Adenocarcinoma of the prostate exhibits a marked propensity to metastasize to the skeleton, where it commonly produces osteoblastic rather than osteolytic lesions. Such lesions appear to be due to increased osteoblast numbers and activity. We have identified apparently unique growth factors for cells of the osteoblast phenotype in freshly isolated human prostatic cancer as well as in benign prostatic hyperplasia. Similar activity was present in normal pre-pubertal but not post-pubertal prostate suggesting androgen dependence. Migogenic acivity was demonstrabel in fetal rat calvarial osteoblasts and in osteoblast- derived osteosarcoma cells, but not in fetal rat skin fibroblasta. Mitogens enhanced alkaline phosphatase activity in osteoblast-like cells. The proposed studies are directed at completing the chemical characterization of the peptides by cloning and sequencing cDNAs encoding the prostatic factors. Sites of non- prostatic tissue production will be determined in human and rat tissues by Northern analysis of extracted poly A + mRNA and by in situ hybridization. Regulation of gene expression by gonadal steroids will be examined in cell cultures of normal, hyperplastic and neoplastic human prostatic tissue and, if appropriate, in transplantable rat models of prostatic adenocarcinoma. The specificity of the mitogenic effects for osteoblasts will be explored in detail and the influences of the factors on other parameters of osteoblasts function (synthesis of type I collagen and production of osteocalcin) will be determined. Monoclonal and polyclonal antibodies will be generated for immunoblotting, immunoneutralization and radioimmunassay studies and in vivo receptor binding studies will be performed to localize cellular skeletal and non-skeletal sites of action. The studies therefore seek to examine the mechanisms whereby metastatic prostatic adenocarcinoma alters skeletal function and aim to characterization growth factors derived from gonadal steroid- dependent tissues, which may mediate effects on the skeleton.
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