THE EFFECT OF THE INSULIN-LIKE GROWTH-FACTOR SYSTEM HUMAN PROSTATE EPITHELIAL-CELLS OF IMMORTALIZATION AND TRANSFORMATION BY SIMIAN-VIRUS-40 T-ANTIGEN

The insulin-like growth factor (IGF) system has been demonstrated to b e important for proliferation and differentiation in tissues. This sys tem has also been demonstrated to be an important regulator of the gro wth of normal prostate epithelium and has been implicated in the proce ss of transformation to human epithelial prostate cancer. This study e xamined the function of the various components of the IGF system in be nign prostate epithelium (BPE), simian virus-40 (SV40)-T antigen-immor talized prostate epithelial cells, P69SV40-T (P69), and two sublines g enerated from the parental line by serial passage through athymic mice : one tumorigenic (M2182) and one metastatic (M12). IGF-II messenger r ibonucleic acid (mRNA) and protein were detected in BPE cells, and eac h of the three P69 cell lines. IGF-II protein levels were significantl y higher in medium collected from the P69, M2182, and M12 cells than i n BPE. Proliferation in response to IGF was P69 > BPE > M2182 > M12. T he proliferative responses in the four cell types were paralleled by a n increase in c-jun. In addition, as the cells became progressively mo re tumorigenic, the basal level of c-jun mRNA increased. IGF-binding p rotein-2 (IGFBP-2), -3, -4, -5, and -6 could be detected in the primar y epithelial cell medium; however, as the cells became progressively m ore tumorigenic, there was a decrease in IGFBP-2,- 3, -5, and -6 in th e medium. The type 1 IGF receptor (IGFr) also decreased as the cells b ecame more tumorigenic. The M12 cells had 80% fewer receptors than the P69 cells and 70% fewer than M2182 cells. There was no change in the K-d for IGF between the cell lines. Based on these data it would appea r that the difference in proliferation between the BPE cells and P69s may be due to an increased concentration of inhibitory IGFBPs in the P 69 medium. The decrease in proliferation seen in response to IGF in M2 182 and M12 cells compared to the P69s would appear at least in part t o be due to a decreased IGFr number. IGFr mRNA is represented by 11.0- and 7.0-kilobase bands in the BPE and P69 cells, but only by an 11.0- kilobase band in M2182 and M12 cells. These data indicate that there a re significant changes that occur in the IGF system during the process of malignant transformation of the prostate epithelium. The changes d escribed in the P69 cell system are similar to those seen in vivo and suggest that an intact IGF system may be important in maintaining a di fferentiated epithelial cell.