Smooth muscle in prostate tumorigenesis

The adult prostate is an organ with low cellular turnover. According to a theory of prostate cell interactions in health and disease, this homeostasis is accomplished by reciprocal interaction of the epithelium with the surrounding smooth muscle. Following genetic insult to the epithelium, signaling to the smooth muscle is disturbed, resulting in phenotypic changes of the smooth muscle. This in turn leads to incorrect signaling to the epithelium, which then proliferates at a higher rate. This model is supported by various findings, including anatomical observations on differently graded prostate cancers and in vitro cell culture studies. In a previous project, our group has found loss of smooth muscle cells concomitant with hyperproliferative intraepithelial tumors in an inflammatory tumor mouse model. We have identified candidate genes which could be responsible for the histological changes in the stroma and the epithelium. In the current project, we want to investigate (I) how smooth muscle is lost in the inflammatory tumor model by performing pathway studies of the dedifferentiation phenomenon, (II) whether smooth muscle markers and molecules involved in the dedifferentiation pathway are differentially expressed between normal, inflamed and neoplastic prostate tissue, (III) how re-differentiation of dedifferentiated fibroblastic cells changes global gene expression and possibly identifies candidate molecules of stromal-epithelial interactions, and (IV) how in vivo tumor growth can be influenced by surrounding neoplastic cells with an enforced smooth muscle barrier. We expect the results from this study to extend our knowledge on epithelial-stromal interactions in health and disease, detail the role of smooth muscle cells in tumorigenesis, and fuel research in other areas of cancerogenesis.