Biomedical subjects

B Sipos

Publications and source records attributed to B Sipos.

At least 19 recordsLinked to original sources

PubMed2007

WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer.

Previously, we have identified the transcription factor CUTL1 as an important mediator of tumor invasion and target of tumor growth factor-beta. Using high-throughput approaches, we identified several putative downstream effectors of CUTL1, among them WNT5A, a secreted member of the Wnt multigene family. The aim of this study was to investigate the role of WNT5A as a novel target of CUTL1 in pancreatic cancer. CUTL1 and WNT5A were stably over-expressed as well as transiently and stably knocked down by RNA interference. Effects on proliferation, migration and invasiveness were investigated by thymidine incorporation, Boyden chamber experiments and time-lapse microscopy. Expression of WNT5A in pancreatic cancer tissues was analyzed by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. We found that CUTL1 transcriptionally up-regulated WNT5A on RNA, protein and promoter level. WNT5A significantly enhanced migration, proliferation and invasiveness, mediating the pro-invasive effects of CUTL1 to a major extent. WNT5A effects were accompanied by a marked modulation of marker genes associated with epithelial-mesenchymal transition. Using RT-PCR and immunohistochemistry, we found that WNT5A is up-regulated early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias lesions and in invasive pancreatic adenocarcinomas, as compared with normal pancreas tissues. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.

Cell Line, Tumor↗

PubMed2006

Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.

Anthracenes↗

PubMed2006

Drug-induced expression of the cellular adhesion molecule L1CAM confers anti-apoptotic protection and chemoresistance in pancreatic ductal adenocarcinoma cells.

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.

Adenocarcinoma↗

PubMed2006

TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted considerable attention for its potential use in tumor therapy, as some recombinant variants of this ligand induce apoptosis in tumor cells without harming most normal cells. Here, we show that TRAIL strongly induces the expression of the proinflammatory cytokines interleukin-8 and monocyte chemoattractant protein 1 and enhances the invasion of apoptosis-resistant pancreatic ductal adenocarcinoma cells in vitro by upregulation of the urokinase-type plasminogen activator expression. Most importantly, we also demonstrate for the first time that TRAIL treatment results in strongly increased distant metastasis of pancreatic tumors in vivo. We orthotopically transplanted human pancreatic ductal adenocarcinoma cells to the pancreata of severe combined immunodeficiency mice and observed a dramatic increase in metastatic spread including a sixfold increase in the volume and fourfold increase in the number of liver metastases upon TRAIL treatment. Our results point to the necessity to carefully evaluate in vivo side effects of TRAIL and to select therapy conditions that not only enhance apoptosis induction but in addition prevent proinvasive and proinflammatory non-apoptotic TRAIL signaling.

Animals↗

PubMed2006

Multihormonality and entrapment of islets in pancreatic endocrine tumors.

We analyzed pancreatic endocrine tumors (PETs) from 200 patients for the incidence of multihormonality and entrapped islets and correlated the results with clinicopathological features. Our series included 86 cases (43%) of functioning PET and 114 cases (57%) of nonfunctioning PET. Classified according to the WHO classification, there were 32 well-differentiated benign PETs, 85 well-differentiated PETs with uncertain behavior, and 83 well-differentiated malignant PETs. All tumors were immunostained for pancreatic hormones (insulin, glucagon, somatostatin, and pancreatic polypeptide) and for additional hormones such as gastrin, vasoactive intestinal polypeptide, calcitonin, seratonin, and adrenocorticotropic hormone. Multihormonality was found in 34% of all PETs and it was a frequent finding in the tumors of the uncertain behavior (38.8%) group. Islet entrapment was found in 57 tumors (28.5%) and was significantly more frequent in PETs with uncertain and malignant behavior than benign ones (p=0.01). In 57 cases, we also investigated whether ductule entrapment accompanied islet entrapment. Of these 57 tumors, 45 (79%) tumors had accompanying ductule entrapment. Ductule entrapment did not show significant correlation with malignancy and was a more frequent finding in nonfunctioning tumors. We conclude that the incidence of multihormonality in PETs is not as high as suggested previously and islet entrapping may reflect aggressive tumor growth and may be a complementary criterion for predicting the biological behavior of PETs.

