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Molecular and Cellular Radiobiology
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Prof. Dr. med. Nils Cordes Group Leader Nils.Cordes[at]Oncoray.de |
Target identification, understanding the molecular mechanisms a specific target molecule is involved, drug development and therapeutic administration of targeting agents are the challenging issues focused on in this research group.
Particularly in radiation oncology, the following aspects are of interest:
Identification of tumor-specific target molecules critical for tumor cell radiosensitivity
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Designing targeting strategies to inhibit these radiosensitivity-related target molecules
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Evaluation of molecular differences between tumor and, especially, the tumor-surrounding normal stroma
Focusing on cell adhesion molecules of the integrin family and their signaling pathways, the group “Biological and Molecular Targeting” has made considerable contributions to the molecular understanding of the cellular phenotypes cell adhesion-mediated radioresistance (CAM-RR) and cell adhesion-mediated drug resistance (CAM-DR).
To uncover the molecular mechanisms responsible for integrin-growth factor receptor interactions during cell adhesion to matrix proteins and/or cell-cell contact, efficient and biological relevant translation of proof-of-principle- into proof-of-concept-studies with regard to the central theme "role of cell-matrix and cell-cell interactions in the cellular radiation response of tumor cells" will be conducted. Important methods used in our group are two- and particularly three-dimensional cell culture models. 3D cell cultures mimic the physiological growth conditions of tumor and normal cells, thus, data generation more reliably reflects cell behavior in vivo.
The mechanistic basis of CAM-RR lies in integrin-mediated adhesion to matrix proteins such as fibronectin and collagen, which results in complex pro-survival signal transduction. Mutual and cooperative crosstalk of integrins with growth factor receptors such as EGFR channels into the regulation and modification of the cellular radiation response.
Integrins, their interactions with transmembrane growth factor receptors (Receptor-tyrosine-kinase, RTK) and intracellular signaling and adapter proteins. Cooperatively, these signaling cascades are involved in the regulation of the cell´s fate upon treatment with anticancer agents. Scheme delineates a selection of molecules investigated by the group members of “Biological & Molecular Targeting” (from Cordes N, Hehlgans S, Eke I. Adhesion, Invasion, Integrins and Beyond. In Medical Radiology - Radiation Oncology. Vol.: The Impact of Tumor Biology on Cancer Treatment and Multidisciplinary Strategies. Eds.: M. Molls, A.J. Giaccia, C. Nieder, M.S. Anscher. Springer-Verlag Heidelberg, in press)
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A) Three-dimensional growth of normal human fibroblasts (Picture from Hehlgans S, Haase M, Cordes N. Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta. 2007;1775(1):163-80.). |
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B) Embryonic mouse fibroblasts in three-dimensional culture stained against Pinch1-1 (red), f-actin (green) and DNA (DAPI, blue). Picture was obtained by laser scanning microscopy. |
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