Inflammation in prostate tumorigenesis
Inflammation is thought to have a causative role in about 20% of human cancers. In prostate cancer, epidemiological data suggest a link between chronic inflammation and early events in tumorigenesis, although a proof of this concept in a genetic model is lacking. In this project, we have established a mouse model combining monoallelic loss of the tumor suppressor PTEN together with expression of a constitutively active version of the IkappaB kinase 2 (IKK2), a key mediator in the central inflammatory NF-kappaB pathway, in prostate epithelial cells. We find that these double transgenic mice exhibit proliferative neoplasia (PIN) with large tumors, in contrast to non-enlarged single transgenic (monoallelic PTEN or IKK2ca-only) prostates. This phenotype correlates with persistent inflammation of the prostate tissue, characterized by infiltrating granulocytes and macrophages. Molecularly, the inflammatory phenotype is due to expression of inflammatory chemokines and cytokines in the double transgenic epithelium.
Strikingly, smooth muscle is lost around neoplastic prostate ducts. In human tumors, loss of smooth muscle is lost in carcinomas, and absent smooth muscle cell staining is regarded as an indication for invasive tumor formation in some prostate tumor models. However, in our model we show that loss of smooth muscle is just one step in the progression of the tumor, with a subsequent step necessary for carcinoma formation.
In the epithelium, proliferative growth correlated with downregulation of the tumor suppressor Nkx3-1. This gene is positively regulated by the androgen receptor; in inflamed prostates, androgen receptor activation was decreased, offering a potential explanation for hyperplastic changes.
See our publication in Neoplasia for details.
Inducible models of inflammatory skin diseases
Genetic models of inflammatory skin diseases like psoriasis have become quite common. Expression of a variety of inflammatory mediators or signaling molecules induces a "psoriasiform" or inflammatory phenotype in the skin. We have also discovered that the expression of a signaling molecule in mouse skin yields a phenotype resembling human psoriasis in histological and molecular aspects. We have established an inducible version of this model characterized by good reproducibility and high temporal resolution. The temporal resolution of our model should allow us to reveal early changes in gene expression and tissue alteration, at a timepoint when the phenotype is not yet macroscopically apparent.
This project proposal was awarded the Theodor Körner Preis 2011.
Mouse models for inducible manipulation of the prostate
Using cell type-specific promoters located on bacterial artificial chromosomes (BACs), we aim to express inducible proteins in different cell types of the mouse prostate. We have already successfully established a mouse strain expressing the inducible Cre protein MerCreMer in prostate epithelial cells. This mouse line is useful for inducible gene deletion using loxP-flanked strains or for inducible gene expression when used with mouse lines carrying transgenes behind a loxP-flanked Stop cassette. An ongoing project is to use the BAC technology of this model to create a mouse line for inducible, regulatable gene expression in epithelial cells via the Tetracycline system. A future plan is to create models for inducible ablation of various cell types in the mouse prostate.
Ming Jiang, MD/PhD, Vanderbilt University, Nashville, Tennessee, USA
Nicolas Kozakowski, MD, Medical University of Vienna, Austria
Lukas Kenner, MD, Medical University of Vienna, Austria
Emilio Casanova, PhD, Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
Marc Schmidt-Supprian, PhD, Max Planck Institute of Biochemistry, Martinsried, Germany
Yang Liu, PhD, University of Michigan, Michigan, USA
Joseph Miano, PhD, University of Rochester, Rochester, New York, USA