Journal Article•
Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer (Cancer Research (2003) (2649-2657))
TL;DR: Comparisons between pancreatic adenocarcinoma, pancreatic cancer cell lines, normal pancreas, and chronic pancreatitis have identified genes that are selectively expressed in the neoplastic epithelium of pancreatic adsorption.
Abstract: The molecular basis of pancreatic cancer is not understood. Previous attempts to determine the specific genes expressed in pancreatic cancer have been hampered by similarities between adenocarcinoma and chronic pancreatitis. In the current study, microarrays (Affymetrix) were used to profile gene expression in pancreatic adenocarcinoma (10), pancreatic cancer cell lines (7), chronic pancreatitis (5), and normal pancreas (5). Molecular profiling indicated a large number of genes differentially expressed between pancreatic cancer and normal pancreas but many fewer differences between pancreatic cancer and chronic pancreatitis, likely because of the shared stromal influences in the two diseases. To specifically identify genes expressed in neoplastic epithelium, we selected genes more highly expressed (>2-fold, p < 0.01) in adenocarcinoma compared with both normal pancreas and chronic pancreatitis and which were also highly expressed in pancreatic cancer cell lines. This strategy yielded 158 genes, of which 124 were not previously associated with pancreatic cancer. Quantitative-reverse transcription-PCR for two molecules, S100P and 14-3-3sigma, validated the microarray data. Support for the success of the neoplastic cell gene expression identification strategy was obtained by immunocytochemical localization of four representative genes, 14-3-3sigma, S100P, S100A6, and beta4 integrin, to neoplastic cells in pancreatic tumors. Thus, comparisons between pancreatic adenocarcinoma, pancreatic cancer cell lines, normal pancreas, and chronic pancreatitis have identified genes that are selectively expressed in the neoplastic epithelium of pancreatic adenocarcinoma. These data provide new insights into the molecular pathology of pancreatic cancer that may be useful for detection, diagnosis, and treatment.
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TL;DR: Mirk is a survival factor for pancreatic ductal adenocarcinoma because knockout of Mirk does not cause embryonic lethality, Mirk is not essential for normal cell growth and may represent a novel therapeutic target.
Abstract: Ductal adenocarcinoma of the pancreas is almost uniformly lethal as this cancer is invariably detected at an advanced stage and is resistant to treatment. The serine/threonine kinase Mirk/Dyrk1B has been shown to be antiapoptotic in rhabdomyosarcomas. We have now investigated whether Mirk might mediate survival in another cancer in which Mirk is widely expressed, pancreatic ductal adenocarcinoma. Mirk was an active kinase in each pancreatic cancer cell line where it was detected. Mirk knockdown by RNA interference (RNAi) reduced the clonogenicity of Panc1 pancreatic cancer cells 4-fold and decreased tumor cell number, showing that Mirk mediates survival in these cells. Mirk knockdown by synthetic duplex RNAis in Panc1, AsPc1, and SU86.86 pancreatic cancer cells induced apoptosis and enhanced the apoptosis induced by gemcitibine. Mirk knockdown did not increase the abundance or activation of Akt. However, four of five pancreatic carcinoma cell lines exhibited either elevated Mirk activity or elevated Akt activity, suggesting that pancreatic cancer cells primarily rely on Mirk or Akt for survival signaling. Mirk protein was detected by immunohistochemistry in 25 of 28 cases (89%) of pancreatic ductal adenocarcinoma, with elevated expression in 11 cases (39%). Increased expression of Mirk was seen in pancreatic carcinomas compared with primary cultures of normal ductal epithelium by serial analysis of gene expression and by immunohistochemistry. Thus, Mirk is a survival factor for pancreatic ductal adenocarcinoma. Because knockout of Mirk does not cause embryonic lethality, Mirk is not essential for normal cell growth and may represent a novel therapeutic target.
32 citations
18 Mar 2014
TL;DR: The objectives were to determine the incidence of chromosomal abnormalities by aCGH and identify ways of intratumoral clonal evolution.
Abstract: [ES] Antecedentes Hasta ahora los estudios genomicos de alto rendimiento (aCGH) no se han correlacionado con las caracteristicas clinico-patologicas en series amplias de cancer gastrico ni se ha estudiado adecuadamente la heterogeneidad intratumoral. Los objetivos fueron: 1) determinar la incidencia de alteraciones cromosomicas mediante aCGH 2) correlacionarlas con el comportamiento clinico-patologico y evolucion 3) determinar las vias de evolucion clonal intratumorales.
