Jan Georg Hengstler

Leibniz Research Center for Working Enviroment and Human Factors, Dortmund, North Rhine-Westphalia, Germany

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Publications (69)250.6 Total impact

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    ABSTRACT: Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell-lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n = 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n = 196). Both were analyzed with regard to frequency, distribution, and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho = 0.4-0.8).CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate (HR: 1.8; p = 0.03) and multivariate COX regression model (HR: 1.9; p = 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2014; · 6.20 Impact Factor
  • 14th International Neurotoxicology Association meeting, Egmond aan Zee, The Netherlands; 06/2013
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    ABSTRACT: Acrylamide (AA), classified as class 2A carcinogen (probably carcinogenic to humans) by the International Agency for Research on Cancer (IARC), is formed during heating of food from reducing carbohydrates and asparagine by Maillard reaction chemistry. After dietary uptake, AA is in part metabolically converted into the proximate genotoxic phase I metabolite glycidamide (GA). GA reacts with nucleophilic base positions in DNA, primarily forming N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua) adducts. In a competing phase II biotransformation pathway AA, as well as its phase I metabolite GA, is coupled to glutathione (GSH). The GSH coupling products are further biotransformed and excreted via urine as mercapturic acids (MA), N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA). In the present study, hepatic biotransformation pathways and DNA adduct formation were studied in primary rat hepatocytes, incubated with AA (0.2-2,000 μM) for up to 24 h. Contents of AA-GSH, GA, AAMA, and GAMA were measured in the cell culture medium after solid phase extraction (SPE). N7-GA-Gua adducts in DNA of hepatocytes were determined by HPLC-ESI-MS/MS after lysis of the cells and neutral thermal hydrolysis. Formation of AA-GSH was linear with AA concentration and incubation time and became detectable already at 0.2 μM (4 h). In contrast to AA, GA was not detected before 16 h incubation at 10-fold higher AA concentration (2 μM). In summary, the rate of AA-GSH formation was found to be about 1.5-3 times higher than that of GA formation. N7-GA-Gua adducts were found only at the highest AA concentration tested (2,000 μM).
    Archives of Toxicology 04/2013; · 5.22 Impact Factor
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    ABSTRACT: Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4(-/-)), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD. Furthermore, we investigated the influence of vitamin D on bone quality in this model. The bone morphology analyses revealed reduced bone mineral contents as well as changes in trabecular bone architecture and decreased cortical bone densities in Abcb4(-/-) mice with severe liver fibrosis. We observed dysregulation of genes involved in bone remodeling (osteoprotegerin, osteocalcin, osteopontin) and vitamin D metabolism (7-dehydrocholesterol reductase, Gc-globulin, Cyp2r1, Cyp27a1) as well as alterations in calcium and vitamin D homeostasis. In addition, serum RANKL and TGF-β levels were increased in Abcb4(-/-) mice. Vitamin D dietary intervention was only partially able to restore the bone phenotypes of Abcb4(-/-) animals. We conclude that the Abcb4(-/-) mouse provides an experimental framework and a preclinical model to gain further insights into the molecular pathobiology of HOD and to study the systemic effects of therapeutic interventions.
    Bone 03/2013; · 3.82 Impact Factor
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    ABSTRACT: A prognostic impact of immunoglobulin kappa C (IGKC) expression has been described in cancer. We analysed the influence of B-cell and plasma cell markers, as well as IGKC expression, in non-small lung cancer (NSCLC) using immunohistochemistry on a tissue microarray. IGKC protein expression was independently associated with longer survival, with particular impact in the adenocarcinoma subgroup. Moreover, a correlation was seen with CD138+ cells, but not with CD20. CD138 expression revealed a comparable association with survival. In conclusion, IGKC expression in stroma-infiltrating plasma cells is a prognostic marker in NSCLC, supporting emerging treatment concepts that exploit the humoral immune response.
    Cancer Letters 01/2013; · 4.26 Impact Factor
