Prostate cancer is the most common cancer among American men and African American men have the highest incidence of any population in the world. Three percent of all deaths in men over 50 years old are attributed to prostate cancer, an estimated 33,000 in 1991. As the population ages, the number of patients will increase steadily over the next decade. Yet prostate cancer is unique among the potentially lethal human malignancies in the wide discrepancy between the high prevalence of histologic changes recognizable as cancer (""""""""latent cancer"""""""") and the much lower prevalence of the clinically recognizable disease (""""""""clinical cancer"""""""") (see Spore Program Description Section II.A.2., Introduction. Fig. 1, Multistep Progression of Human Prostate Cancer). Tests are available to detect prostate cancer early: digital rectal examination, prostate specific antigen, and transrectal ultrasonography. Yet physicians are uncertain about the clinical importance of some cancers detected with such techniques. These cancers are usually low grade and low stage and there are no objective markers able to distinguish stable from unstable latent cancers or to predict the rate of progression of the cancer -- the prognosis of the patient -- so that appropriate intervention can be recommended. We propose to identify effective markers of progression in human prostate cancer by analyzing the pathologic features (stage, grade, zone of origin, extraprostatic spread), the DNA ploidy value, and the presence and distribution in tissue sections of a panel of interrelated markers (the growth control gene products TGF-beta1, p53, c-myc and RB; and the fibronectin-like mesenchymal marker tenascin) in prostate cancers found in: (1) radical prostatectomy specimens from patients with early stage clinical prostate cancer; and, (2) prostates removed during cystoprostatectomy for bladder cancer. Studies in the mouse prostate reconstitution model of prostate cancer [1,2], supported by preliminary data in human prostate cancer [3], suggest that increased expression of transforming growth factor-beta (TGF-beta1) may serve as an early marker of progression. Absence of the retinoblastoma (RB) gene product allows unsuppressed growth in a human prostate cancer cell line [4] and our preliminary studies show a discordance of RB staining and histologic grade. The presence and location of these markers in human prostate cancers will be determined by immunohistochemistry using specific antibodies. Whole mount prostatectomy specimens from the 2 sources listed above will allow us to correlate the expression of these markers with the detailed pathologic features and DNA ploidy of each cancer, and to compare these features in rapid vs. slow (or non-) progressors in our large patient population in order to determine whether any one or a combination of the markers in our panel can be used as objective markers of progression predictive of the biological behavior of the tumor.
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