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Stefan Eser,
Nina Reiff,
Marlena Messer,
Barbara Seidler,
Kathleen Gottschalk,
Melanie Dobler,
Maren Hieber,
Andreas Arbeiter,
Sabine Klein,
Bo Kong, [......], Irene Esposito,
Alexander J Kind,
Lena Rad,
Angelika E Schnieke,
Manuela Baccarini,
Dario R Alessi,
Roland Rad,
Roland M Schmid,
Günter Schneider,
Dieter Saur
[show abstract]
[hide abstract]
ABSTRACT: Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.
Cancer cell 02/2013; · 25.29 Impact Factor
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Sandra Diersch,
Patrick Wenzel,
Melanie Szameitat,
Philipp Eser,
Mariel C Paul,
Barbara Seidler,
Stefan Eser,
Marlena Messer,
Maximilian Reichert,
Philipp Pagel, Irene Esposito,
Roland M Schmid,
Dieter Saur,
Günter Schneider
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease with a poor prognosis and targeted therapies have failed in the clinic so far. Several evidences point to the phosphatidylinositol 3-kinase (PI3K)-mTOR pathway as a promising signaling node for targeted therapeutic intervention. Markers, which predict responsiveness of PDAC cells towards PI3K inhibitors are unknown. However, such markers are needed and critical to better stratify patients in clinical trials. We used a large murine KrasG12D- and PI3K (p110αH1047R)-driven PDAC cell line platform to unbiased define modulators of responsiveness towards the dual PI3K-mTOR inhibitor Bez235. In contrast to other tumor models, we show that KrasG12D- and PI3K (p110αH1047R)-driven PDAC cell lines are equally sensitive towards Bez235. In an unbiased approach we found that the extracellular matrix protein Efemp1 controls sensitivity of murine PDAC cells towards Bez235. We show that Efemp1 expression is connected to the cyclin-dependent kinase inhibitor p27Kip1. In a murine KrasG12D-driven PDAC model, p27Kip1 haploinsufficiency accelerates cancer development in vivo. Furthermore, p27Kip1 controls Bez235 sensitivity in a gene dose-dependent fashion in murine PDAC cells and lowering of p27Kip1 decreases Bez235 responsiveness in murine PDAC models. Together, we define the Efemp1-p27Kip1 axis as a potential marker module of PDAC cell sensitivity towards dual PI3K-mTOR inhibitors, which might help to better stratify patients in clinical trials.
Oncotarget 02/2013; 4(2):277-88. · 4.78 Impact Factor
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Günther Hs Richter,
Annette Fasan,
Kristina Hauer,
Thomas Gp Grunewald,
Colette Berns,
Sabine Rössler,
Ivonne Naumann,
Martin S Staege,
Simone Fulda, Irene Esposito,
Stefan Burdach
[show abstract]
[hide abstract]
ABSTRACT: Metastatic spread in Ewing sarcomas (ES) is frequent and haematogenous. G-protein coupled receptor 64 (GPR64), an orphan receptor with normal expression restricted to human epididymis is specifically over-expressed in ES among sarcoma, but also up-regulated in a number of carcinomas derived from prostate, kidney or lung. Inhibition of GPR64 expression in ES by RNA interference impaired colony formation in vitro and suppressed local tumour growth and metastasis in Rag2(-/-) γ(C) (-/-) mice. Microarray analysis after GPR64 knock down revealed a GPR64-mediated repression of genes involved in neuronal development like SLIT, drosophila, homolog of, 2 (SLIT2), and genes regulating transcription including pre-B cell leukemia homeobox 2 (PBX2). Concurrently, the suppression of GPR64 increased ES susceptibility to TRAIL induced apoptosis. Moreover, a GPR64-mediated induction of placental growth factor (PGF) in ES was observed. PGF suppression by RNA interference resulted in a reduction of metastatic growth similar to that observed after GPR64 knock down. Importantly, inhibition of GPR64 as well as PGF expression was associated with a reduced expression of matrix metalloproteinase (MMP) 1 and invasiveness in vitro. Furthermore, MMP1 knock down abrogated lung metastasis in Rag2(-/-) γ(C) (-/-) mice. Thus, GPR64 expression in ES maintains an immature phenotype that is less sensitive to TRAIL-induced apoptosis and via its up-regulation of PGF and MMP1 orchestrates and promotes invasiveness and metastatic spread.