Adenoma, Islet Cell↗

PubMed2005

Significant growth inhibition of orthotopic pancreatic ductal adenocarcinoma by CpG oligonucleotides in immunodeficient mice.

BACKGROUND/AIMS: The high rate of local recurrence after radical resection of pancreatic ductal adenocarcinoma fosters intensive efforts to develop new approaches for adjuvant treatment. Antisense and modified oligodeoxynucleotides (ODNs) have demonstrated significant tumour growth inhibitory effects in preclinical systems. Our aim was to evaluate the possible therapeutic potential of ODNs containing unmethylated deoxycytidyl-deoxyguanosine dinucleotides (CpG motifs). METHODOLOGY: For in vitro analysis, [(3)H]thymidine incorporation for DNA synthesis, colorimetric cell vitality assay (EZ4U assay), and DNA fragmentation assay (JAM-[(3)H]thymidine incorporation assay) to test for apoptosis were performed. In vivo testing was done on an orthotopic pancreatic xenotransplantation model using severe combined immunodeficient (SCID) beige and nude mice. RESULTS: No significant differential effect of either control ODN or CpG-1826 ODN with regard to tumour cell proliferation or induction of apoptosis was observed in vitro. In vivo, ODN-1826 proved to have a significant inhibitory effect (up to 40% reduction of tumour weight) when compared with tumour-bearing animals treated with saline or control ODN. This was accompanied by sevenfold increase in splenomegaly and moderate hepatomegaly. The reduction of tumour weight by ODN-1826 was only slightly more pronounced in nude compared with SCID beige mice. CONCLUSION: CpG-1826 induces significant growth-inhibitory effects on orthotopic xenotransplanted pancreatic tumours in highly immunodeficient mice, which might be explained by innate immunity mechanisms and possibly a complex interaction of tumour and stroma cells.

Animals↗

PubMed2005

[Tumors of the endocrine pancreas].

The neuroendocrine tumors of the pancreas are rare, but belong to the most common endocrine neoplasms of the abdomen. In most cases they present as solitary tumors, composed of monomorphic cells. Functionally active cells are associated with characteristic hormonal syndromes. Using morphological, immunohistochemical and biological criteria, the classification distinguishes between well differentiated tumors with benign or uncertain behavior, well differentiated (low grade malignant) carcinomas and poorly differentiated (high grade malignant) carcinomas. In recent years the percentage of non-functional tumors has increased.

Carcinoma, Neuroendocrine↗

PubMed2005

[Solid pseudopapillary neoplasms. Enigmatic entity with female preponderance].

Solid pseudopapillary neoplasms (SPN) of the pancreas represent a special tumor entity, both morphologically and biologically. They form large solitary tumors that occur predominantly in young women. Histologically, they show solid, pseudopapillary, and pseudocystic patterns. The tumor cells are monomorphous and typically express vimentin, neuron-specific enolase, nuclear beta-catenin, and the progesterone receptor. Complete resection cures the tumor in about 90% of the cases. However, because recurrences and even metastases may occur in a small number of cases, SPN are classified as low-grade malignant tumors. Predicting malignancy histologically is not yet possible. The most important differential diagnosis to consider is neuroendocrine tumor of the pancreas. The etiology and pathogenesis of SPN are obscure.

Biomarkers, Tumor↗

PubMed2005

[Mesenchymal tumors of the pancreas. Surprising, but not uncommon].

Mesenchymal tumors of the pancreas are rare. They are resected because a solid or cystic pancreatic tumor is suspected. Benign mesenchymal tumors comprise lymphangiomas, hemangiomas, schwannomas, solitary fibrous tumors, adenomatoid tumors, clear cell tumors, and hamartomas. Inflammatory pseudotumors are a special case. Malignant mesenchymal tumors include leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), liposarcomas, malignant fibrous histiocytomas, Ewing's sarcomas, and primitive neuroectodermal tumors (PNET). It is important to differentiate these tumors from anaplastic carcinomas and retroperitoneal tumors that infiltrate pancreatic tissue.

