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  • 1
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; CELL ; Germany ; TISSUE ; LINES ; TIME ; FAMILY ; INDUCTION ; TISSUES ; CONTRAST ; CELL-LINES ; DOWN-REGULATION ; MEMBER ; MEMBERS ; PHOSPHORYLATION ; BREAST-CANCER ; antibodies ; antibody ; immunohistochemistry ; ASSAY ; CARCINOMA CELLS ; CELL-LINE ; LINE ; CANCER-CELLS ; BETA ; RT-PCR ; adenocarcinoma ; p21 ; CELL-SURFACE ; RECEPTORS ; DIFFERENTIAL EXPRESSION ; cell lines ; pancreatic cancer ; CELL-GROWTH ; signaling ; PANCREATIC-CANCER ; FAMILIES ; DUCTAL ADENOCARCINOMA ; independent growth ; ENHANCED EXPRESSION ; TGF-beta 1 ; HEPARAN-SULFATE PROTEOGLYCANS ; LEVEL ; pancreatic ; ASSAYS ; SULFATE ; downregulation ; lymph node ; LYMPH-NODE ; correlation ; VIEW ; DECREASED SURVIVAL ; activin ; bone morphogenic protein ; CONTROLS CELLULAR-RESPONSES ; glypican ; heparan sulfate proteoglycans ; SMAD PROTEINS
    Abstract: Glypican 1 (GPC1) is a cell surface heparan sulfate proteoglycan that acts as a co-receptor for heparin-binding growth factors as well as for members of the TGF-beta family. GPC1 plays a role in pancreatic cancer by regulating growth factor responsiveness. In view of the importance of members of the TGF-beta family in pancreatic cancer, in the present study, the role of GPC1 in TGF-beta, BMP and activin signaling was analyzed. Quantitative RT-PCR and immunohistochemistry were utilized to analyze GPC1 and TGF-beta, BMP and activin receptor expression levels. Panc-1 and T3M4 pancreatic cancer cells were transfected in a stable manner with a GPC1 antisense expression construct. Anchorage-dependent and -independent growth was determined by MTT and soft agar assays. TGF-beta 1, activin-A and BMP-2 responsiveness was determined by MTT assays and immunoblotting with p21, p-Smad1, and p-Smad2 antibodies. QRT-PCR demonstrated increased GPC1 mRNA levels in pancreatic ductal adenocarcinoma (PDAC) compared to normal pancreatic tissues (NPT), as described previously. There was a significant correlation between GPC1 mRNA levels and T beta RII, act-R1a, act-R1b, act-R2a, BMP-R1a, and BMP-R2 mRNA expression in NPT. In contrast, GPC1 mRNA expression correlated directly with act-R1a and BMP-R1a in NO PDAC cases and with act-R2a and BMP-R1a in lymph node positive cases. Down-regulation of GPC1 resulted in increased doubling time in Panc-1 but not in T3M4 cells, and decreased anchorage-independent growth in both cell lines. GPC1 down-regulation resulted in a slightly altered response towards TGF-beta 1, activin-A and BMP-2 in terms of growth, p21 induction and Smad2 phosphorylation. In conclusion, enhanced GPC1 expression correlates with BMP and activin receptors in pancreatic cancer. GPC1 down-regulation suppresses pancreatic cancer cell growth and slightly modifies signaling of members of the TGF-beta family of growth factors
    Type of Publication: Journal article published
    PubMed ID: 17016645
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  • 2
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; SURVIVAL ; carcinoma ; TRIAL ; CANCER-PATIENTS ; HUMAN TUMOR-CELLS ; TRANSFERRIN RECEPTOR ; QUALITY-OF-LIFE ; ANEMIA ; CHRONIC HEART-FAILURE ; EPOETIN-BETA ; STIMULATING AGENTS
    Type of Publication: Journal article published
    PubMed ID: 21829709
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; FACTOR RECEPTOR ; Germany ; GENES ; HYBRIDIZATION ; microarray ; PROTEIN ; TISSUE ; MICE ; TIME ; PATIENT ; COMPLEX ; COMPLEXES ; DONOR ; DOMAIN ; TISSUES ; 5-FLUOROURACIL ; TRANSPORT ; IN-SITU ; LESIONS ; immunohistochemistry ; MALIGNANCIES ; ASSAY ; UP-REGULATION ; PROSTATE-CANCER ; NUDE-MICE ; chemotherapy ; CANCER-CELLS ; LOCALIZATION ; adenocarcinoma ; sensitivity ; CISPLATIN ; MICROARRAY ANALYSIS ; OVEREXPRESSION ; expression profiling ; microdissection ; pancreatic cancer ; REGULATOR ; chronic pancreatitis ; CELL-GROWTH ; in situ hybridization ; MALIGNANCY ; GEMCITABINE ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; INCREASE ; independent growth ; TRANSFECTION ; ENHANCED EXPRESSION ; LEVEL ; ASSAYS ; downregulation ; PROLIFERATIVE ACTIVITY ; CHLORIDE ; chloride channel ; COLO-357 CELLS ; DECREASED SURVIVAL ; NA+/K+-ATPASE ; TGF-BETA RESPONSIVENESS ; TGFP