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    ABSTRACT: Hepatocyte transplantation is considered to be an alternative to orthotopic liver transplantation. Cells can be used to bridge patients waiting for a donor organ, decrease mortality in acute liver failure, and to support metabolic liver diseases. The limited availability of primary human hepatocytes for such applications has lead to the generation of alternative hepatocyte-like cells from various adult stem or precursor cells. The aim of this study was to generate hepatocyte-like cells from adipose-derived mesenchymal stem cells (Ad-MSCs) for clinical applications, which are available "off the shelf". Epigenetic changes in hepatocyte-like cells were induced by 5-azacytidine, which in combination with other supplements leads to significantly improved metabolic and enzymatic activities compared to non-treated cells. Cells with sufficient hepatic features were generated with a 4-step protocol: 5-azacytidine (Step1), epidermal growth factor (Step2), fibroblast growth factor-4, dexamethasone, insulin-transferrin-sodiumselenite, nicotinamide (Step3) and hepatocyte growth factor, dexamethasone, insulintransferrin- sodium-selenite and nicotinamide (Step 4). Generated differentiated cells had higher phase I (CYP1A1/2, CYP2E1, CYP2B6, CYP3A4) and phase II activities compared to the undifferentiated cells. A strong expression of CYP3A7 and a weak expression of 3A4, as well as the important detoxification markers, α-fetoprotein and albumin, could also be detected at the mRNA-level. Importantly, urea metabolism (basal, NH₄-stimulated, NH₄ and ornithine-stimulated) was comparable to freshly isolated human hepatocytes and, unlike cryopreserved human hepatocytes, this activity was maintained after six months of cryopreservation. These findings suggest that these cells may be suitable for clinical application, especially for treatment of urea cycle disorders.
    Cell Transplantation 04/2012; · 4.42 Impact Factor
  • 78th annual meeting of DGPT, Dresden, Germany; 03/2012
  • 78th annual meeting of DGPT, Dresden, Germany; 03/2012
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    ABSTRACT: PURPOSE: Although the central role of the immune system for tumor prognosis is generally accepted a single robust marker is not yet available. EXPERIMENTAL DESIGN: Based on ROC (receiver operating characteristic) analyses robust markers were identified from a 60 gene B-cell derived metagene and analyzed in gene expression profiles of 1810 breast cancer, 1056 non-small cell lung cancer, 513 colorectal and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin embedded tissue of 330 breast cancer patients. The cell types were identified using immunohistochemical co-staining and confocal fluorescence microscopy. RESULTS: We identified immunoglobulin kappa C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis free survival across different molecular subtypes in node-negative breast cancer (n=965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n=845) [P less than 0.001]. In addition, IGKC gene expression was prognostic in non-small cell lung cancer and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin embedded tissues of 330 breast cancer patients. Tumor infiltrating plasma cells were identified as the source of IGKC expression CONCLUSION: Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anti-cancer therapy. It could be validated in several independent cohorts and performed similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.
    Clinical Cancer Research 02/2012; · 7.84 Impact Factor
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    ABSTRACT: The use of isolated human liver cells in research and development has gained increasing interest during the past years. The possible application may vary between elucidation of new biochemical pathways in liver diseases, drug development, safety issues, and new therapeutic strategies up to direct clinical translation for liver support. However, the isolation of human liver cells requires a well-developed logistic network among surgeons, biologists, and technicians to obtain a high quality of cells. Our laboratories have been involved in various applications of human liver cells and we have long-lasting experiences in human liver cell isolation and their application in R&D. We here summarize the present protocol of our laboratories for cell isolation from normal resected liver tissue, the most common tissue available. In addition, we discuss the necessary network in the clinic and quality controls to maintain human liver cells in culture and the effect of 3D extracellular matrix in cultured cells which results in preservation of hepatocyte epithelial polarity in the form of bile canaliculi and repression of epithelial to mesenchymal transitions occurring in 2D cultures.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 806:99-120.