Material y metodos Se incluyeron 138 muestras del Hospital Universitario de Salamanca mediante aCGH de 1Mb de resolucion. En 87 pacientes se analizo la heterogeneidad intratumoral mediante FISH.
Resultados Las alteraciones mas frecuentes fueron perdidas en 17p (94%), 16q (87%), 12q (73%), 22q (56%), 7q (49%), 15q (29%) y ganancias en 13q (63%), 20p (47%), 10q (44%), 20q (32%), 1q (20%). Los pacientes con perdidas en 4p, 12q, 15q y/o ganancias en 6p, 7p, 13q y 20p se asocio con estadios avanzados, ademas ganancias en 20p y 10q presentaron una alta incidencia en metastasis a distancia y tipo histologico intestinal. Una vez determinados los factores pronosticos independientes intentamos establecer un sistema de estratificacion pronostica en tres grupos de riesgo tanto para supervivencia global como libre de recidiva.
El tipo histologico de Lauren, las anomalias en 6p y pT, son la mejor combinacion pronostica de supervivencia global, mientras que pN y las anomalias en 7p y 15q lo son para la supervivencia libre de recidiva. Los estudios de FISH mostraron que el 24% de los casos analizados presentaban un unico clon tumoral, identificandose en los casos restantes (76%) dos o mas clones tumorales. En el 57% de los casos analizados, la celula ancestral tumoral mostro ganancias o amplificacion de uno o mas cromosomas, siendo frecuente la ganancia de 20q13 (31%) en combinacion con las ganancias encontradas en 13q14 y amplificacion de HER2 (17%)
Conclusion Nuestros resultados muestran que los ADC gastricos son tumores geneticamente heterogeneos que presentan diferentes patrones de alteraciones cromosomicas, coexistiendo dos o mas clones tumorales. Ademas, podemos identificar en el momento del diagnostico distintos grupos de pacientes con ADC gastrico con diferente riesgo de recidiva y supervivencia.; [EN] Background Until now genomic high-throughput studies ( aCGH ) have not been correlated with clinicopathologic features in a large series of gastric cancer is not well studied the intratumoral heterogeneity. The objectives were to : 1 ) determine the incidence of chromosomal abnormalities by aCGH 2) you correlate with clinical - pathological behavior and evolution 3) identify ways of intratumoral clonal evolution.
Methods 138 samples Salamanca University Hospital were included by aCGH 1Mb resolution . In 87 patients, the intratumoral heterogeneity was analyzed by FISH .
Results The most frequent alterations were losses in 17p ( 94%), 16q ( 87%), 12q ( 73%), 22q ( 56%), 7q ( 49%), 15q (29 % ) and gains on 13q (63% ) , 20p ( 47% ) , 10q ( 44 % ) , 20q (…
12 citations
TL;DR: The molecular causes of gemcitabine resistance in PDAC are analyzed and the possibilities of new approaches aimed at decreasing, delaying or even reversing chemoresistance in pancreatic cancer are discussed.
Abstract: Simple Summary PDAC is one of the most malignant tumors and its treatment, whether surgery or chemotherapy, has shown poor results. Resistance to gemcitabine and other chemotherapeutic drugs is an essential factor in this failure. This review analyzes the molecular causes of gemcitabine resistance and discusses the possibilities of new approaches aimed at decreasing, delaying or even reversing chemoresistance in pancreatic cancer. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a poor prognosis and inadequate response to treatment. Many factors contribute to this therapeutic failure: lack of symptoms until the tumor reaches an advanced stage, leading to late diagnosis; early lymphatic and hematic spread; advanced age of patients; important development of a pro-tumoral and hyperfibrotic stroma; high genetic and metabolic heterogeneity; poor vascular supply; a highly acidic matrix; extreme hypoxia; and early development of resistance to the available therapeutic options. In most cases, the disease is silent for a long time, andwhen it does become symptomatic, it is too late for ablative surgery; this is one of the major reasons explaining the short survival associated with the disease. Even when surgery is possible, relapsesare frequent, andthe causes of this devastating picture are the low efficacy ofand early resistance to all known chemotherapeutic treatments. Thus, it is imperative to analyze the roots of this resistance in order to improve the benefits of therapy. PDAC chemoresistance is the final product of different, but to some extent, interconnected factors. Surgery, being the most adequate treatment for pancreatic cancer and the only one that in a few selected cases can achieve longer survival, is only possible in less than 20% of patients. Thus, the treatment burden relies on chemotherapy in mostcases. While the FOLFIRINOX scheme has a slightly longer overall survival, it also produces many more adverse eventsso that gemcitabine is still considered the first choice for treatment, especially in combination with other compounds/agents. This review discusses the multiple causes of gemcitabine resistance in PDAC.
