Regulatory Proteins in Progenitors and Differentiated Cells of the Human Prostate

Sammanfattning: Prostate cancer (PC) develops from an androgen-dependent tissue that contains androgen receptors in both the stromal and glandular compartments. Surgical removal of the prostate may cure the patient, but if metastatic spread has occurred, androgen suppression therapy is the standard treatment. However, most men will eventually fail this therapy and develop recurrent androgen-independent disease, for which there is no effective therapy. Our understanding of PC, including cell source and mechanisms in initiation and progression of PC, is impeded by our lack of knowledge regarding cell regulation, self-renewal, and cellular differentiation mechanisms in the prostate gland. In this study, we aimed to investigate these processes in the adult human prostate, by investigating localization, activity, and regulation of growth and differentiation modulating proteins in mature and differentiating cells of the adult prostate, including the benign and malignant prostate. In this thesis, I provide evidence for epithelial renewal in response to prostate tissue culture, and for basal and epithelial stem cell (SC) recruitment leading to an expansion of differentiating glandular precursor cells, and report the identification of several novel candidate epithelial SC-antigens in the prostate, including the putative suppressor of differentiation Dlk-1. We also supply evidence that nuclear Notch-1 activity down-regulates the candidate SC marker Dlk-1 in differentiating glandular precursor cells, that Notch-signalling regulates proliferation of precursor cells, and that inactive Notch-1 is a marker of mature glandular cells in the prostate. In addition, the identification of rare Dlk-1 expressing neuroendocrine cells suggests the existence of a common prostate epithelial progenitor, and a late precursor phenotype to this cell lineage. Data further suggest that stem cell factor (SCF) regulates prostate SC/progenitor biology through KIT-receptors, and the existence of a novel stromal progenitor phenotype in the prostate. We further show that the inhibitory peptide somatostatin (SS) is expressed in the prostate epithelial and mesenchymal SC/progenitor niche, and that SS regulates expansion of immature epithelia in primary prostate cell cultures, and that specific SS-receptors are up-regulated in PC. New therapeutics may be based on inhibitors/agonists of critical SC/niche and precursor cell signalling and differentiation-modulating molecules, or of their receptors; current results may set the stage for the development of new therapies in prostate glandular and stromal diseases.