The Journal of Pathology 01/2013; · 6.32 Impact Factor
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Kristina Hauer,
Julia Calzada-Wack,
Katja Steiger,
Thomas G P Grunewald,
Daniel Baumhoer,
Stephanie Plehm,
Thorsten Buch,
Olivia Prazeres da Costa, Irene Esposito,
Stefan Burdach,
Günther H S Richter
[show abstract]
[hide abstract]
ABSTRACT: Ewing sarcoma (ES), an osteolytic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. In this study, we identified the pro-metastatic gene DKK2 as a highly overexpressed gene in ES compared to corresponding normal tissues. Using RNA interference, we demonstrated that DKK2 was critical for malignant cell outgrowth in vitro and in an orthotopic xenograft mouse model in vivo. Analysis of invasion potential in both settings revealed a strong correlation of DKK2 expression to ES invasiveness that may be mediated by the DKK effector matrix metalloproteinase 1 (MMP1). Further, gene expression analyses established the ability of DKK2 to differentially regulate genes such as CXCR4, PTHrP, RUNX2 and TGFβ1, that are associated with homing, invasion and growth of cancer cells in bone tissue as well as genes important for osteolysis, including HIF1α, JAG1, IL6 and VEGF. DKK2 promoted bone infiltration and osteolysis in vivo and further analyses defined DKK2 as a key factor in osteotropic malignancy. Interestingly, in ES cells DKK2 suppression simultaneously increased the potential for neuronal differentiation while decreasing chondrogenic and osteogenic differentiation. Our results provide strong evidence that DKK2 is a key player in ES invasion and osteolysis and also in the differential phenotype of ES cells.
Cancer Research 11/2012; · 7.86 Impact Factor
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Peter Krieg,
Sabine Rosenberger,
Silvia de Juanes,
Susanne Latzko,
Jin Hou,
Angela Dick,
Ulrich Kloz,
Frank van der Hoeven,
Ingrid Hausser, Irene Esposito,
Manfred Rauh,
Holm Schneider
[show abstract]
[hide abstract]
ABSTRACT: Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R-LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway.Journal of Investigative Dermatology advance online publication, 26 July 2012; doi:10.1038/jid.2012.250.
Journal of Investigative Dermatology 07/2012; · 6.31 Impact Factor
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Robert Waltereit,
Uwe Leimer,
Oliver von Bohlen Und Halbach,
Jutta Panke,
Sabine M Hölter,
Lillian Garrett,
Karola Wittig,
Miriam Schneider,
Camie Schmitt,
Julia Calzada-Wack, [......],
Stefan Berger,
Kai Schönig,
Jerzy Adamski,
Thomas Klopstock, Irene Esposito,
Wolfgang Wurst,
Martin Hrabe de Angelis,
Gudrun Rappold,
Thomas Wieland,
Dusan Bartsch
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders. Waltereit, R., Leimer, U., von Bohlen und Halbach, O., Panke, J., Hölter, S. M., Garrett, L., Wittig, K., Schneider, M., Schmitt, C., Calzada-Wack, J., Neff, F., Becker, L., Prehn, C., Kutscherjawy, S., Endris, V., Bacon, C., Fuchs, H., Gailus-Durner, V., Berger, S., Schönig, K., Adamski, J., Klopstock, T., Esposito, I., Wurst, W., Hrabě de Angelis, M., Rappold, G., Wieland, T., Bartsch, D. Srgap3(-/-) mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.
The FASEB Journal 07/2012; · 5.71 Impact Factor
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Caroline M Wernicke,
Günther H S Richter,
Beate C Beinvogl,
Stephanie Plehm,
Anna M Schlitter,
Obul R Bandapalli,
Olivia Prazeres da Costa,
Uwe E Hattenhorst,
Ines Volkmer,
Martin S Staege, Irene Esposito,
Stefan Burdach,
Thomas G P Grunewald
[show abstract]
[hide abstract]
ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. To identify novel candidates for targeted therapy, we performed a comprehensive transcriptome analysis identifying MondoA (MLXIP) - a transcription factor regulating glycolysis - to be overexpressed in ALL compared to normal tissues. Using microarray-profiling, gene-set enrichment analysis, RNA interference and functional assays we show that MondoA overexpression increases glucose catabolism and maintains a more immature phenotype, which is associated with enhanced survival and clonogenicity of leukemia cells. These data point to an important contribution of MondoA to leukemia aggressiveness and make MondoA a potential candidate for targeted treatment of ALL.
Leukemia research 06/2012; 36(9):1185-92. · 2.36 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: At the recent consensus conference on autoimmune pancreatitis (AIP) in Honolulu, we presented preliminary data from our study of surgically treated AIP patients. Our data strongly supported the separation of AIP into type 1 and type 2. Our study is based on a total of 114 surgically treated European AIP patients. Our aims were to elucidate serum IgG4 elevation, other organ involvement, relapse of disease, steroid treatment and diabetes after surgery in 114 surgically treated European AIP patients.
