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RESEARCH
Neoplastic diseases: signal pathways, target molecules & inflammation
The role of microglia in malignant gliomas
Roland Kälin, Frank Heppner
Malignant gliomas such as glioblastoma multiforme (GBM) are the most common malignant tumours with invasive and destructive growth patterns. The aim of this project is to better understand the role of microglia in the appearance and growth of malignant gliomas, as it is well known that a significant accumulation and activation of microglia occurs in and around gliomas. As microglia cells are, according to contradicting references suspected of encouraging tumour growth, but also of curbing it - an obvious contradiction, we wish to evaluate i) tumour growth, i) size and iii) phenotype after injection of syngenes GL621 glioma cells in the brains of CD11b-HSVTK, allowing the ablation of microglia cells. In doing so we are thus able to analyse the kinetics and tumour growth in one and the same mouse at different times.
Collaboration partners include Prof. Kettenmann and Dr. Glass, MDC-Berlin, and Prof. Burkhard Becher, experimentelle Immunologie, Universitität Zürich.
Generation of a mouse model for CNS-lymphomas
Elif Gül, Roland Kälin, Frank Heppner
This project aims to generate a mouse model of primary CNS-lymphomas (PCNSL). We will pursue the question of to what extent changes in the local chemokin milieus influence the migration of lymphoma cells into the CNS. As initial studies have hinted at a specific expression of selected chemokines and their receptors (CXCR5 and CXCL13) in PCNSL, we wish to simulate this chemokine interaction in mice. The ectopic CXCL13-expression in peripheral organs for example, induces the migration of lymphom cells in Eµ-myc mice, which then develop CXCR5-positive B cell lymphomas. We are currently examining whether the crossing of Eµ-myc mice with mice expressing ectopic CNS-specific CXCL13 leads to the manifestion of lymphoma cells in the brain.
The proof of concept experiment on CXCL13.CXCR5 interaction was funded by the Schweizer Krebsliga. Collaboration partners include DR. M. Baier, Robert-Koch-Institut, Berlin
Neurofibromatosis Type 1 genetic and epigenetic influences, tumour development and NF1-Gene regulation
Katrin Guse, Sabrina Titze, Frank Heppner, Anja Harder
Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder presenting with tumour development mainly on the skin as well as in the peripheral and central nervous systems. Even in cases of identical genotypes, e.g. in monozygotic twins with NF1, the phenotype shows considerable variability. One project aims to identify linked and unlinked genetic and epigenetic modifiers such as DNA methylation and alterations of mismatch repair genes which might explain these differences. In a further project, regulatory elements of the NF1 gene promoter are to be examined. As well as tests on human tissue, aspects of another project will also involve use of the NF1 specific knockout mouse model. These molecular biological investigations will deal with tumour development and therapy of NF1 associated tumors. The experiments should lead to a better understanding of disease development and NF1 gene regulation.
Molecular causes and target molecules in the progression of malignant brain tumours
Nikola Holtkamp, Frank Heppner
This project aims to identify oncogenes in glioblastomas and malignant peripheral nerve sheath tumours (MPNST), which could prove to be interesting target molecules for a new generation of pharmaceuticals such as inhibitors of receptor tyrosine kinases. The efficacy of such pharmaceuticals is to be examined in cell culture approaches and then extended to animal models. Furthermore, we will also deal with progression associated changes in malignant brain tumours with the goal of identifying these as diagnostic and prognostic markers.
Collaborative partners include Prof. von Deimling, Department of Neuropathology, Ruprecht-Karls-University Heidelberg and Prof. Mautner, University Clinic Hamburg Eppendorf. The project is funded by the U.S. Department of Defence (grant NF050145).
The significance of development control signal pathways in the origins of tumours
Arend Koch, Frank Heppner
The influence of development control signal pathways ((Wnt, Notch, Hedgehog) in the pathogenesis of malignant embryonal, cerebral and extra cerebral tumours is to be examined. These signal pathways convey decisions regarding cell destiny during embryogenesis and if oncogenic activation occurs lead to tumour development.
On the basis of molecular and cell-biological approaches, we were able to identify activating somatic mutations in genes, which lead to activation of these signal pathways, in malignant childhood tumours of the cerebellum (medulloblastomas), in malignant embryonal liver tumours (hepatoblastomas) and in kidney tumours (Wilm's tumours). A result of this activation is an increased expression of specific genes, which are above all responsible for growth and differentiation in tumour cells. By functional activation and inhibition of these signal pathways in human tumour cells, we aim to identify and characterise specific target genes. In doing so, we hope to provide a better understanding of the molecular realisation of over-activation of these signal pathways in human embryonal tumours and to generate new approaches to molecular therapies.
