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FRIBIO-Biologi og biomedisin

Epigenetic and transcription factor patterns in regulation of cancer-stroma-vascular interactions of human urogenital cancer

Tildelt: kr 5,0 mill.

In cancer increased cell proliferation outweighs apoptosis and the cancer cells lose contact inhibition and invade surrounding stroma. Genomic instability provides substrate for the evolution and selection of increasingly aggressive cells that invade and metastasize. We have previously reported phenotypes that correlate with expression levels of transcription factors, antioncogenes, adhesion molecules, matrix remodelling enzymes and angiogenic factors. We have now discovered that a group of transcription factors that are known to be activated and shut down at specific stages of normal embryogenesis, so called developmental transcription factors, is differentially expressed in a very pronounced way in prostate cancer and that this is associated with syste matic changes of epigenetic regulation. Utilizing our biobanks of more than 1000 tumors with clinical and follow-up parameters attached and global gene expression databanks of fresh frozen prostate and endometrial cancers we plan to explore the relationsh ip between epigenetic changes in cancer, associated transcription factor changes and the concerted activation of downstream gene expression that affects cancer-stroma-vascular interactions. Based on the complementing expertise of our consortium (surgery, pathology, cell and molecular biology, functional genomics, bioinformatics) a strategy is proposed to uncover the systems biology of urogenital cancer. The complexity of regulatory networks necessitates valid in vitro models and new technology in this pro ject. Cultures of primary cells (prostate and endothelial) and cancer cell lines have been established. Global gene expression data are combined with ChIP-on-chip analysis, new models of primary cells and transformed progeny and constructs for gene overex pression and knock down. Modelling of regulatory networks and angiogenic targeting include outstanding international collaboration. Markers of potential use in screening, prognosis and treatment will be developed.

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FRIBIO-Biologi og biomedisin

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