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  • 1
    ISSN: 0167-0115
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 2
    Abstract: Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.
    Type of Publication: Journal article published
    PubMed ID: 28059096
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  • 3
    Abstract: Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index 〉20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index 〉20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.
    Type of Publication: Journal article published
    PubMed ID: 28059098
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  • 4
    Abstract: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by immunohistochemistry for KRT81 (QM/squamous/basal like) and HNF1A (non-QM, overlap with exocrine/ADEX subtype). EXPERIMENTAL DESIGN: We validated the different outcome of the HNF1A / KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were either treated with FOLFIRINOX (64 patients) or Gemcitabine (61 patients). RESULTS: In both cohorts with resected PDAC the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst and the double negative subtype an intermediate survival (p 〈0.013 and 〈0.009, respectively). In the chemotherapy cohort the survival difference between the double negative and the HNF1A-positive subtype was lost, while the dismal prognosis of KRT81-positive PDAC patients was retained (p 〈0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX-therapy, while those with HNF1A-positive tumors responded better compared to Gemcitabine-based treatment (p 〈0.038). CONCLUSIONS: Immunohistochemical stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly differing outcomes and responses to chemotherapy. These results may pave the way towards future pretherapeutic biomarker based stratification of PDAC patients.
    Type of Publication: Journal article published
    PubMed ID: 29101303
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; neoplasms ; DIAGNOSIS ; NEW-YORK ; microarray ; transcription ; TISSUE ; DNA ; MICROARRAY DATA ; MUTATIONS ; Jun ; PHENOTYPE ; vimentin ; HEAD ; adenocarcinoma ; pathology ; BEHAVIOR ; MICROARRAY ANALYSIS ; expression profiling ; TUMOR CELLS ; DIFFERENTIAL-DIAGNOSIS ; CELL CARCINOMA ; OF-THE-LITERATURE ; pancreas ; review ; DUCTAL ADENOCARCINOMA ; AUTOPSY ; analysis ; pancreatic ; TUMOR-CELL ; GENOTYPE ; DNA-MICROARRAY ; USA ; pancreatic ductal adenocarcinoma ; MYOEPITHELIAL CARCINOMA ; pancreatic neoplasm ; PSEUDOPAPILLARY TUMORS
    Abstract: Pancreatic neoplasms have been reliably classified on the basis of their histopathology and immunophenotype. In this study, we report on a pancreatic tumor whose phenotype and genotype could not be assigned to any known tumor entity. The tumor was observed in the pancreatic head of a 54-year-old woman. It was found to be a solid infiltrating carcinoma with abundant clear cells. Apart from cytokeratin, the tumor cells expressed vimentin, S100, and MUC-1. DNA microarray analysis revealed a transcription profile clearly differing from that of normal pancreatic tissue and pancreatic ductal adenocarcinoma. Despite metastatic behavior, the tumor displayed a more favorable course than conventional pancreatic ductal adenocarcinoma. We suggest that this tumor be called solid type clear cell carcinoma of the pancreas
    Type of Publication: Journal article published
    PubMed ID: 17453235
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; CELL ; INHIBITION ; LONG-TERM ; RNA ; DRUG ; cell line ; ACTIVATION ; NITRIC-OXIDE ; MECHANISM ; DONOR ; INDUCTION ; mechanisms ; treatment ; MOLECULE ; PROGRESSION ; MALIGNANCIES ; TUMOR PROGRESSION ; CELL-LINE ; chemotherapy ; LINE ; EFFICIENT ; BETA ; ADHESION ; PHENOTYPE ; INVOLVEMENT ; adenocarcinoma ; ADHESION MOLECULE ; ECTODOMAIN ; OVEREXPRESSION ; pancreatic cancer ; HIGH-LEVEL ; chemoresistance ; CASPASE ; INHIBITORS ; MALIGNANCY ; MOLECULAR-MECHANISM ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; INCREASE ; secretion ; SYNTHASE ; INTERLEUKIN-1 ; CASPASE ACTIVATION ; LEVEL ; analysis ; pancreatic ; IMMUNOHISTOCHEMICAL ANALYSIS ; POTENTIAL ROLE ; nitric oxide ; SPECIMENS ; interleukin ; metastatic potential ; METALLOPROTEINASE ; ectodomain shedding ; anticancer drug
