Alam, T.; (2007) Changes in gene expression during human prostate epithelial cell differentiation. Doctoral thesis , University of London.

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Abstract

The prostate is the most common site of disease in the human male. An understanding of its normal growth and development is required in order to elucidate the underlying mechanisms of prostatic diseases, namely benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate epithelium consists of three distinct cells types: basal, luminal and neuroendocrine cells. Several authors have postulated that there is a putative stem cell population in the prostate epithelium that gives rise to all three of these cell types. The stem cells are thought to reside in the basal cell layer and upon cell division give rise to an intermediate, transit amplifying (TA) cell. TA cells undergo rapid proliferation before undergoing terminal differentiation into a luminal or neuroendocrine cell. Despite accumulating evidence for the existence of prostatic stem cells, the regulation of cell growth and differentiation in the normal and diseased prostate is poorly understood. The aims of this research project are to identify genes that are involved in the regulation of growth and differentiation in the normal human prostate. As a model for investigating epithelial cell differentiation, a conditionally immortalised prostate epithelial cell line was employed. BPH cells were conditionally immortalised using a SV40 construct containing the large T antigen to give rise to the prostate epithelial cell line PrE2.8 (Daly-Burns et al., in preparation). These cells exhibit a basal phenotype at the permissive temperature of 33 C and are highly proliferative. When switched to 39 C, growth of the PrE2.8 cells is inhibited and they begin to differentiate. Using the differential display technique and microarray analysis, changes in gene expression between a proliferative and a non-proliferative phenotype were investigated. The protein expression of genes of interest were then confirmed in prostate tissue using immunohistochemistry. These genes may represent early markers of prostate epithelial cell differentiation and may also play a role in the progression of BPH and prostate cancer.

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