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  • 1
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; CELL ; Germany ; human ; COHORT ; PROTEIN ; PROTEINS ; cell line ; TISSUE ; TUMORS ; LINES ; PATIENT ; FAMILY ; CARCINOGENESIS ; TISSUES ; CELL-LINES ; LESIONS ; PROGRESSION ; immunohistochemistry ; CELL-LINE ; LINE ; LOCALIZATION ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; ADENOCARCINOMAS ; pathology ; OVEREXPRESSION ; cell lines ; pancreatic cancer ; protein expression ; chemoresistance ; SUBCELLULAR-LOCALIZATION ; SUBSET ; pancreas ; PANCREATIC-CANCER ; FAMILIES ; DUCTAL ADENOCARCINOMA ; polymerase chain reaction ; TUMOR TISSUE ; LEVEL ; analysis ; methods ; pancreatic ; RARE ; SURVIVAL-DATA ; Reverse Transcriptase Polymerase Chain Reaction
    Abstract: AIMS: To determine the role of two antiapoptotic proteins of the IAP family, cIAP1 and cIAP2, in human pancreatic carcinogenesis. METHODS: mRNA levels were measured in pancreatic tissues and pancreatic cancer cell lines by quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR). Protein expression was assessed in pancreatic cancer cell lines by immunoblotting and in pancreatic tissues by immunohistochemistry and correlated with pathological and survival data. RESULTS: cIAP1 expression was constantly high in non-neoplastic pancreatic tissues, in PanIN lesions, as well as in a subset of primary and metastatic pancreatic ductal adenocarcinomas (PDAC), and a preferential cytoplasmatic localization was observed in the tumor tissues. cIAP1 expression was rare in a cohort of cystic tumors. cIAP2 mRNA levels were significantly higher (2.4 fold) in PDAC than in the normal tissues. cIAP2 protein was overexpressed in PDAC and was detectable in low-grade and high-grade PanIN lesions. Moreover, cIAP2 was frequently expressed in pancreatic cystic tumors. cIAP1 and cIAP2 mRNA and protein were detected in all the examined cell lines. Survival analysis revealed a shorter survival in patients with cIAP1/cIAP2-positive tumors. CONCLUSIONS: cIAP1 might contribute to the regulation of the apoptotic process in the normal and in the neoplastic pancreas, depending on its subcellular localization. cIAP2 overexpression is a frequent and early event in pancreatic cancer progression and could therefore potentially influence important pathophysiological aspects of PDAC, such as anoikis or chemoresistance
    Type of Publication: Journal article published
    PubMed ID: 16775116
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  • 2
    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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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; DISTINCT ; GENES ; HYBRIDIZATION ; PROTEIN ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TUMORS ; COMPLEX ; COMPLEXES ; primary ; renal ; colon ; RATS ; TISSUES ; CONTRAST ; DOWN-REGULATION ; BREAST ; BREAST-CANCER ; IDENTIFICATION ; IN-SITU ; immunohistochemistry ; MALIGNANCIES ; UP-REGULATION ; BRCA1 ; metastases ; CANCER-CELLS ; COLON-CANCER ; LOCALIZATION ; RT-PCR ; TRACT ; RECEPTORS ; pancreatic cancer ; chronic pancreatitis ; protein expression ; HUMAN TISSUES ; F ; in situ hybridization ; colon cancer ; TGF-BETA ; gastric cancer ; MAC30 ; PRIMARY TUMORS
    Abstract: Meningioma-associated protein, MAC30, is a protein with unknown function and cellular localization that is differentially expressed in certain malignancies. In the present study, the expression of MAC30 in a variety of normal and cancerous human gastrointestinal tissues, with special emphasis on pancreatic tissues was analyzed. Quantitative RT-PCR was utilized to compare MAC30 expression levels. In situ hybridization and immunohistochemistry were carried out to localize MAC30 mRNA and protein expression in normal and cancerous tissue samples of the esophagus, stomach, colon and pancreas. Furthermore, the effects of TGF-beta on the transcription of MAC30 mRNA were examined in pancreatic cancer cells. MAC30 mRNA was expressed in a wide variety