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by rapid tumor progression, high metastatic potential and profound chemoresistance. We recently reported that induction of a chemoresistant phenotype in the PDAC cell line PT45-P1 by long-term chemotherapy involves an increased interleukin 1 beta (IL1beta)-dependent secretion of nitric oxide (NO) accounting for efficient caspase inhibition. In the present study, we elucidated the involvement of L1CAM, an adhesion molecule previously found in other malignancies, in this NO-dependent chemoresistance. Chemoresistant PT45-P1res cells, but not chemosensitive parental PT45-P1 cells, express high levels of L1CAM in an ILbeta-dependent fashion. PT45-P1res cells subjected to short interfering RNA (siRNA)-mediated L1CAM knock-down exhibited reduced inducible nitric oxide synthase expression and NO secretion, as well as a significant increase of anti-cancer drug-induced caspase activation, an effect reversed by the NO donor S-nitroso-N-acetyl-D,L-penicillamine. Conversely, overexpression of L1CAM in PT45-P1 cells conferred anti-apoptotic protection to anti-cancer drug treatment. Interestingly, L1CAM ectodomain shedding, in example, by ADAM10, as reported for other L1CAM-related activities, seemed to be dispensable for anti-apoptotic protection by L1CAM. Neither the shedded L1CAM ectodomain was detected in chemoresistant L1CAM-expressing PT45-P1 cells nor did the administration of various metalloproteinase inhibitors affect L1CAM-dependent chemoresistance. Immunohistochemical analysis revealed L1CAM expression in 80% of pancreatic cancer specimens, supporting a potential role of L1CAM in the malignancy of this tumor. These findings substantiate our understanding of the molecular mechanisms leading to chemoresistance in PDAC cells and indicate the importance of L1CAM in this scenario.Oncogene (2007) 26, 2759-2768. doi:10.1038/sj.onc.1210076; published online 6 November 2006.
    Type of Publication: Journal article published
    PubMed ID: 17086212
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  • 7
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; proliferation ; CELL ; FACTOR RECEPTOR ; Germany ; human ; MICROSCOPY ; VITRO ; GENE ; PROTEIN ; RNA ; MOLECULES ; TISSUE ; LINES ; RELEASE ; PATIENT ; FAMILY ; TISSUES ; FLOW ; CELL-LINES ; LESIONS ; PROSTATE-CANCER ; NECROSIS-FACTOR-ALPHA ; CELL-LINE ; LINE ; CANCER-CELLS ; EXTRACELLULAR-MATRIX ; ADHESION ; EPITHELIAL-CELLS ; INVOLVEMENT ; adenocarcinoma ; intraepithelial neoplasia ; BEHAVIOR ; cell lines ; pancreatic cancer ; chronic pancreatitis ; TNF-ALPHA ; EPIDERMAL-GROWTH-FACTOR ; FACTOR-ALPHA ; signaling ; pancreas ; RE ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; INCREASE ; ENZYME ; pancreatic ; PHASE ; technique ; function ; NECROSIS ; METALLOPROTEINASE ; ADAM ; ADAMS ; TACE
    Abstract: A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, I of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-alpha, was inhibited by TNF-alpha protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G(2)-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process
    Type of Publication: Journal article published
    PubMed ID: 16982746
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; carcinoma ; CELL ; Germany ; PATHWAY ; PATHWAYS ; VITRO ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; RNA ; SAMPLE ; SAMPLES ; transcription ; COMPONENTS ; TISSUE ; LINES ; TRANSDUCTION ; ACTIVATION ; TISSUES ; BIOLOGY ; CELL-LINES ; fibroblasts ; MOLECULAR-BIOLOGY ; signal transduction ; SIGNAL ; BREAST-CANCER ; PROGRESSION ; immunohistochemistry ; gene expression ; DIFFERENCE ; NUMBER ; METASTASIS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; adenocarcinoma ; TARGETS ; MICROARRAY ANALYSIS ; OVEREXPRESSION ; DIFFERENTIAL EXPRESSION ; gene expression profiling ; expression profiling ; microdissection ; pancreatic cancer ; pancreatic carcinoma ; chronic pancreatitis ; WNT ; molecular biology ; molecular ; PANCREATIC-CANCER ; fibroblast ; DUCTAL ADENOCARCINOMA ; PANCREATITIS ; PROTOCOL ; quantitative RT-PCR ; interaction ; analysis ; DIFFERENTIALLY EXPRESSED GENES ; signalling ; WNT pathway ; tumor microenvironment ; ENGLAND ; SET ; MEDICINE ; quantitative ; PROFILE ; pancreatic ductal adenocarcinoma ; response ; interactions ; SFRP1 ; expression profile ; stroma ; in vitro ; ABERRANT METHYLATION ; WNT5a
