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Prof. Dr. Christoph Klein
Department of Pathology
Division of Oncogenomics
University of Regensburg
Franz-Josef-Strauß-Allee 11
D-93053 Regensburg, Germany
Tel: +49-941-944-6720
Fax: +49-941-944-6719
Lab Homepage
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christoph.klein(at)klinik.uni-regensburg.de
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Molecular mechanisms of early tumour cell dissemination |
Analysing the Balb/NeuT mouse model of breast cancer, we found that metastatic dissemination of cancer cells takes place shortly after malignant transformation. Already one to four weeks after induction of the transgene, we detected disseminated tumour cells (DTC) in lung and bone marrow. Surprisingly, DTCs were found in bone marrow before macroscopic or microscopic tumours were detectable. No increase of DTCs in bone marrow was observed with increasing size of the primary tumours neither in mice nor in patients. First molecular studies revealed an upregulation of proteolytic enzymes and of the transcription factor Twist in early lesions that even exceeded the levels detectable in the invasion front of large carcinomas. In the proposed project we want to use the Balb/NeuT model and other mouse models of our collaborators to identify the molecular mechanisms of early cancer spread. Candidate regulators will be tested on human samples. Central to our project is the attempt to precisely identify the invading and disseminating tumour cells and to provide a detailed description of their phenotype and genotype. Functional assays will test candidate regulators. We will also ask whether the physiological mechanisms of cancer spread seen in sporadically arising tumours are different to currently proposed mechanisms mostly identified in cell lines, which imply that metastatic dissemination is a late event. |
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| - Relevant recent publications - |
Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009 Apr;9(4):302-12. |
Weckermann D, Polzer B, Ragg T, Blana A, Schlimok G, Arnholdt H, Bertz S, Harzmann R, Klein CA. Perioperative Activation of Disseminated Tumor Cells in Bone Marrow of Patients With Prostate Cancer. J Clin Oncol. 2009 Feb 23. [Epub ahead of print] |
Hüsemann Y, Klein CA. The analysis of metastasis in transgenic mouse. Transgenic Res. 2009 Feb;18(1):1-5. |
Klein CA. The direct molecular analysis of metastatic precursor cells in breast cancer: A chance for a better understanding of metastasis and for personalised medicine. Eur J Cancer. 2008 Dec;44(18):2721-5. |
Klein CA. The Metastasis Cascade.Science. 2008 Sep 26; 321(5897):1785-7. |
Sienel W, Polzer B, Elshawi K, Lindner M, Morresi-Hauf A, Vay C, Eder F, Passlick B, Klein CA. Cellular localization of EMMPRIN predicts prognosis of patients with operable lung adenocarcinoma independent from MMP-2 and MMP-9. Mod Pathol. 2008 Sep;21(9):1130-8. |
Stoecklein NH, Hosch SB, Bezler M, Stern F, Hartmann CH, Vay C, Siegmund A, Scheunemann P, Schurr P, Knoefel WT, Verde PE, Reichelt U, Erbersdobler A, Grau R, Ullrich A, Izbicki JR, Klein CA. Direct Genetic Analysis of Single Disseminated Cancer Cells for Prediction of Outcome and Therapy Selection in Esophageal Cancer. Cancer Cell. 2008 May 6;13(5):441-453. |
Fuhrmann C, Schmidt-Kittler O, Stoecklein NH, Petat-Dutter K, Vay C, Bockler K, Reinhardt R, Ragg T, Klein CA. High-resolution array comparative genomic hybridization of single micrometastatic tumor cells. Nucleic Acids Res. 2008 Apr;36(7):e39. |
Hüsemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmüller G,Klein CA. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68. |
Klein CA, Hartmann CH. Amplification of cDNA from single or rare cells by global PCR (exponential amplification). In Microarrays in Inflammation, edited by Bosio A, Gerstmayer G. 2008; p.81-94. Birkhäuser Verlag, Basel, CH. |
Klein CA. Random mutations, selected mutations: A PIN opens the door to new genetic landscapes. Proc Natl Acad Sci U S A. 2006. Nov 28;103(48):18033-4. |
Hartmann CH, Klein CA. Gene expression profiling of single cells on large-scale oligonucleotide arrays. Nucleic Acids Res. 2006;34(21):e143. |
Klein CA, Holzel D. Systemic Cancer Progression and Tumor Dormancy: Mathematical Models Meet Single Cell Genomics. Cell Cycle. 2006 Aug 15;5(16):1788-98. |
Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dolle ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature. 2006 Jun 22;441(7096):1011-4. |
Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C, Polzer B, Petronio M, Eils R, Klein CA. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell. 2005 Sep;8(3):227-39. |
Ulmer A, Fischer JR, Schanz S, Sotlar K, Breuninger H, Dietz K, Fierlbeck G, Klein CA. Detection of melanoma cells displaying multiple genomic changes in histopathologically negative sentinel lymph nodes. Clin Cancer Res. 2005 Aug 1;11(15):5425-32. |
Klein CA. Single cell amplification methods for the study of cancer and cellular ageing. Mech Ageing Dev. 2005 Jan;126(1):147-51. |
Klein CA, Zohlnhöfer D, Petat-Dutter K, Wendler N. Gene expression analysis of a single or few cells. In Curr Protoc Hum Genet edited by Haines JL, Korf BR, Morton CC, Seidman CE, Seidman JG, Smith DR. 2005; 11.8.1-11.8.18. John Wiley & sons, Hoboken, NJ, USA. |
Stoecklein NH, Luebke AM, Erbersdobler A, Knoefel WT, Schraut W, Verde PE, Stern F, Scheunemann P, Peiper M, Eisenberger CF, Izbicki JR, Klein CA, Hosch SB. Copy number of chromosome 17 but not HER2 amplification predicts clinical outcome of patients with pancreatic ductal adenocarcinoma. J Clin Oncol. 2004 Dec 1;22(23):4737-45. (Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248.) |
Ulmer A, Schmidt-Kittler O, Fischer J, Ellwanger U, Rassner G, Riethmuller G, Fierlbeck G, Klein CA. Immunomagnetic enrichment, genomic characterization, and prognostic impact of circulating melanoma cells.Clin Cancer Res. 2004 Jan 15;10(2):531-7. |
Klein CA. Gene expression sigantures, cancer cell evolution and metastatic progression. Cell Cycle. 2004 Jan;3(1):29-31. |
Klein CA. The systemic progression of human cancer: a focus on the individual disseminated cancer cell - the unit of selection. Adv Cancer Res. 2003;89:35-67. |
Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, Kaufmann M, Diebold J, Arnholdt H, Muller P, Bischoff J, Harich D, Schlimok G, Riethmuller G, Eils R, Klein CA. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7737-42. |
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