of normal human tissues, being most abundant in testicular and gastric tissue samples. MAC30 mRNA levels were significantly increased in breast and colon cancer, but significantly decreased in pancreatic and renal cancer. TGF-beta down-regulated MAC30 mRNA levels in certain pancreatic cancer cells. MAC30 protein was localized in normal pancreatic tissues, mainly in acinar and islet cells, and in normal colon, gastric and esophageal tissues especially in the mucosal cells. MAC30 was strongly present in tubular complexes in pancreatic cancer tissues but weak to absent in pancreatic cancer cells of primary tumors and metastases. In contrast, esophageal, gastric and colon tumors displayed strong MAC30 immunoreactivity in the cancer cells. In conclusion, MAC30 is expressed in various normal and diseased human tissues. MAC30 up-regulation in certain tumors and down-regulation in others suggests that this protein plays a distinct role in human malignancies
    Type of Publication: Journal article published
    PubMed ID: 15375745
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  • 4
    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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  • 5
    Keywords: RECEPTOR ; SPECTRA ; ANGIOGENESIS ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; tumor ; CELL ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TYROSINE KINASE ; VIVO ; QUANTIFICATION ; DEATH ; DISEASE ; GENE ; PROTEIN ; cell line ; LINES ; PATIENT ; LIGAND ; FLOW ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; protein kinase ; PROTEIN-KINASE ; TYROSINE KINASE INHIBITOR ; TARGET ; PROGRESSION ; immunohistochemistry ; ASSAY ; CELL-DEATH ; MUTATION ; CELL-LINE ; LINE ; MUTATIONS ; CANCER-PATIENTS ; POLYMERASE-CHAIN-REACTION ; PROTEIN-KINASE-C ; CHAIN-REACTION ; RECEPTORS ; CANCER PATIENTS ; point mutation ; cell lines ; pancreatic cancer ; RANDOMIZED-TRIAL ; TUMOR ANGIOGENESIS ; MANAGEMENT ; CELL-CYCLE PROGRESSION ; INHIBITORS ; CELL-GROWTH ; CHAIN ; ONCOLOGY ; PANCREATIC-CANCER ; TUMOR-GROWTH ; flow cytometry ; THERAPIES ; ACUTE MYELOID-LEUKEMIA ; polymerase chain reaction ; REAL-TIME ; POINT MUTATIONS ; MURINE MODEL ; TYROSINE KINASES ; analysis ; methods ; pancreatic ; ASSAYS ; cell death ; BIOLOGICAL-ACTIVITY ; USA ; POTENTIAL ROLE ; vascular endothelial growth factor ; COMPOUND ; in vivo ; SPECTRUM ; SPECIMENS ; KINASE INHIBITOR ; GROWTH-FACTOR-RECEPTOR ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; - ; POINT ; modeling ; quantitative ; block ; ACTIVATING MUTATION ; ENDOTHELIAL GROWTH ; FLT3 ; FLT3 MUTATIONS ; INTERNATIONAL CONSENSUS ; PKC412 ; SOLID HUMAN TUMORS ; VEGF-RII
    Abstract: BACKGROUND. PKC412 is a kinase inhibitor that blocks protein kinase C (PKC), vascular endothelial growth factor receptors, platelet-derived growth factor receptor FLT3, and other class III receptor tyrosine kinases. The enthusiasm for this compound is based on its inhibitory effect even in the case of FLT3 mutations. The aim of this study was to analyze the role of FLT3 in pancreatic cancer and to study the biological activity of combined inhibition of neovascularization and mitogenesis in this disease. METHODS. FLT3 expression was analyzed in 18 pancreatic cancer specimens by real-time quantitative polymerase chain reaction (RTQ-PCR) and immunohistochemistry. Sixteen pancreatic cancer cell lines were screened for ITD and D835 point mutations of the FLT3 gene. MTT assays and anchorage-independent growth assays were used to study cell growth. Flow cytometry was used for cell cycle analysis and apoptosis quantification. In vivo AsPC-1 and HIAF-II cells were used for orthotopic tumor modeling. Immunohistochemistry was used to quantity tumor angiogenesis. RESULTS. FLT3 expression is down-regulated in pancreatic cancer. Activating FLT3 mutations (ITD, D835) were not detectable in any of the pancreatic cancer cell lines. Cell growth was significantly inhibited as cell-cycle progression was reduced and programmed cell death increased. In vivo PKC412 therapy resulted in a significant inhibition of orthotopic tumor growth with abrogation of tumor angiogenesis. CONCLUSIONS. These data highlight that PKC412 may be a new compound in target therapy of inoperable pancreatic cancer patients and suggest a potential role for the combined use of broad spectrum kinase inhibitors in the management of these patients