Adenoma↗

PubMed2005

[Acinar cell carcinomas and pancreatoblastomas: related but not the same].

Acinar cell carcinomas and pancreatoblastomas are malignant tumors of the pancreas, showing predominantly acinar differentiation characterized by the immunohistochemical expression of pancreatic enzymes. Histologically, they usually display acinar and/or solid patterns, but may occasionally also exhibit cystic structures. The key feature of pancreatoblastomas is the presence of squamoid corpuscles. Acinar cell carcinomas predominantly occur in adults, pancreatoblastomas in children. Both tumor types commonly show allelic losses on chromosome 11p and mutations in the APC/beta-catenin signaling pathway. Pancreatoblastomas, in contrast to acinar cell carcinomas, are potentially curable.

Carcinoma, Acinar Cell↗

PubMed2005

[Spectrum of chronic pancreatitis. On the way to etiological classification].

Chronic pancreatitis is a fibroinflammatory disease that is induced by injuries to the interstitial, ductal, and/or acinar cells. The most important causes are alcohol abuse, gene mutations, autoimmune processes, special anatomic changes, and obstructive duct lesions. The morphologic spectrum of the various types of chronic pancreatitis related to the above causes shows features that increasingly allow an etiological distinction and categorization to be made. A catalog of five criteria is presented for distinguishing chronic pancreatitis from ductal adenocarcinoma of the pancreas.

Alcoholism↗

PubMed2005

[Cystic pancreas tumors and their classification: features old and new].

Cystic tumors and tumor-like lesions of the pancreas are rare, but have attracted a great deal of attention because they are easily recognized with new imaging methods and, in contrast to ductal adenocarcinoma, they can usually be cured surgically. The increasing resection rate in recent years has also increased our knowledge of cystic pancreatic tumors by conspicuously enlarging their morphological spectrum. Known entities have been better characterized (i.e. solid pseudopapillary neoplasm, intraductal papillary mucinous neoplasm) and new ones described (serous oligocystic adenoma, mucinous non-neoplastic cyst, acinar cell cystadenoma and cystic hamartoma). This review discusses the most important cystic tumors and tumor-like lesions, presents a new classification, and summarizes the immunohistochemical differential diagnosis.

Humans↗

PubMed2004

Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal.

Although cystic neoplasms and lesions of the pancreas are rare, they have attracted a great deal of attention because of their potential curability. Since, in recent years, several new entities have been identified, the relative frequency of the tumors and their classification need to be reevaluated. In a series of 1454 tumorous lesions of the pancreas collected between 1971 and 2003 in our surgical pathology files and consultation files, all cystic pancreatic neoplasms and tumor-like lesions were identified and typed both histologically and immunohistochemically. There were 418 cases (29%) showing cysts with a diameter ranging between 0.5 cm and 27 cm. Most common were solid pseudopapillary neoplasms (21%) and intraductal papillary-mucinous neoplasms (18%). When only the cystic neoplasms and lesions that had been resected in a single institution were considered, intraductal papillary mucinous neoplasms were the most frequent cystic neoplasms, while solid pseudopapillary neoplasms took fifth place behind ductal adenocarcinomas with cystic features, serous cystic neoplasms and mucinous cystic neoplasms. The most frequent cystic tumor-like lesions were pancreatitis-associated pseudocysts. New and rare entities that have recently been identified are mucinous nonneoplastic cysts, acinar cell cystadenomas and cystic hamartomas. Bearing in mind that figures from referral centers such as ours may be biased regarding the relative frequency of lesions, we concluded from our data that intraductal papillary-mucinous neoplasms are the most frequently occurring pancreatic cystic neoplasms, rather than solid pseudopapillary neoplasms. It was possible to classify all cystic lesions encountered in our files or described in the literature in a new system that distinguishes between neoplastic and nonneoplastic lesions, with further subdivisions into epithelial (adenomas, borderline neoplasms and carcinomas) and nonepithelial tumors. This classification is easy to handle and enables a distinction on the basis of clinical behavior and prognosis.