  • Xi’an International Neurotoxicology Conference, Xi'an, China; 06/2011
  • Xi’an International Neurotoxicology Conference, Xi'an, China; 06/2011
  • EnTox Scientific Symposium, Dortmund, Germany; 05/2011
  • EnTox Scientific Symposium, Dortmund, Germany; 05/2011
  • EnTox Scientific Symposium, Dortmund, Germany; 05/2011
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    ABSTRACT: Transplantation of hepatocytes is a therapeutic approach for diverse acute and chronic liver diseases. As the availability of primary cells is limited, there exists an increasing demand for hepatocyte‐like cells that can be obtained by stem cell technology. Among which adiposederived mesenchymal stem cells (Ad‐MSCs) represent a promising source, as they are easily assessable and can be obtained in sufficient amounts. Human Ad‐MSCs were isolated from different patients, with their informed consent according to ethical guidelines of the MRI. Hepatic differentiation was induced by addition of 5‐azacytidine, FGF‐4, dexamethasone, nicotinamide, ITS, HGF and EGF. After 18 days those hepatocyte‐like cells (Ad‐HLCs) were able to metabolize ammonium‐chloride to urea and perform glucose metabolism comparable to primary human hepatocytes. Furthermore, phase I and II enzyme activities reached levels up to 80 % of human hepatocytes. After labeling with red fluorescent dye DiI both Ad‐HLCs and Ad‐MSCs (0.5*106 cells/mouse) were transplanted into CCl4 treated C57/Bl6 or Scid/beige mice via injection into the spleen. After 4, 10 and 21 days mice were sacrificed and livers were analyzed for the presence of the injected cells by 3D confocal microscopy. Cells were found located within hepatic sinusoids, while a minor fraction particularly of the Ad‐HLCs also revealed integration into parenchymal tissue. Transplanting undifferentiated Ad‐MSCs led to a massive accumulation of immune cells within the livers of C57/Bl6 mice. In case of Ad‐HLCs, significantly less immune cells were recruited. Our data show that hepatic differentiation seems to protect Ad‐MSCs to some extent from the mice’s immune reaction. Further investigation is necessary to investigate whether loss of surface markers on the differentiated Ad‐MSCs allows the immune escape.
    The 27th congress of German Association for the Studying of the Liver (GASL), Regensburg- GERMANY; 01/2011
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    ABSTRACT: Abstract We present a nearly fully automated method to construct single-cell-based models of mouse liver lobes in 3D based on whole slide scans using image processing and analysis. The method is robust and requires manual input only in few cases where the type of larger hepatic vessels cannot be determined automatically. We verify the dynamics of the constructed models by comparing them to experimental data of the growth of liver lobules during the regeneration after partial hepatectomy and during the physiological, homeostatic situation in mice.
    Living Imaging 2011 Workshop (LIVIM); 01/2011
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    ABSTRACT: Alterations in lipid metabolism and in the lipid composition of cellular membranes are linked to the pathology of numerous diseases including cancer. However, the influence of oncogene expression on cellular lipid profile is currently unknown. In this work we analyzed changes in lipid profiles that are induced in the course of ERBB2-expression mediated premature senescence. As a model system we used MCF-7 breast cancer cells with doxycycline-inducible expression of NeuT, an oncogenic ERBB2 variant. Affymetrix gene array data showed NeuT-induced alterations in the transcription of many enzymes involved in lipid metabolism, several of which (ACSL3, CHPT1, PLD1, LIPG, MGLL, LDL and NPC1) could be confirmed by quantitative realtime PCR. A study of the glycerophospholipid and lyso-glycerophospholipid profiles, obtained by high performance liquid chromatography coupled to Fourier-transform ion cyclotron resonance-mass spectrometry revealed senescence-associated changes in numerous lipid species, including mitochondrial lipids. The most prominent changes were found in PG(34:1), PG(36:1) (increased) and LPE(18:1), PG(40:7) and PI(36:1) (decreased). Statistical analysis revealed a general trend towards shortened phospholipid acyl chains in senescence and a significant trend to more saturated acyl chains in the class of phosphatidylglycerol. Additionally, the cellular cholesterol content was elevated and accumulated in vacuoles in senescent cells. These changes were accompanied by increased membrane fluidity. In mitochondria, loss of membrane potential along with altered intracellular distribution was observed. In conclusion, we present a comprehensive overview of altered cholesterol and glycerophospholipid patterns in senescence, showing that predominantly mitochondrial lipids are affected and lipid species less susceptible to peroxidation are increased.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 01/2011; · 4.13 Impact Factor
