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Project number   Stand-alone Projects  P21919
Title   Inflammatory signaling in prostate tumorigenesis
Principal investigator   BIRBACH Andreas
Approval date   30.06.2009
University / Research institution   Zentrum für Physiologie und Pharmakologie Institut für Gefäßbiologie und Thromboseforschung, Medizinische Universität Wien
Scientific field(s)  
Keywords   prostate cancer, allograft, inflammation, kinase, mouse model

Prostate cancer is the second-leading cause of cancer-related death in industrialized countries. However, the reasons for the high incidence of cancers of the prostate in comparison to other organs are still poorly understood. A growing amount of evidence points to a role of chronic inflammatory processes and inflammatory signaling in prostate carcinogenesis. The primary goal of this project is to elucidate the role of inflammatory signaling in prostate tumorigenesis by developing and analyzing a mouse model for inflammation-induced prostate cancer. To this end, three mouse lines are being intercrossed, one conferring prostate-specificity to the model by organ-specific expression of the Cre recombinase, one simulating a genetic event by partially deleting a tumor suppressor gene (phosphatase and tensin homologue, PTEN), and one imitating signaling during a chronic inflammatory state by expressing a constitutively active form of the IkappaB kinase 2 (IKK2ca). We have initiated a mouse colony and aim at characterizing the histopathological phenotype of the mouse prostate tissue together with a pathologist. Early results suggest neoplastic lesions in combined PTEN+/- IKK2ca prostates. Moreover, we have started to determine expression levels of putative target genes mediating a neoplastic effect using Oligo Array and Real Time PCR technologies. We have identified Interleukin-1beta as a candidate gene mediating the neoplastic growth. We intend to select 2-3 putative downstream effector genes for functional studies. To this end, we will establish primary epithelial and stromal cultures and target downstream effectors by shRNA or ectopic overexpression. We will use grafting of established cell lines, with or without modification of effector genes, into immunocompromised mice in order to determine the contribution of potential downstream effectors to neoplastic growth. Taken together, we expect the project to deliver a novel mouse model for inflammation-induced prostate tumor with potential to be used for basic research and in preclinical screenings. The identification of downstream effectors could also lead to novel ways of individualized diagnosis of prostate cancer patients.

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