Benign prostatic hyperplasia (BPH) is a very common disease in the aging male. Both BPH and chronic prostatitis are pathologically imprecisely defined. Prostatitis, as detailed in the body of this proposal, has been described by one prominent urologist as a 'wastebasket of clinical ignorance.' Both of these disease states (a) are more common among diabetics and (b) involve changes in the prostate that are, at the level of the tissue, both multiple and diverse. Attempts to understand the pathogenesis, biochemistry, molecular biology, endocrinology, and immunology of these lesions will be very frustrating until precise definitions of the many diverse entities in the 'wastebasket' can be defined. This task will be approached with the morphometric quantification of the anatomical and pathological structures that are observed in men starting with men in their early twenties. Alternating serial sections of whole prostates at intervals of 0.5 cm will be processed in paraffin and methacrylate. With corrections for differences in tissue shrinkage with these two methods, a computer-assisted three-dimensional image of each prostate will be constructed. The use of methacrylate allows superior in situ hybridization and the demonstration of most enzymes and antigens. The use of paraffin allows the recovery of nuclei that are satisfactory for use with the polymerase chain reaction and for flow cytometry. The frequency of each recognizable lesion will be catalogued as a function of age. We shall then continue a study already begun in an attempt to identify phenotypic changes that are characteristic of each of the lesions that are observed in BPH. We have recently describe a new method that permits the growth as xenografts of most prostatic carcinomas (PCA). We have observed that, with this new method for xenografting, epithelial tumors form in the xenografts of some samples of BPH from patients without PCA; this system will be used to determine which lesions are capable of growing as xenografts and to define growth fractions, growth potentials, and ability to express dif- ferentiation markers in immunologically deficient mice with and without exogenously supplied growth factors. In preliminary experiments, we have found in some samples of BPH multiple messages for EGF-R (similar to those described in the A431 line of malignant cells), overexpression of TGF-alpha, and evidence of the deletion of genes in the vicinity of 1Oq24. We shall investigate these and other markers to define differences that distinguish these entities from each other and to better understand the biological potentials of these entities.
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