88 pancreaticoduodenectomies, 22 left-sided resections and 4 total pancreatectomies were examined. All cases were graded for granulocytic epithelial lesions, IgG4-positive cells, storiform fibrosis, phlebitis and eosinophilic granulocytes. Follow-up data were obtained from 102/114 patients, mean follow-up was 5.3 years.
Histologically, 63 (55.3%) of the 114 patients fulfilled the criteria of type 1 AIP, while 51 (44.7%) patients fulfilled the criteria of type 2 AIP. Type 1 AIP patients were older and more often males than type 2 AIP patients. Elevation of serum IgG4, involvement of extrapancreatic organs, disease relapse, systemic steroid treatment and diabetes after surgery were noted more often in type 1 AIP, while inflammatory bowel disease (IBD) was observed mainly in type 2 AIP.
Histological typing of AIP is clinically important because type 1 AIP is part of the IgG4-related disease and type 2 AIP is associated with IBD. Our data also show that relapse of disease and steroid treatment after surgery occur more frequently in type 1 than in type 2 AIP.
Pancreatology 05/2012; 12(3):276-83. · 1.99 Impact Factor
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Michael Rosemann,
Alesia Ivashkevich,
Jack Favor,
Claudia Dalke,
Sabine M. Hölter,
Lore Becker,
Ildikó Rácz,
Ines Bolle,
Martina Klempt,
Birgit Rathkolb, [......],
Thomas Klopstock,
Martin Klingenspor,
Markus Ollert,
Eckhard Wolf,
Wolfgang Wurst,
Andreas Zimmer,
Martin Hrabé de Angelis,
Michael Atkinson,
Ulrich Heinzmann,
Jochen Graw
[show abstract]
[hide abstract]
ABSTRACT: A new spontaneous mouse mutant was characterized by closed eyelids at weaning and without apparent eyes (provisional gene
name, eyeless; provisional gene symbol, eyl). The mutation follows a recessive pattern of inheritance and was mapped to the region of chromosome 19 containing Pitx3. Genetic complementation tests using Pitx3
ak/+
mice confirmed eyl as a new allele of Pitx3 (Pitx3
eyl
). Sequencing of the Pitx3 gene in eyl mutants identified an inserted G after cDNA position 416 (416insG; exon 4). The shifted open reading frame is predicted to
result in a hybrid protein still containing the Pitx3 homeobox, but followed by 121 new amino acids. The novel Pitx3
eyl/eyl
mutants expressed ophthalmological and brain defects similar to Pitx3
ak/ak
mice: microphthalmia or anophthalmia and loss of dopamine neurons of the substantia nigra. In addition, we observed in the homozygous eyeless mutants increased extramedullary hematopoiesis in the spleen, frequently liver steatosis, and reduced body weight. There
were also several behavioral changes in the homozygous mutants, including reduced forelimb grip strength and increased nociception.
In addition to these alterations in both sexes, we observed in female Pitx3
eyl/eyl
mice increased anxiety-related behavior, reduced locomotor activity, reduced object exploration, and increased social contacts;
however, we observed decreased anxiety-related behavior and increased arousal in males. Most of these defects identified in
the new Pitx3 mutation are observed in Parkinson patients, making the Pitx3
eyl
mutant a valuable new model. It is the first mouse mutant carrying a point mutation within the coding region of Pitx3.
Mammalian Genome 04/2012; 21(1):13-27. · 2.89 Impact Factor
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The Chinese-German Journal of Clinical Oncology 04/2012; 6(2):95-101.
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Sibylle Sabrautzki,
Isabel Rubio-Aliaga,
Wolfgang Hans,
Helmut Fuchs,
Birgit Rathkolb,
Julia Calzada-Wack,
Christian M Cohrs,
Matthias Klaften,
Hartwig Seedorf,
Sebastian Eck,
Ana Benet-Pagès,
Jack Favor, Irene Esposito,
Tim M Strom,
Eckhard Wolf,
Bettina Lorenz-Depiereux,
Martin Hrabě de Angelis
[show abstract]
[hide abstract]
ABSTRACT: Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.
