Epithelial cell tumors of prostate in rat and man are both androgen- responsive and androgen-independent. Androgen-responsive tumors eventually evolve to the androgen-independent stage. Proliferation of epithelial cells from normal rat prostate is androgen-independent but requires direct- acting polypeptide growth factors [(cholera toxin, insulin, EGF, glucocorticoid and heparin-binding growth factors/""""""""prostatropins"""""""" (HBGF/PTR)]. Proliferation of epithelial cells from androgen-responsive rat tumors is also androgen-independent. However, proliferation still requires insulin, glucocorticoid and either EGF or HBGF/PTR, not both. In addition, tumor epithelial cells are independent on cholera toxin. In this project, the growth factor requirements for proliferation of epithelial cells from highly anaplastic, androgen-independent tumors will be compared to the above two cell types. The following parameters in normal epithelial cells and epithelial cells from both androgen-responsive and androgen-independent tumors will be compared: 1. Receptor binding kinetics and metabolism of HBGF/PTR using 125 I-HBGF/PTR as ligand. Antibody will be raised against the rat HBGF/PTR receptor to measure receptor antigen by immunochemical techniques. 2. Effect of androgen, cholera toxin, insulin, glucocorticoid, EGF and HBGF/PTR on HBGF/PTR and EGF receptor. 3. Expression of HBGF/PTR-like, EGF-like and insulin-like factors by mitogenic activity, radioreceptor assay and Northern analysis of mRNA levels by cDNA probes. The specific polypeptide gene product that accounts for the activity of known members of the prostate epithelial cell growth factor families will be isolated and characterized from relevant prostate tissue or conditioned medium from cultured cells expressing the activity. These results will determine whether alterations at the level of endogenous growth factor gene expression, growth factor receptor or the signal generated by growth factor-receptor coupling account for altered growth factor requirements in both androgen-responsive and androgen-independent prostate tumors. Lastly, the role of androgen on endogenous expression of growth factors and growth factor receptor characteristics will be determined to probe for alterations that may explain androgen-independence of isolated cells.
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