10 citations
Dissertation•
01 Feb 2011
TL;DR: This dissertation aims to provide a history of web exceptionalism from 1989 to 2002, a period chosen in order to explore its roots as well as specific cases up to and including the year in which descriptions of “Web 2.0” began to circulate.
Abstract: ................................................................................................... 5 List of Figures .......................................................................................... 6 List of Tables ............................................................................................ 9 Abbreviations ......................................................................................... 10 List of publications ................................................................................ 14 Acknowledgements ............................................................................... 15
8 citations
Dissertation•
01 May 2012
TL;DR: Using nanofiltration membranes for the recovery of phosphorous with a second type of technology for the Recovery of nitrogen is suggest to be a viable process.
Abstract: ..............................................................................................................3 ACKNOWLEDGEMENTS ..........................................................................................5 TABLE OF CONTENTS ............................................................................................7 LIST OF TABLES ....................................................................................................10 LIST OF FIGURES ..................................................................................................11 APPENDICES .........................................................................................................14 GLOSSARY OF ABBREVIATIONS ........................................................................15
7 citations
Cites background or methods or result from "Molecular profiling of pancreatic a..."
...S100P also has been shown to be expressed at higher levels in PDAC as compared to chronic pancreatitis (93)....
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..., S100P was confirmed to be expressed exclusively in the neoplastic epithelial compartment of PDAC, using GEP with subsequent IHC validation (93)....
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...198 Due to its well-established role in PanIN progression and PDAC in human tissue samples (91,93), and based on previously published data supporting a causative role for S100P in PDAC invasion both in vitro and in vivo (92,94–97), we went on to...
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...Importantly, analysis of S100P expression in this study included a comparison with tissue samples of chronic pancreatitis, a condition which is often difficult to differentiate from PDAC (93)....
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References
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TL;DR: A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression, finding in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function.
Abstract: A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is de- scribed that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be inter- preted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly charac- terized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
16,371 citations
"Molecular profiling of pancreatic a..." refers methods in this paper
...Probe sets and samples were arranged and displayed using Cluster and Treeview software (18)....
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...We used Eisen matrix formats (18) of the 921 genes selected above to investigate the variation in gene expression, show clusters of coordinately expressed genes, and indicate relationships between specimens....
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TL;DR: Estimates of the number of new cancer cases and deaths expected in the US in the current year and the most recent data on cancer incidence, mortality, and survival reveal large disparities in cancer incidence and mortality across racial/ethnic groups.
Abstract: Each year the American Cancer Society compiles estimates of the number of new cancer cases and deaths expected in the US in the current year and the most recent data on cancer incidence, mortality, and survival. An estimated 1,268,000 new cases of cancer will be diagnosed in the year 2001 and an estimated 553,400 Americans will die from cancer. Overall cancer incidence and death rates have continued to decrease in men and women since the early 1990s, and the decline in overall cancer mortality has been greater in recent years. Despite reductions in age-adjusted rates of cancer death, the total number of recorded cancer deaths in the US continues to increase, due to an aging and expanding population. Large disparities in cancer incidence and mortality across racial/ethnic groups continue. Black men and women experience higher incidence of cancer and poorer survival than white men and women. The disparity in survival reflects both diagnosis of cancer at later disease stages, and poorer survival within each stage of diagnosis.
3,346 citations
TL;DR: The American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year, and compiles the most recent data on cancer incidence, mortality, and survival by using incidence data from the National Cancer Institute (NCI) and mortality data from National Center for Health Statistics (NCHS).
