INCIDENCE OF APOPTOSIS AND CELL-PROLIFERATION IN PROSTATE-CANCER - RELATIONSHIP WITH TGF-BETA(1) AND BCL-2 EXPRESSION

The incidence of programmed cell death (apoptosis) and cell proliferat ion was investigated in the normal and malignant human prostate to def ine the significance of their potential deregulation in human prostate cancer. The incidence of ''spontaneous'' apoptosis was analyzed using an in situ end-labeling procedure for detection of nucleosomal DNA fr agmentation, as well as the pattern and topological localization of ex pression of the 2 proteins regulating apoptosis, TGF-beta(1) and bcl-2 , in 40 primary prostatic adenocarcinomas with varying tumor grades, 1 7 lymph nodes positive for metastatic prostate cancer and 9 normal pro state specimens. The basal level of cell proliferation of the differen t prostatic cell populations in the same specimens was determined, uti lizing the Ki-67 nuclear antigen. Localized prostate cancer cells exhi bited a relatively low rate of apoptosis, which was significantly lowe r than the apoptotic index of normal prostate glandular epithelial cel ls. Metastatic prostate tumor cells, however, exhibited a significantl y higher apoptotic index compared with localized prostate cancer cells . A significant increase in the proliferative index was detected in pr astatic tumors compared with the normal gland (5-fold), and there was an even more marked elevation in the proliferative index of the metast atic prostate tumor cells compared to the normal prostate epithelial c ells (approximately 24-fold). Immunohistochemical analysis of normal a nd malignant prostate specimens revealed a predominant TGF-beta immuno reactivity in the glandular epithelial cells, while the stromal compon ent was totally negative. There was a significant increase in the leve ls of TGF-beta in primary prostatic tumors compared to the normal pros tate. Bcl-2 expression was detected among certain populations of tumor epithelial cells in a mutually exclusive topological distribution pat tern for apoptosis. In marked contrast, neither TGF-beta(1) nor bcl-2 immunoreactivity was detected in metastatic prostate tumor cells, desp ite their high proliferative and apoptotic rates. Balancing the prosta tic growth equation for the prostatic tumor epithelial cell population s revealed a substantial net increase in cell number in both primary a nd metastatic prostate cancers. This loss of apoptotic control in favo r of cell proliferation may be responsible for prostate cancer initiat ion and progression. (C) 1996 Wiley-Liss, Inc.