    Abstract: The expression and localization of FXYD domain containing ion transport regulator 3 (FXYD3), a transmembrane protein that acts as a chloride channel or chloride channel regulator, was analyzed in pancreatic tissues derived from donors and patients suffering from chronic pancreatitis (CP) or pancreatic ductal adenocarcinoma (PDAC) as well as in pancreatic cancer cells using QRT-PCR, laser-capture microdissection and microarray analysis, in situ hybridization and immunohistochemistry. FXYD3 antisense expressing T3M4 pancreatic cancer cells were generated and compared to control cells using anchorage-dependent and independent growth assays, and xenotransplantation into nude mice. FXYD3 mRNA levels were 3.4-fold increased in PDAC tissues compared to donor specimens (p = 0.006), and 3.9-fold increased in microdissected cancer cells compared to normal pancreatic ductal cells (p = 0.02). FXYD3 was localized in the tubular complexes and PanIN lesions of both CP and PDAC, as well as in pancreatic cancer cells. Downregulation of FXYD3 by stable antisense transfection increased significantly the doubling time of T3M4 pancreatic cancer cells from 44 +/- 2 hr to 55 +/- 12 hr (p = 0.02). Nude mice transplanted with antisense transfected cells displayed a significant increase in tumor doubling time from 3.3 days +/- 1.0 to 4.3 days +/- 0.43 (p = 0.058). Anchorage-independent growth and sensitivity to 5-fluorouracil, gemcitabine and cisplatin as well as to MgCl2 were not dependent on the level of FXYD3 expression. In conclusion, overexpression of FXYD3 in pancreatic cancer may contribute to the proliferative activity of this malignancy. (c) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16003754
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  • 4
    Keywords: EXPRESSION ; INVASION ; GENE ; MARKER ; VARIANTS ; MUTATIONS ; EPITHELIAL-CELLS ; GEMCITABINE ; GENOME-WIDE ASSOCIATION ; DUCTAL ADENOCARCINOMAS
    Abstract: Standard cancer cell lines do not model the intratumoural heterogeneity situation sufficiently. Clonal selection leads to a homogeneous population of cells by genetic drift. Heterogeneity of tumour cells, however, is particularly critical for therapeutically relevant studies, since it is a prerequisite for acquiring drug resistance and reoccurrence of tumours. Here, we report the isolation of a highly tumourigenic primary pancreatic cancer cell line, called JoPaca-1 and its detailed characterization at multiple levels. Implantation of as few as 100 JoPaca-1 cells into immunodeficient mice gave rise to tumours that were histologically very similar to the primary tumour. The high heterogeneity of JoPaca-1 was reflected by diverse cell morphology and a substantial number of chromosomal aberrations. Comparative whole-genome sequencing of JoPaca-1 and BxPC-3 revealed mutations in genes frequently altered in pancreatic cancer. Exceptionally high expression of cancer stem cell markers and a high clonogenic potential in vitro and in vivo was observed. All of these attributes make this cell line an extremely valuable model to study the biology of and pharmaceutical effects on pancreatic cancer.
    Type of Publication: Journal article published
    PubMed ID: 23152778
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  • 5
    Keywords: CANCER ; IN-VITRO ; GENE ; MOUSE ; STEM-CELLS ; VON-HIPPEL-LINDAU ; DUCTAL ADENOCARCINOMA ; uveal melanoma ; PAPILLARY-MUCINOUS NEOPLASMS ; NG2 PROTEOGLYCAN
    Abstract: CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissuehigh/seralow-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.
