The morbidity and/or mortality associated with prostatic diseases affects an increasing number of men and is a major medical condition within our aging population. Aging and steroid hormones, including androgens and estrogens, have been implicated as major endogenous risk factors for abnormal and continued growth of the prostate leading to BPH and adenocarcinoma in later life. The role of steroid hormones, particularly androgens, would be obvious if the levels of testosterone and/or DHT were increasing with age and thereby providing a hormonal milieu conducive to the perceived mitogenic actions of androgens on the androgen-dependent prostate gland. The paradox has been, however, that actual reductions in androgens occur relative to the aging process. This infers a larger role for estrogens, the concentrations of which donor change appreciably with increasing age, in the age-related phenomenon of increased prostate growth. However, BPH and adenocarcinoma do not develop exclusively due to changes in the hormonal milieu. In fact, overt BPH and adenocarcinoma are the end-points of a life-long process of prostate growth involving hormonal, dietary, environmental and genetic factors that modify homeostatic mechanisms within the prostate leading to a progressive and insidious escape from normal tissue maintenance to one in which cell growth is poorly controlled. Investigators have been increasingly successful in defining molecular phenotypes that distinguish between normal and tumor cells in the prostate; however, the mechanisms leading to adenocarcinoma are still poorly understood. Moreover, many of the features that distinguish normal and cancer cells are not applicable to the abnormal, but benign, growth of prostatic cells leading to BPH. The broad array of topics discussed at this conference emphasizes many, but not all, of the related areas of research by which our knowledge is rapidly increasing, but our present understanding of the age-related phenomena of prostate growth and disease remains inadequate and effective therapeutic intervention is a futuristic goal. Epidemiologic studies have led to the identification of a number of risk factors for prostate growth and there is evidence that modification of at least some of these factors, such as diet and environment, can reduce the attendant risk of prostate disease. Manipulation of the endogenous endocrine milieu has had limited utility in the ultimate outcome of prostatic diseases, suggesting that the incidence of BPH and adenocarcinoma is multifactoral. Numerous age-related alterations in prostatic histopathology are known to occur and are represented by a combination of inflammation, atrophy, hyperplasia, intra-epithelial neoplasia, and carcinoma. These lesions become increasingly more prevalent with age and are universally present, to a varying extent, in prostates of all middle-aged and older men. Although these morphologic changes provide a number of indications toward the evolution of disease, only PIN lesions are prognostic as a precursor lesion to adenocarcinoma. The study of prostate developmental biology using both normal and experimentally altered human and animal models has provided clues to the regulation and factors involved in cell proliferation, apoptosis, cell-cell communication, and cellular differentiation. Certain practical limitations govern the availability and experimental manipulation of human tissue samples to study various aspects of prostate growth. However, the recent identification of the chimpanzee as a non-human primate model for BPH and the experimental use of various rat and mouse strains, including transgenic and specific gene knockout mice, will expand our repertoire of available models in which to define the molecular mechanisms that regulate prostate growth. Although experimental alterations in the androgen and/or estrogen microenvironment cause dramatic changes in prostate development and growth, their direct actions as mitogenic agents has not been proven. Instead, steroid hormone action may be more proximal in signal transduction pathways that involve the paracrine and autocrine actions of growth factors between cells within the stromal and epithelial compartments of the prostate. Changes in prostate histology that occur in prostate disease and involve the influx of immune cells during inflammation and the atrophy of cells during aging are likely to alter the intracellular communication and the soluble factors that are involved in maintaining tissue homeostasis. Dietary factors and environmental agents serve to modify the effects of endogenous factors, such as hormones and growth factors, during developmental periods and over the period of life-long exposure. In certain cases, these dietary factors (e.g., fat) or environmental chemicals (e.g., dioxin or estrogenic chemicals), may be detrimental to good prostate health, whereas the consumption of phytoestrogens, lycopene, vitamins, and antioxidants may be protective against age-related prostate disease. Fundamental knowledge relative to basic aspects of cell biology provide promise toward the prevention, diagnosis, and treatment of prostatic disease. Of particular relevance are the molecular mechanisms of cell cycle regulation involving various mitogen-activated kinases, cyclins, and cyclin-dependent kinases. Cell-cell communication involves dissemination of soluble factors as well as physical links between cells such as cadherins, integrins, other cell adhesion molecules and the extracellular matrix. The balance between cell proliferation, cell death, and cell senescence holds the key to growth regulation that is influenced by reactivation of telomerase activity, genetic instability caused by oxidative DNA damage and expression of inappropriate mitogenic signals. An ultimate goal is to identify the elusive stem cell population within the prostate that responds to proliferative signals resulting in BPH and/or adenocarcinoma. Evolving technologies in the areas of functional genomics that utilize cDNA microarrays and proteomics will undoubtedly widen the scope and range of many studies directed toward the identification of molecular regulatory pathways that function in normal physiology as well as in pathophysiologic conditions.
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