC Cancer ; 19(1): 253, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898113

RESUMO

BACKGROUND: Despite its relatively low incidence, pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths because of the aggressive growth/metastasis of the tumor, the lack of early symptoms, and the poor treatment options. Basic research to identify potential therapeutic targets for PDAC is greatly needed. METHODS: We used a negative-selection genome-wide CRISPR screen to identify essential genes in the PANC-1 human pancreatic carcinoma cell line. We validated the top hits with follow-up siRNA screens, using the HPNE, HPAF-II, AsPC-1, and Mia PaCa-2 cell lines. RESULTS: The PSMA6 gene was an identified candidate hit after the CRISPR screen, siRNA validation screen, and siRNA deconvolution screen. Spheroid formation assays and flow cytometry analysis showed that PSMA6 is critical for survival in many pancreatic ductal carcinoma cell models. Lastly, as PSMA6 protein is a proteosomal subunit of the 20S core complex, we showed that bortezomib, a proteasome inhibitor, was especially toxic in PANC-1 cells. CONCLUSIONS: Further study of PSMA6 and the proteasome subunit that it encodes, along with other hits identified in our CRISPR screens, may provide valuable insights into potential therapeutic targets for PDAC.


Assuntos
Carcinoma Ductal Pancreático/genética , Oncogenes/genética , Neoplasias Pancreáticas/genética , Complexo de Endopeptidases do Proteassoma/genética , Bortezomib/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genoma Humano/genética , Genômica/métodos , Humanos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/farmacologia , Inibidores de Proteassoma/farmacologia , RNA Interferente Pequeno/genética , Esferoides Celulares
20.
Cancer Treat Rev ; 75: 27-38, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30927677

RESUMO

CONTEXT: Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. OBJECTIVE: A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. METHOD: A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. RESULTS: A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. CONCLUSION: Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Genômica/métodos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico
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