Collaborative partner is Prof. T. Pietsch, Institute of Neuropathology, University of Bonn.
Selected publications:
Waha A, Koch A, Hartmann W, Milde U, Felsberg J, Hübner A, Mikeska T, Goodyer CG, Sörensen N, Wiestler OD, Pietsch T, Waha A. SGNE1 is epigenetically altered and down-regulated in human medulloblastomas. Oncogene 26(38):5662-8 (2007).
Koch A, Hrychyk A, Hartmann W, Waha A, Schüller U, Sörensen N, Berthold F, Goodyer CG, Wiestler OD, Birchmeier W, Behrens J, Pietsch T. Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas. Int J Cancer 121(2):284-91 (2007).
Holtkamp N., Atallah I., Okuducu AF, Mucha J, Hartmann C, Mautner VF, Friedrich RE, Mawrin C, and von Deimling A. MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia 9(8), 671-7 (2007).
Holtkamp N, Ziegenhagen N, Malzer E, Hartmann C, Giese A, and von Deimling A. Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme. Neuro Oncol 9(3), 291-7 (2007).
Kälin RE, Kretz MP, Meyer AM, Kispert A, Heppner FL and Brändli AW. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Dev Biol 305(2):599-614 (2007).
Harder A, Mautner VF, Friedrich RE, Harder T, Plagemann A, von Deimling, A. Transcription factor AP-2 is expressed in human schwann cell derived tumors. Histopathology 49 (4):442-443 (2006).
Ohgaki H, Kita D, Favereaux A, Huang H, Homma T, Dessen P, Weiss WA, Kleihues P, and Heppner FL. Brain tumors in S100?-v-erbB transgenic rats. J Neuropathol Exp Neurol 65(12):1111-7 (2006).
Holtkamp N, Okuducu AF, Mucha J, Afanasieva A, Hartmann C, Atallah I, Estevez-Schwarz L, Mawrin C, Friedrich RE, Mautner VF, and von Deimling A. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors (MPNST), and its implications for imatinib sensitivity. Carcinogenesis 27(3), 664-71 (2006).
Holtkamp N, Afanasieva A, Elstner A, van Landeghem FK., Konneker M, Kuhn SA, Kettenmann H, and von Deimling A. Brain slice invasion model reveals genes differentially regulated in glioma invasion. Biochem Biophys Res Commun 336(4), 1227-33 (2005).
Hartmann W, Koch A, Brune H, Waha A, Denkhaus D, Dani I, Langmann W, Bode U, Wiestler OD, Schilling K, Pietsch T. IGF-II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. Am J Pathol 166(4):1153-62 (2005).
Koch A, Waha A, Hartmann W, Hrychyk A, Schüller U, Waha A, Wharton Jr KA, Fuchs SY, von Schweinitz D, Pietsch T. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res 11(12):4295-304 (2005).
Schüller U*, Koch A*, Hartmann W, Garrč ML, Goodyer CG, Cama A, Sörensen N, Wiestler OD, Pietsch T. Subtype-specific expression and genetic alterations of the chemokine receptor gene CXCR4 in medulloblastomas. Int J Cancer 20;117(1):82-9 (2005).
Holtkamp N, Reuss DE, Atallah I, Kuban RJ, Hartmann C, Mautner VF, Frahm S, Friedrich RE. Algermissen B, Pham VA, Prietz S, Rosenbaum T, Estevez-Schwarz L, and von Deimling A. Subclassification of nerve sheath tumors by gene expression profiling. Brain Pathol 14(3), 258-64 (2004).
Koch A, Waha A, Hartmann W, Milde U, Goodyer CG, Sörensen N, Berthold F, Digon-Söntgerath B, Kraetzschmar J, Wiestler OD, Pietsch T. No evidence for mutations or altered expression of the Suppressor of Fused gene (SUFU) in primitive neuroectodermal tumours. Neuropathol Appl Neurobiol 30(5):532-9 (2004).
Koch A, Weber N, Waha A, Hartmann W, Denkhaus D, Behrens J, Birchmeier W, von Schweinitz D, Pietsch T. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol 204(5):546-54 (2004).
Harder A, Rosche M, Reuß DE, Holtkamp N, Uhlmann K, Friedrich R, Mautner VF, von Deimling A. Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours. Eur J Cancer 2004, 40:2820-2828.
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