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic stroma. Interactions between cancer and stromal cells play a critical role in tumour invasion, metastasis and chemoresistance. Therefore, we hypothesized that gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. We investigated the gene expression of eleven stromal tissues from PDAC, nine from chronic pancreatitis and cell lines of stromal origin using the Affymetrix U133 GeneChip set. The tissue samples were microdissected, the RNA was extracted, amplified and labelled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified and validated using quantitative RT-PCR and immuno-histochemistry. We found 255 genes to be overexpressed and 61 genes to be underexpressed within the stroma of pancreatic carcinoma compared to the stroma of chronic pancreatitis. Analysis of the involved signal transduction pathways revealed a number of genes associated with the Wnt pathway of which the differential expression of SFRP1 and WNT5a was confirmed using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during cocultivation with a pancreatic carcinoma cell line. The identified differences in the expression profile of stroma cells derived from tumour compared to cells of inflammatory origin suggest a specific response of the tissue surrounding malignant cells. The overexpression of WNT5a, a gene involved in the non canonical Wnt signalling and chondrocyte development might contribute to the strong desmoplastic reaction seen in pancreatic cancer
    Type of Publication: Journal article published
    PubMed ID: 18298655
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  • 9
    Abstract: Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, to identify potential targets for personalized treatment, we perform integrative genome-wide and epigenome-wide analyses. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are detected. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies promising therapeutic targets in ACC for drugs recently approved for precision cancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 29109526
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  • 10
    Keywords: CANCER ; EXPRESSION ; carcinoma ; Germany ; DISEASE ; GENE ; TUMORS ; PATIENT ; FREQUENCY ; LESIONS ; MUTATION ; meta-analysis ; PCR ; MUTATIONS ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; intraepithelial neoplasia ; K-RAS ; chronic pancreatitis ; ALLELIC LOSS ; K-ras mutation ; pancreatic ductal carcinoma ; molecular ; DUCTAL ADENOCARCINOMA ; KRAS MUTATIONS ; METAANALYSIS ; CODON ; DNA ADDUCT ; duration ; K-RAS MUTATIONS ; KRAS ; GENETIC PROGRESSION ; ONCOGENE ACTIVATION ; pancreatic intraepithelial neoplasia
    Abstract: Molecular analyses have demonstrated mutations in the K-ras gene at codon 12 in the majority of pancreatic ductal adenocarcinomas (PDACs). In order to determine whether the K-ras mutation rate increases parallel to the grade of dysplasia in duct lesions, we performed a meta-analysis of the studies published between 1988 and 2003 that provide information on K-ras mutations in hyperplastic and dysplastic duct lesions in the pancreas. The described duct lesions were reclassified according to the nomenclature for pancreatic intraepithelial neoplasia (PanIN), and the molecular methods for detecting K-ras were reviewed. In PanIN lesions from pancreata of patients with PDAC, there was a stepwise increase in K-ras mutations that correlated with the grade of dysplasia of the PanIN lesion. K-ras mutations were found in 36%, 44%, and 87% of PanIN-1a, 1b, and 2-3 lesions, respectively (trend statistic P 〈 .001). Mutation-enriched polymerase chain reaction (PCR) resulted in higher rates of K-ras mutations in PanIN than plain PCR did. The incidence of K-ras mutations in PanIN lesions associated with chronic pancreatitis (CP) or normal pancreas was low (around 10%). In CP, K-ras mutations were only found after a disease duration of 3 years. The correlation of the incidence of K-ras mutations with the grade of dysplasia in PanIN and the occurrence of these mutations in CP with a duration of more than 3 years underlines the importance of this genetic change for the development of PDAC
    Type of Publication: Journal article published
    PubMed ID: 15720814
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