Mammalian Genome 04/2012; 23(7-8):416-30. · 2.89 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Around 95% of patients diagnosed with pancreatic cancer will die of their disease within 5 years, three quarters within a year. The major hurdle in improving prognosis is the lack of a therapeutic time window. Early cancerous lesions are far beneath our threshold of detection. Therefore, at the time of diagnosis even early (T1) tumors can be metastatic and resistant to conventional treatments. Several therapies targeting epithelial tumor cells-all showing impressive results in vitro and in animal experiments-have failed to show relevant effects in clinical trials. This discrepancy between experimental data and clinical reality results mostly from the inefficiency of our current experimental setups in recreating the tumor microenvironment. Forming more than 80% of the tumor mass, the fibrotic stroma of pancreatic ductal adenocarcinoma is not a passive scaffold for the malignant cells but an active player in carcinogenesis. This component is mostly missing in the xeno-/allograft- mouse models. Although tumors are bigger if stellate cells are co-implanted, due to the disproportionate cancer/stromal cell ratio and -possibly- too rapid tumor growth, the stromal reaction is much smaller than in human pancreatic cancer. One the other hand, desmoplasia is present only in some of the genetically engineered mouse models. Clinically, stromal activity of the pancreatic ductal adenocarcinoma has as great an impact on patient prognosis as the lymph node status of the tumor. The exact molecular mechanisms behind this observation remain obscure. However, one possible fundamental biologic explanation could be that selective pressure applied by the stroma leads to the evolution of cancer cells. Consequently, somatic evolution of invasive cancer could be viewed as a sequence of phenotypical adaptations to this barrier, highlighting the importance of the fibrotic tumor microenvironment in the behavior of pancreatic cancer. In this review, the interaction of the epithelial tumor cells with the stroma in humans and in various animal models is scrutinized, and novel therapeutic options for uncoupling cancer-stroma interactions are discussed.
Current Molecular Medicine 01/2012; 12(3):288-303. · 5.10 Impact Factor
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Michaela Aichler,
Christopher Seiler,
Monica Tost,
Jens Siveke,
Pawel K Mazur,
Patricia Da Silva-Buttkus,
Detlef K Bartsch,
Peter Langer,
Sara Chiblak,
Anna Dürr,
Heinz Höfler,
Günter Klöppel,
Karin Müller-Decker,
Markus Brielmeier, Irene Esposito
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions, pancreatic intraepithelial neoplasia (PanIN), display a ductal phenotype. However, there is evidence in genetically defined mouse models for PDAC harbouring a mutated kras under the control of a pancreas-specific promoter that ductal cancer might arise in the centroacinar-acinar region, possibly through a process of acinar-ductal metaplasia (ADM). In order to further elucidate this model of PDAC development, an extensive expression analysis and molecular characterization of the putative and already established (PanIN) precursor lesions were performed in the Kras; Ptf1a-Cre mouse model and in human tissues, focusing on lineage markers, developmental pathways, cell cycle regulators, apomucins, and stromal activation markers. The results of this study show that areas of ADM are very frequent in the murine and human pancreas and represent regions of increased proliferation of cells with precursor potential. Moreover, atypical flat lesions originating in areas of ADM are the most probable precursors of PDAC in the Kras; Ptf1a-Cre mice and similar lesions were also found in the pancreas of three patients with a strong family history of PDAC. In conclusion, PDAC development in Kras; Ptf1a-Cre mice starts from ADM and a similar process might also take place in patients with a strong family history of PDAC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 01/2012; 226(5):723 - 734. · 6.32 Impact Factor
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Barbara M Grüner,
Hannes Hahne,
Pawel K Mazur,
Marija Trajkovic-Arsic,
Stefan Maier, Irene Esposito,
Evdokia Kalideris,
Christoph W Michalski,
Jörg Kleeff,
Sandra Rauser,
Roland M Schmid,
Bernhard Küster,
Axel Walch,
Jens T Siveke
[show abstract]
[hide abstract]
ABSTRACT: The identification of new biomarkers for preneoplastic pancreatic lesions (PanINs, IPMNs) and early pancreatic ductal adenocarcinoma (PDAC) is crucial due to the diseases high mortality rate upon late detection. To address this task we used the novel technique of matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) on genetically engineered mouse models (GEM) of pancreatic cancer. Various GEM were analyzed with MALDI IMS to investigate the peptide/protein-expression pattern of precursor lesions in comparison to normal pancreas and PDAC with cellular resolution. Statistical analysis revealed several discriminative m/z-species between normal and diseased tissue. Intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) could be distinguished from normal pancreatic tissue and PDAC by 26 significant m/z-species. Among these m/z-species, we identified Albumin and Thymosin-beta 4 by liquid chromatography and tandem mass spectrometry (LC-MS/MS), which were further validated by immunohistochemistry, western blot, quantitative RT-PCR and ELISA in both murine and human tissue. Thymosin-beta 4 was found significantly increased in sera of mice with PanIN lesions. Upregulated PanIN expression of Albumin was accompanied by increased expression of liver-restricted genes suggesting a hepatic transdifferentiation program of preneoplastic cells. In conclusion we show that GEM of endogenous PDAC are a suitable model system for MALDI-IMS and subsequent LC-MS/MS analysis, allowing in situ analysis of small precursor lesions and identification of differentially expressed peptides and proteins.
