Inflammatory signaling in prostate tumorigenesis

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.

The project aimed at elucidating how cellular signalling pathways activated during the course of inflammation could influence the onset or progression of prostate tumors. An in vivo model of prostate tumorigenesis was established in the course of this work.The results demonstrated that constitutive activation of the NF-kappaB signalling pathway in the prostate epithelium did not suffice for dysplastic tissue transformation. However, partially transformed prostate tissue can be further transformed by additional activation of inflammatory gene expression: In animal studies it was shown that slightly transformed tissue only showing few dysplastic cells could be induced to show enhanced proliferation and an increase in tumor mass by additional activation of inflammatory signalling via the NF-kappaB pathway. This increase in tumor mass was due to increased proliferation in both the genetically modified epithelium and the indirectly affected stroma. Changes in the stroma were characterized by a loss of smooth muscle tissue which de-differentiated into stronger proliferating fibroblastic tissue.Gene expression analysis revealed that activating inflammatory gene expression in the epithelium induced the formation of chemokines, which served to attract inflammatory immune cells into the tumor tissue and reinforced the inflammatory reaction. The persisting inflammation can contribute to dedifferentiation of smooth muscle cells.Interestingly, only few tumors could take the step of invading nearby tissue and thus forming an invasive prostate carcinoma. Our current hypothesis is that dedifferentiation of smooth muscle leads to an increased tissue barrier and thus can be seen as a response of the surrounding stromal tissue to prevent spread of the tumorigenic epithelial tissue into the nearby organs. This hypothesis shall be investigated in a follow-up project approved by the FWF.