Adolescent↗

PubMed2004

ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma.

Gene expression profiling revealed ADAM9 to be distinctly overexpressed in pancreatic ductal adenocarcinoma (PDAC). We examined the relevance of ADAM9 expression in PDAC diagnosis and prognosis. A total of 59 infiltrating PDACs, 32 specimens from patients with chronic pancreatitis, 11 endocrine tumours and 24 acinar cell carcinomas were immunohistochemically analysed for ADAM9 expression. Staining for ADAM9 was detected in 58 out of 59 (98.3%) PDACs and in two out of 24 (8.3%) acinar cell carcinomas, but not in endocrine tumours. In the non-neoplastic pancreas, whether normal or chronically inflamed, ADAM9 was expressed in centroacinar and intralobular duct cells, but not in interlobular duct cells and their hyperplastic lesions. Pancreatic ductal adenocarcinomas showing cytoplasmic ADAM9 expression correlated with poor tumour differentiation and also with shorter overall survival than in cases showing only an apical membranous staining pattern (P=0.001). Multivariate analysis identified cytoplasmic ADAM9 expression as an independent marker of shortened survival in a set of 42 curatively (R0) resected PDAC (P<0.05, hazard ratio 2.85, 95% confidence interval: 1.21-6.71). The results show that ADAM9 expression distinguishes PDACs from other solid pancreatic tumours. In addition, cytoplasmic ADAM9 overexpression is associated with poor differentiation and shortened survival. Therefore, ADAM9 overexpression might contribute to the aggressiveness of PDACs.

ADAM Proteins↗

PubMed2004

Regulation of T-cell death-associated gene 51 (TDAG51) expression in human T-cells.

T-cell death-associated gene 51 (TDAG51) has been described to regulate T-cell receptor/CD3-dependent induction of CD95/Fas and subsequent activation-induced cell death (AICD) in a murine T-cell hybridoma. Using well-defined pharmacological inhibitors, we investigated the regulation of TDAG51 expression in human T-cells and the correlation with cell death. TDAG51 was induced in resting T-cells, lymphoid cell lines and AICD-susceptible as well as AICD-resistant T-cell clones, and induction was inhibited by MAP-kinase inhibitors and PKC inhibitor Gö6983. No correlation between the effects of inhibitors on TDAG51 expression and cell death was observed. The constitutive TDAG51 expression in five pancreatic carcinoma cell lines was reduced by MAP-kinase inhibitors but not by Gö6983. Furthermore, the inducible overexpression of TDAG51 in TetOn Jurkat cells did not modulate cellular proliferation, phorbolester/ionomycin-induced growth arrest, or the expression of various cell surface molecules. Our results indicate that the expression of TDAG51 in human T-cells does not correlate with AICD.

Apoptosis↗

PubMed2004

Immunohistochemical screening for beta6-integrin subunit expression in adenocarcinomas using a novel monoclonal antibody reveals strong up-regulation in pancreatic ductal adenocarcinomas in vivo and in vitro.