PLoS ONE 01/2012; 7(6):e39424. · 4.09 Impact Factor
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Mert Erkan,
Guido Adler,
Minoti V Apte,
Max G Bachem,
Malte Buchholz,
Sönke Detlefsen, Irene Esposito,
Helmut Friess,
Thomas M Gress,
Hans-Joerg Habisch, [......],
Claus Kordes,
Craig D Logsdon,
Atsushi Masamune,
Christoph W Michalski,
Junseo Oh,
Phoebe A Phillips,
Massimo Pinzani,
Carolin Reiser-Erkan,
Hidekazu Tsukamoto,
Jeremy Wilson
Gut 11/2011; 61(2):172-8. · 10.11 Impact Factor
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Thomas G P Grunewald,
Isabel Diebold, Irene Esposito,
Stephanie Plehm,
Kristina Hauer,
Uwe Thiel,
Patricia da Silva-Buttkus,
Frauke Neff,
Rebekka Unland,
Carsten Müller-Tidow,
Colette Zobywalski,
Katharina Lohrig,
Urs Lewandrowski,
Albert Sickmann,
Olivia Prazeres da Costa,
Agnes Görlach,
Andrea Cossarizza,
Elke Butt,
Günther H S Richter,
Stefan Burdach
[show abstract]
[hide abstract]
ABSTRACT: Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1.
Molecular Cancer Research 11/2011; 10(1):52-65. · 4.29 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A hepatic angiomyolipoma is a rare benign tumor of the liver composed of a mixture of smooth muscle cells, blood vessels and a variable amount of adipose tissue. Differentiating them from malignant liver tumors can often be very difficult.
We report the case of a 43-year-old Caucasian man presenting with a large liver mass in the right lobe. The results of magnetic resonance imaging and contrast-enhanced ultrasonography were consistent with a well-demarcated adipose tissue- containing tumor, showing prolonged hyperperfusion in comparison with the surrounding liver tissue. Surgery was performed and the diagnosis of hepatic angiomyolipoma was made with histopathology.
Preoperative radiological characterization using magnetic resonance imaging and contrast-enhanced ultrasonography may improve diagnostic accuracy of hepatic angiomyolipoma. Identification of smooth muscle cells, blood vessels and adipose tissue with a positive immunohistochemical reaction for HMB-45 is the final evidence for an angiomyolipoma.
Journal of Medical Case Reports 09/2011; 5:481.
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Monika Raab,
Sven Kappel,
Andrea Krämer,
Mourad Sanhaji,
Yves Matthess,
Elisabeth Kurunci-Csacsko,
Julia Calzada-Wack,
Birgit Rathkolb,
Jan Rozman,
Thure Adler, [......],
Eckhard Wolf,
Nicole Sänger,
Florian Prinz,
Martin de Angelis,
Jost Seibler,
Juping Yuan,
Martin Bergmann,
Rainald Knecht,
Bertolt Kreft,
Klaus Strebhardt
Nature Communications 07/2011; 2:395. · 7.40 Impact Factor
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Stefan Eser,
Marlena Messer,
Philipp Eser,
Alexander von Werder,
Barbara Seidler,
Monther Bajbouj,
Roger Vogelmann,
Alexander Meining,
Johannes von Burstin,
Hana Algül,
Philipp Pagel,
Angelika E Schnieke, Irene Esposito,
Roland M Schmid,
Günter Schneider,
Dieter Saur
[show abstract]
[hide abstract]
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcome often resulting from late diagnosis in advanced stages. To date methods to diagnose early-stage PDAC are limited and in vivo detection of pancreatic intraepithelial neoplasia (PanIN), a preinvasive precursor of PDAC, is impossible. Using a cathepsin-activatable near-infrared probe in combination with flexible confocal fluorescence lasermicroscopy (CFL) in a genetically defined mouse model of PDAC we were able to detect and grade murine PanIN lesions in real time in vivo. Our diagnostic approach is highly sensitive and specific and proved superior to clinically established fluorescein-enhanced imaging. Translation of this endoscopic technique into the clinic should tremendously improve detection of pancreatic neoplasia, thus reforming management of patients at risk for PDAC.
Proceedings of the National Academy of Sciences 06/2011; 108(24):9945-50. · 9.68 Impact Factor
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Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2011; 458(6):761-5. · 2.49 Impact Factor
