CHANGES IN BIOMARKER EXPRESSION IN THE DEVELOPMENT OF PROSTATIC ADENOCARCINOMA

In spite of the prevalence of prostatic adenocarcinoma, the developmen t and natural history of this malignancy is poorly understood. This pa per reviews the current knowledge of biomarker expression during the d evelopment and progression of prostatic adenocarcinoma. Emphasis is pl aced on the comparison of biomarker expression in benign prostatic epi thelium, intraepithelial neoplasia (PIN), a putative preinvasive lesio n, and prostatic adenocarcinoma, Within the benign epithelium, the pro liferative potential is restricted to the basal cells as demonstrated by the expression of proliferating cellular nuclear antigen [PCNA]. Th e strong expression of the bcl-2 protein, an inhibitor of apoptosis, s upports the concept that the basal cells or a subpopulation of the bas al cells represent the stem cell of the epithelium. In addition, the s trong expression of growth factor receptors such as the epidermal grow th factor receptor (EGFr), p185(erbB-2), p180(erbB-3), and c-met sugge sts that the growth of the basal cells is regulated by autocrine or pa racrine factors. The luminal cells express secretory products such as prostate specific antigen and prostatic acid phosphatase, but demonstr ate little expression of PCNA as well as growth factor receptors and p roto-oncogene products, These observations are consistent with the the ory that the luminal cell population is derived from the differentiati on of the basal cells. In contrast to the normal epithelium, PCNA expr ession is frequently detected in the dysplastic luminal cells of the P IN lesion. Likewise, strong expression of p185(erbB-2), p180(erbB-3) a nd the c-met proto-oncogene product is also detected in the luminal ce lls of PIN lesions. Other factors which are strongly expressed by the dysplastic luminal cells include the nm23-H1 gene product, tumor assoc iated glycoprotein-72 (TAG-72), fatty acid synthetase (FASE) and prote olytic enzymes. These findings suggest that PIN lesions are derived fr om an impairment of the differentiation of basal cells, The majority o f biomarkers such as PCNA, p185(erbB-2), p180(erbB-3), TAG-72, nm23-H1 and EASE which we strongly expressed in PIN lesions are also expresse d in prostatic adenocarcinoma supporting the concept that PIN is a pre invasive lesion, Mutations of the p53 tumor suppressor gene, as well a s strong expression of transforming growth factor alpha and bcl-2 typi cally occur in advanced stage prostatic adenocarcinomas and therefore likely represent late events in the development of prostatic adenocarc inoma.