    Type of Publication: Journal article published
    PubMed ID: 24932730
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  • 6
    Keywords: INVASION ; GROWTH ; CANCER ; CELL ; pancreatic cancer ; ONCOLOGY ; CELL-GROWTH ; PANCREATIC-CANCER ; Jun ; METASTASIS ; pancreatic ; BONE ; bone sialoprotein
    Type of Publication: Meeting abstract published
    PubMed ID: 16488077
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  • 7
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; CELL ; Germany ; human ; IN-VIVO ; GENE-EXPRESSION ; transcription ; TISSUE ; RELEASE ; COMPLEX ; COMPLEXES ; TRANSCRIPTION FACTOR ; TISSUES ; tumour ; DOWN-REGULATION ; treatment ; cytokines ; TRANSCRIPTION FACTORS ; LESIONS ; immunohistochemistry ; VECTOR ; PCR ; SIGNALING PATHWAY ; CANCER-CELLS ; EXTRACELLULAR-MATRIX ; MAMMALIAN-CELLS ; adenocarcinoma ; GROWTH-FACTOR-BETA ; OVEREXPRESSION ; real-time PCR ; pancreatic cancer ; microenvironment ; CYTOKINE ; MATRIX ; ONCOLOGY ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; INCREASE ; extracellular matrix ; regulation ; ENHANCED EXPRESSION ; REAL-TIME ; TGF-BETA ; TGF-beta 1 ; LEVEL ; analysis ; pancreatic ; pancreatic adenocarcinoma ; coculture ; quantitative ; FULL-LENGTH ; transforming growth factor ; pancreatic ductal adenocarcinoma ; beta-tumour microenvironment ; CHEMICAL-MODIFICATIONS ; INDIAN-HEDGEHOG ; matrix metalloprotease ; osteonectin ; stellate cells ; STELLATE-CELLS
    Abstract: Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-beta 1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (P〈0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-beta 1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMPI release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-beta 1 and BMP2 in an auto- and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMPI, thereby influencing the tumour microenvironment
    Type of Publication: Journal article published
    PubMed ID: 17876328
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  • 8
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INVASION ; proliferation ; carcinoma ; CELL ; Germany ; GENE ; microarray ; SAMPLES ; cell line ; TISSUE ; LINES ; COMPLEX ; COMPLEXES ; DNA ; TISSUES ; CELL-LINES ; GLYCOPROTEIN ; immunohistochemistry ; ASSAY ; ELEMENTS ; METASTASIS ; PROSTATE-CANCER ; CELL-LINE ; LINE ; CANCER-CELLS ; LOCALIZATION ; ADHESION ; MIGRATION ; adenocarcinoma ; cell lines ; pancreatic cancer ; chronic pancreatitis ; HUMAN BREAST-CANCER ; RECOMBINANT ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; MATRIX PROTEINS ; LEVEL ; analysis ; pancreatic ; ASSAYS ; DNA-MICROARRAY ; function ; MIDDLE-EAR ; OSTEOPONTIN EXPRESSION ; VASCULAR CALCIFICATION
    Abstract: Bone sialoprotein (BSP) is an acidic glycoprotein that plays an important role in cancer cell growth, migration and invasion. The expression, localization and possible function of BSP in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) were analyzed by QRT-PCR, laser capture microdissection, DNA microarray analysis, immunoblotting, radioimmunoassays and immunohistochemistry as well as cell growth, invasion, scattering, and adhesion assays. BSP mRNA was detected in 40.7% of normal, in 80% of CP and in 86.4% of PDAC samples. The median BSP mRNA levels were 6.1 and 0.9 copies/mu l cDNA in PDAC and CP tissues, respectively, and zero copies/mu l cDNA in normal pancreatic tissues. BSP was weakly present in the cytoplasm of islet cells and ductal cells in 20% of normal pancreatic tissues. BSP was localized in the tubular complexes of both CP and PDAC, as well as in pancreatic cancer cells. Five out of 8 pancreatic cancer cell lines expressed BSP mRNA. Recombinant BSP (rBSP) inhibited Capan-1 and SU8686 pancreatic cancer cell growth, with a maximal effect of -46.4 +/- 12.0% in Capan-1 cells and -45.7 +/- 14.5% in SU8686 cells. rBSP decreased the invasion of SU8686 cells by -59.1 +/- 11.2% and of Capan-1 cells by -13.3 +/- 3.8% (P 〈 0.05), whereas it did not affect scattering or adhesion of both cell lines. In conclusion, endogenous BSP expression levels in pancreatic cancer cells and low to absent BSP expression in the surrounding stromal tissue elements may indirectly act to enhance the proliferation and invasion of pancreatic cancer cells. (c) 2006 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16488077
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