Summary

In this project the fundamental translational aspects of hypoxia are to be analysed with a particular focus on “Hypoxia-inducible Factor-1” (HIF-1) induced transcriptional regulation. Hypoxia as well as inflammatory stimuli often leads to the induction of hypoxia-inducible transcription factors in solid tumors. Of paramount importance in this context is HIF-1α which supports tumor growth by adaptation of cell metabolism and stimulation of tumor angiogenesis. Upregulated expression of HIF-1α in tumors is frequently associated with an unfavorable prognosis. Our own results indicate that HIF expression in tumor cells mediates resistance to in vitro and in vivo. Recently, a number of studies have suggested that connective tissue cells as well as vascular cells and cells of the immune system may positively or negatively affect tumor growth in the host organism. The role of HIF-1α in this tumor stroma interaction remains largely undefined. We intend to generate genetically modified mice that have lost expression of HIF-1α and to inject murine Lewis Lung Carcinoma (LLC) cells which are engineered to be either HIF-1α competent or HIF-1α deficient and to determine tumor growth and responsiveness to IR.

Selected Publications

Hussmann M, Janke K, Kranz P, Neumann F, Mersch E, Baumann M, Goepelt K, Brockmeier U, Metzen E. Depletion of the thiol oxidoreductase ERp57 in tumor cells inhibits proliferation and increases sensitivity to ionizing radiation and chemotherapeutics. Oncotarget. 2015 Nov 17;6(36):39247-61.

Janke K, Brockmeier U, Kuhlmann K, Eisenacher M, Nolde J, Meyer HE, Mairbäurl H, Metzen E. Factor inhibiting HIF-1 (FIH-1) modulates protein interactions of apoptosis-stimulating p53 binding protein 2 (ASPP2). J Cell Sci 2013 Jun 15;126(12):2629-40.

Jin F, Brockmeier U, Otterbach F, Metzen E. New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required for tumor cell intravasation. Mol Cancer Res 2012 Aug;10(8):1021-31.

Su Y, Loos M, Giese N, Hines OJ, Diebold I, Görlach A, Metzen E, Pastorekova S, Friess H, Büchler P. PHD3 regulates differentiation, tumor growth and angiogenesis in pancreatic cancer. Br J Cancer 2010 Nov 9;103(10):1571-9. Epub 2010 Oct 26.

Wotzlaw C, Otto T, Berchner-Pfannschmidt U, Metzen E, Acker H, Fandrey J. Optical analysis of the HIF-1 complex in living cells by FRET and FRAP. FASEB J 2007; 21:700-707.

Doege K, Heine S, Jensen I, Jelkmann W, Metzen E. Inhibition of mitochondrial respiration elevates oxygen concentration, but leaves regulation of hypoxia-inducible factor (HIF) intact. Blood 2005;106:2311-2317.