    Type of Publication: Journal article published
    PubMed ID: 17676584
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  • 6
    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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  • 7
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; EXPRESSION ; tumor ; Germany ; DISEASE ; GENE ; GENES ; GENOME ; PROTEIN ; RNA ; TUMORS ; IDENTIFICATION ; LESIONS ; immunohistochemistry ; MICROARRAY DATA ; expression profiling ; pancreatic cancer ; pancreatic carcinoma ; review ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; MEDIATED APOPTOSIS ; development ; CYSTIC LESIONS ; pancreatic tumor ; EXPERIMENT ANNOTATIONS ; Fas-activated serine/threonine kinase ; PAPILLARY MUCINOUS NEOPLASMS ; siRNA silencing
    Abstract: Aim: The diversity in the aggressiveness of cystic tumors of the pancreas - ranging from the usually benign serous cystadenoma to lesions of variable degrees of malignancy - was utilized for the identification of molecular factors that are involved in the occurrence of malignancy. Methods: We analyzed the transcript profiles of different cystic tumor types. The results were confirmed at the protein level by immunohistochemistry. Also, functional studies with siRNA silencing were performed. Results: Expression variations at the RNA and protein level were identified that are closely correlated with the degree of malignancy. Besides, all tumors could be classified effectively by this means. Many of the identified factors had not previously been known to be associated with malignant cystic lesions. siRNA silencing of the gene with the most prominent variation - the anti-apoptotic factor FASTK (Fas-activated serine/threonine kinase) - revealed a regulative effect on several genes known to be relevant to the development of tumors. Conclusion: By a molecular analysis of rare types of pancreatic cancer, which are less frequent in terms of disease, variations could be identified that could be critical for the regulation of malignancy and thus relevant to the treatment of also the majority of pancreatic tumors. Copyright (C) 2008 S. Karger AG, Basel and IAP
    Type of Publication: Journal article published
    PubMed ID: 19077453
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  • 8
    Keywords: CANCER ; CANCER CELLS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INVASION ; proliferation ; tumor ; TUMOR-CELLS ; Germany ; VITRO ; DISEASE ; GENE ; GENES ; TISSUE ; TUMORS ; PATIENT ; prognosis ; INDUCTION ; CONTRAST ; fibroblasts ; GLYCOPROTEIN ; PROGRESSION ; immunohistochemistry ; ASSAY ; CANCER-CELLS ; EXTRACELLULAR-MATRIX ; NEOPLASTIC PROGRESSION ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; OVEREXPRESSION ; POOR-PROGNOSIS ; pancreatic cancer ; chronic pancreatitis ; HUMAN BREAST-CANCER ; SERUM ; MATRIX ; quantitative polymerase chain reaction ; PANCREATIC-CANCER ; DUCTAL ADENOCARCINOMA ; extracellular matrix ; OLIGONUCLEOTIDE ; interaction ; TARGET GENE ; TARGET GENES ; ANTISENSE OLIGONUCLEOTIDE ; MALIGNANT-TUMORS ; EXTRACELLULAR-MATRIX PROTEINS ; DISEASE PROGRESSION ; CYSTEINE SPARC ; DEGRADING PROTEASES ; ESOPHAGEAL-CARCINOMA ; I COLLAGEN ; MATRICELLULAR PROTEIN ; SPARC EXPRESSION