AIMS: To analyse the expression of alphavbeta6, an epithelial integrin involved in wound healing and tumorigenesis, in various human carcinoma types. METHODS AND RESULTS: A new monoclonal antibody to the human beta6 subunit, 5C4, was used to locate alphavbeta6 in 157 cancers of gastroenteropancreatic and 21 of lung origin. The data were validated by analysis of alphavbeta6 extracted from histological sections. Alphavbeta6 integrin showed strongest expression in 34 pancreatic ductal adenocarcinomas (mean score 2.88 +/- 0.52), followed by 24 intestinal-type gastric carcinomas (1.45 +/- 1.06) and eight lung adenocarcinomas (1.37 +/- 1.1). Moderate expression was found in 31 diffuse-type gastric carcinomas (0.94 +/- 0.83), seven duodenal adenocarcinomas (0.8 +/- 1.34) and 26 colorectal adenocarcinomas (0.76 +/- 0.71). Little alphavbeta6 was seen in seven liver cell carcinomas and six neuroendocrine tumours. Well-differentiated carcinomas expressed more beta6 than poorly differentiated tumours. Peritumoral epithelial tissues where alphavbeta6-expressing tumours arose also expressed alphavbeta6. There was no correlation between expression of alphavbeta6 and its ligands tenascin and fibronectin in pancreatic and gastric carcinomas. Spheroid formation by pancreatic carcinoma cell lines led to alphavbeta6 up-regulation, but appeared independent of classical ligand binding to alphavbeta6. CONCLUSIONS: Our findings indicate that: (i) alphavbeta6 is overexpressed in pancreatic adenocarcinomas; (ii) alphavbeta6-positive carcinomas originate from alphavbeta6-expressing tissues; (iii) alphavbeta6 expression in tumours seems to be regulated independently from that of its ligands tenascin and fibronectin; and (iv) in-vitro overexpression of alphavbeta6 in pancreatic carcinoma cell lines accompanies spheroid formation.

Adenocarcinoma↗

PubMed2001

Human endostatin inhibits growth of human non-small-cell lung cancer in a murine xenotransplant model.

Overall prognosis in human NSCLC remains poor. Antiangiogenic treatment has become a promising concept for the treatment of solid malignancies. Our purpose was to evaluate the efficacy of recombinant HSENDO for the treatment of human NSCLC in an orthotopic murine xenotransplantation model. The efficacy of HSENDO was tested in vitro in cell-proliferation, cell-migration and tube-formation assays. In vivo, the effect of HSENDO on tumor growth was tested in s.c. xenotransplanted human NSCLC and on intrapulmonary induced human NSCLC. In vitro, HSENDO inhibited both human and rodent endothelial cell proliferation in a time- and dose-dependent fashion. Endothelial cell migration was inhibited by 97%. Tube formation of murine endothelial cells was inhibited and preexisting tubes degenerated after HSENDO exposure. In vivo, HSENDO delayed growth of s.c. xenotransplanted tumors. Immunohistochemic staining demonstrated no change in microvessel density but a significant reduction of proliferating tumor cells and an increase in bFGF and VEGF expression, reflecting the antiangiogenic effect of HSENDO. Intrapulmonary tumor induction caused death subsequent to metastatic disease. Systemic HSENDO application extended survival significantly. HSENDO was demonstrated to inhibit endothelial cell proliferation, migration and tube formation effectively. In vivo growth of s.c. transplanted tumors was delayed and survival extended by 32% and 69%, respectively, after intrapulmonary NSCLC induction.

Animals↗

PubMed2001

Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4.

The K-ras, p53, p16 and DPC4 genes are among those most frequently altered in pancreatic ductal carcinoma. We analyzed 22 cell lines for alterations in these genes by direct sequence analysis and methylation-specific polymerase chain reaction. These cell lines showed mutations in K-ras and p53 at frequencies of 91% and 95%, respectively. Alterations in p16INK4a were found in all cases and included nine homozygous deletions, seven mutations and promoter methylation in six cases. Eight cell lines (36%) had an alteration of DPC4, including one mutation and seven homozygous deletions. The most typical mutational profile involved K-ras, p53, and p16INK4a, concurrently aberrated in 20 cases (91%). Eight cell lines had alterations in all four genes. Inactivation of DPC4 was always accompanied by alteration of all of the other three genes. This comprehensive data regarding the cumulative genetic alterations in pancreatic carcinoma cell lines will be of great value for studies involving drug sensitivity or resistance that may be associated with inactivation of a particular gene or molecular pathway.

Carcinoma, Pancreatic Ductal↗