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    ABSTRACT: Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members. ERBB2-regulated Bcl-2 family members were identified by inducible expression of ERBB2 in MCF-7 breast cancer cells and by correlation analysis with ERBB2 expression in breast carcinomas. The prognostic relevance of ERBB2-regulated and all additional Bcl-2 family members was determined in 782 patients with untreated node-negative breast cancer. The biological relevance of ERBB2-induced inhibition of apoptosis was validated in a murine tumor model allowing conditional ERBB2 expression. ERBB2 caused an antiapoptotic phenotype by upregulation of MCL-1, TEGT, BAG1, BNIP1, and BECN1 as well as downregulation of BAX, BMF, BNIPL, CLU, and BCL2L13. Upregulation of the antiapoptotic MCL-1 [P = 0.001, hazard ratio (HR) 1.5] and BNIP3 (P = 0.024; HR, 1.4) was associated with worse prognosis considering metastasis-free interval, whereas clusterin (P = 0.008; HR, 0.88) and the proapoptotic BCL2L13 (P = 0.019; HR, 0.45) were associated with better prognosis. This indicates that ERBB2 alters the expression of Bcl-2 family members in a way that leads to adverse prognosis. Analysis of apoptosis and tumor remission in a murine tumor model confirmed that the prototypic Bcl-2 family member Bcl-x(L) could partially substitute for ERBB2 to antagonize tumor remission. Our results support the concept that ERBB2 influences the expression of Bcl-2 family members to induce an antiapoptotic phenotype. Antagonization of antiapoptotic Bcl-2 family members might improve breast cancer therapy, whereby MCL-1 and BNIP3 represent promising targets.
    Clinical Cancer Research 01/2010; 16(2):451-60. · 7.84 Impact Factor
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    ABSTRACT: It was previously demonstrated that the dipeptide carnosine inhibits growth of cultured cells isolated from patients with malignant glioma. In the present work we investigated whether carnosine also affects tumor growth in vivo and may therefore be considered for human cancer therapy. A mouse model was used to investigate whether tumor growth in vivo can be inhibited by carnosine. Therefore, NIH3T3 fibroblasts, conditionally expressing the human epidermal growth factor receptor 2 (HER2/neu), were implanted into the dorsal skin of nude mice, and tumor growth in treated animals was compared to control mice. In two independent experiments nude mice that received tumor cells received a daily intra peritoneal injection of 500 microl of 1 M carnosine solution. Measurable tumors were detected 12 days after injection. Aggressive tumor growth in control animals, that received a daily intra peritoneal injection of NaCl solution started at day 16 whereas aggressive growth in mice treated with carnosine was delayed, starting around day 19. A significant effect of carnosine on tumor growth was observed up to day 24. Although carnosine was not able to completely prevent tumor growth, a microscopic examination of tumors revealed that those from carnosine treated animals had a significant lower number of mitosis (p < 0.0003) than untreated animals, confirming that carnosine affects proliferation in vivo. As a naturally occurring substance with a high potential to inhibit growth of malignant cells in vivo, carnosine should be considered as a potential anti-cancer drug. Further experiments should be performed in order to understand how carnosine acts at the molecular level.
    Molecular Cancer 01/2010; 9:2. · 5.13 Impact Factor

Publication Stats

868 Citations
939 Downloads
4k Views
250.60 Total Impact Points

Institutions

  • 2008–2014
    • Leibniz Research Center for Working Enviroment and Human Factors
      Dortmund, North Rhine-Westphalia, Germany
  • 1994–2010
    • Johannes Gutenberg-Universität Mainz
      • • III. Department of Medicine
      • • Institute of Toxicology
      Mayence, Rheinland-Pfalz, Germany
  • 2009
    • Free University of Brussels
      • Department of Toxicology, Dermato-Cosmetology and Pharmacognosy (FAFY)
      Brussels, BRU, Belgium
  • 2008–2009
    • Technische Universität Dortmund
      • Leibniz Research Centre for Working Environment and Human Factors
      Dortmund, North Rhine-Westphalia, Germany
  • 2004–2009
    • University of Leipzig
      • Rudolf Boehm Institute of Pharmacology and Toxicology
      Leipzig, Saxony, Germany
  • 1999
    • Zambon Group
      Bresso, Lombardy, Italy