    Abstract: Objective: We sought to examine the expression and functional role of osteonectin in primary and metastatic pancreatic ductal adenocarcinoma (PDAC). Background: The glycoprotein osteonectin plays a vital role in cell-matrix interactions and is involved in various biologic processes. Overexpression of osteonectin is present in malignant tumors and correlates with disease progression and poor prognosis. Methods: Expression of osteonectin was analyzed by quantitative polymerase chain reaction and immunohistochemistry in pancreatic tissues and by enzyme-linked immunosorbent assay in the serum of patients and donors. Recombinant osteonectin and specific antisense oligonucleotides were used to examine the effects of osteonectin on induction of target genes, and on proliferation and invasiveness of pancreatic cancer cells. Results: There was a 31-fold increase in osteonectin mRNA levels in PDAC and a 16-fold increase in chronic pancreatitis as compared with the normal pancreas (P 〈 0.01). By immunohistochemistry, faint immunoreactivity was detected in the normal pancreas. In contrast, strong staining of the cancer cells was observed in addition to extensive osteonectin immunoreactivity in surrounding fibroblasts and in the extracellular matrix. In metastatic tissues, strong immunoreactivity was observed in fibroblasts and in extracellular matrix surrounding metastatic cancer cells, whereas the signal was absent in most tumor cells. In vitro studies showed that osteonectin was able to inhibit cancer cell growth while promoting invasiveness of pancreatic tumor cells. Conclusion: Osteonectin is markedly overexpressed in pancreatic cancer and has the potential to increase the invasiveness of pancreatic cancer cells
    Type of Publication: Journal article published
    PubMed ID: 16041213
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  • 9
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; BLOOD ; Germany ; SYSTEM ; GENE-EXPRESSION ; microarray ; TUMORS ; LINES ; PATIENT ; DNA ; MECHANISM ; prognosis ; CELL-LINES ; cytokines ; antibodies ; antibody ; immunohistochemistry ; DESIGN ; OBESITY ; LINE ; SKELETAL-MUSCLE ; adenocarcinoma ; MICROARRAY ANALYSIS ; OVEREXPRESSION ; PERIPHERAL-BLOOD ; cell lines ; pancreatic cancer ; THYROID-HORMONE ; SERUM ; ELISA ; PANCREATIC-CANCER ; CAPACITY ; DUCTAL ADENOCARCINOMA ; INTERLEUKIN-6 ; INFLAMMATORY CYTOKINES ; SCREEN ; ABILITY ; DNA-MICROARRAY ; ACUTE-PHASE RESPONSE ; ANOREXIA ; cachexia ; NEUROPEPTIDE-Y ; UNCOUPLING PROTEIN-3
    Abstract: Background and Purpose: The mechanism behind aggressive development of cachexia in patients suffering from pancreatic cancer is not well understood. In this study, we investigated which factors are associated with the cachectic status of the patients and evaluated cachexia-promoting capacity of cancer and inflammatory cells. Experimental Design: DNA microarray analysis and quantitative reverse transcription-PCR were used to screen for cachexia-associated factors in pancreatic specimens obtained from non-cachectic and cachetic patients diagnosed with pancreatic ductal adenocarcinoma. The expression pattern of the most prominently altered cachexia-associated factor, interleukin-6 (IL-6), was further analyzed in patients sera by ELISA, in pancreatic specimens by immunohistochemistry, and in a coculture system by quantitative reverse transcription-PCR using pancreatic cancer cell lines T3M4 (IL-6 positive) and Panc-1 (IL-6 negative) and peripheral blood mononuclear cells (PBMC) obtained from donors and noncachectic and cachectic patients. Results: Among numerous analyzed factors, IL-6 was significantly overexpressed in pancreatic specimens and elevated in serum of cachectic patients. The coculture system revealed that pancreatic cancer T3M4 cells but not Panc-1 cells were able to stimulate IL-6 exclusively in cachectic PBMC (by 14-fold) and this triggering was reduced by half in the presence of IL-6-neutralizing antibodies. Conclusion: IL-6 represents a prominent cachexia-associated factor in pancreatic cancer. IL-6 overexpression in cachectic patients is related to the ability of certain tumors to sensitize PBMC and induce cytokine expression in cachectic PBMC
    Type of Publication: Journal article published
    PubMed ID: 16115919
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  • 10
    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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