Abstract: Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year, and compiles the most recent data on cancer incidence, mortality, and survival by using incidence data from the National Cancer Institute (NCI) and mortality data from the National Center for Health Statistics (NCHS). Incidence and death rates are age adjusted to the 2000 US standard population. In the year 2003, we estimate that 1,334,100 new cases of cancer will be diagnosed, and 556,500 people will die from cancer in the United States. Age-adjusted cancer death rates declined in both males and females in the 1990s, though the magnitude of decline is substantially higher in males than in females. In contrast, incidence rates continued to increase in females while stabilizing in males. African-American males showed the largest decline for mortality. However, African Americans still carry the highest burden of cancer with diagnosis of cancer at a later stage and poorer survival within each stage compared with Whites. In spite of the continued decline in cancer death rates in the most recent time period, the total number of recorded cancer deaths in the United States continues to increase slightly due to the aging and expanding population.
3,111 citations
TL;DR: This work identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA) that showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog.
Abstract: Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44+CD24+ESA+ phenotype (0.2–0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44+CD24+ESA+ cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44+CD24+ESA+ pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44+CD24+ESA+ pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation. [Cancer Res 2007;67(3):1030–7]
3,109 citations
TL;DR: This single institution, high-volume experience indicates that pancreaticoduodenectomy can be performed safely for a variety of malignant and benign disorders of the pancreas and periampullary region.
Abstract: OBJECTIVE: The authors reviewed the pathology, complications, and outcomes in a consecutive group of 650 patients undergoing pancreaticoduodenectomy in the 1990s. SUMMARY BACKGROUND DATA: Pancreaticoduodenectomy has been used increasingly in recent years to resect a variety of malignant and benign diseases of the pancreas and periampullary region. METHODS: Between January 1990 and July 1996, inclusive, 650 patients underwent pancreaticoduodenal resection at The Johns Hopkins Hospital. Data were recorded prospectively on all patients. All pathology specimens were reviewed and categorized. Statistical analyses were performed using both univariate and multivariate models. RESULTS: The patients had a mean age of 63 +/- 12.8 years, with 54% male and 91% white. The number of resections per year rose from 60 in 1990 to 161 in 1995. Pathologic examination results showed pancreatic cancer (n = 282; 43%), ampullary cancer (n = 70; 11%), distal common bile duct cancer (n = 65; 10%), duodenal cancer (n = 26; 4%), chronic pancreatitis (n = 71; 11%), neuroendocrine tumor (n = 31; 5%), periampullary adenoma (n = 21; 3%), cystadenocarcinoma (n = 14; 2%), cystadenoma (n = 25; 4%), and other (n = 45; 7%). The surgical procedure involved pylorus preservation in 82%, partial pancreatectomy in 95%, and portal or superior mesenteric venous resection in 4%. Pancreatic-enteric reconstruction, when appropriate, was via pancreaticojejunostomy in 71% and pancreaticogastrostomy in 29%. The median intraoperative blood loss was 625 mL, median units of red cells transfused was zero, and the median operative time was 7 hours. During this period, 190 consecutive pancreaticoduodenectomies were performed without a mortality. Nine deaths occurred in-hospital or within 30 days of operation (1.4% operative mortality). The postoperative complication rate was 41%, with the most common complications being early delayed gastric emptying (19%), pancreatic fistula (14%), and wound infection (10%). Twenty-three patients required reoperation in the immediate postoperative period (3.5%), most commonly for bleeding, abscess, or dehiscence. The median postoperative length of stay was 13 days. A multivariate analysis of the 443 patients with periampullary adenocarcinoma indicated that the most powerful independent predictors favoring long-term survival included a pathologic diagnosis of duodenal adenocarcinoma, tumor diameter <3 cm, negative resection margins, absence of lymph node metastases, well-differentiated histology, and no reoperation. CONCLUSIONS: This single institution, high-volume experience indicates that pancreaticoduodenectomy can be performed safely for a variety of malignant and benign disorders of the pancreas and periampullary region. Overall survival is determined largely by the pathology within the resection specimen.
1,782 citations
"Molecular profiling of pancreatic a..." refers background in this paper
...Currently, the only curative treatment for pancreatic cancer is surgery, but only 10–20% of patients are candidates for surgery at the time of presentation (2), and of this group, only 20% of patients who undergo a curative operation are alive after 5 years (3)....
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