ALTERED GROWTH-REGULATION OF PROSTATIC EPITHELIAL-CELLS BY HUMAN PAPILLOMAVIRUS-INDUCED TRANSFORMATION

Six lines of human papillomavirus (HPV)-transformed prostatic epitheli al cells, clonally-derived from transfection of three different parent al cell strains, were analyzed for their ability to respond to stimula tory and inhibitory factors known to regulate prostatic cell growth. T he cell lines were tested in a serum-free medium that was developed sp ecifically for analysis of low-density growth of prostatic cells in or der to mitigate any effects of autocrine factors. This medium has been used previously to characterize the growth regulatory pathways of pri mary cultures of prostatic epithelial cells derived from normal, benig n prostatic hyperplasia (BPH), or adenocarcinoma tissues, as well as a n SV40-transformed cell line (pRNS-1-1) that was derived from the same parental cell strain as four of the HPV-transformed lines used in the present study. The responses of the HPV-transformed cell lines to thr ee essential mitogens in the medium - epidermal growth factor (EGF), b ovine pituitary extract (BPE) and insulin-like growth factor (IGF) - w ere similar to those of primary cultures and pRNS-1-1, except that two of the HPV-transformed cell lines were IGF-independent for growth. Th e presence or absence of cholera toxin (CT), which acts synergisticall y with peptide growth factors, only mildly affected the proliferation of HPV-transformed cells, which is also true for primary cultures and pRNS-1-1. However, while hydrocortisone (HC) also has only minimal eff ect on the growth of primary cultures and pRNS-1-1, four of the HPV-tr ansformed lines were very dependent on HC for growth. With regard to g rowth-inhibitory factors, all of the cell lines (HPV- or SV40- transfo rmed) were insensitive to tumor necrosis factor-alpha (TNFalpha), whic h is a common feature of transformed cells. However, the cell lines re mained sensitive to the growth-inhibitory properties of retinoic acid (RA) and transforming growth factor-beta (TGF(beta)). The HPV-transfor med cell lines were also inhibited by 1,25(OH)(2) vitamin D-3 [1,25(OH )(2)D-3], although pRNS-1-1 cells were not. Perhaps the most unexpecte d finding in our study was the apparent loss of responsiveness of all of the transformed lines to fibroblast growth factor (FGF). Alteration s in FGF pathways have been described for prostatic cancer cell lines and changes in expression of FGF or receptors may be involved in prost atic carcinogenesis. Our study demonstrates that the availability of p rimary cultures, SV40- and HPV- transformed cell lines and a well-defi ned culture system will provide an opportunity to characterize the pro cesses involved in malignant transformation of prostatic cells.