Tu H, Jacobs S C, Borkowski A, Kyprianou N
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Int J Cancer. 1996 Oct 21;69(5):357-63. doi: 10.1002/(SICI)1097-0215(19961021)69:5<357::AID-IJC1>3.0.CO;2-4.
The incidence of programmed cell death (apoptosis) and cell proliferation was investigated in the normal and malignant human prostate to define 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 fragmentation, as well as the pattern and topological localization of expression of the 2 proteins regulating apoptosis, TGF-beta1, and bcl-2, in 40 primary prostatic adenocarcinomas with varying tumor grades, 17 lymph nodes positive for metastatic prostate cancer and 9 normal prostate specimens. The basal level of cell proliferation of the different prostatic cell populations in the same specimens was determined, utilizing the Ki-67 nuclear antigen. Localized prostate cancer cells exhibited a relatively low rate of apoptosis, which was significantly lower than the apoptotic index of normal prostate glandular epithelial cells. Metastatic prostate tumor cells, however, exhibited a significantly higher apoptotic index compared with localized prostate cancer cells. A significant increase in the proliferative index was detected in prostatic tumors compared with the normal gland (5-fold), and there was an even more marked elevation in the proliferative index of the metastatic prostate tumor cells compared to the normal prostate epithelial cells (approximately 24-fold). Immunohistochemical analysis of normal and malignant prostate specimens revealed a predominant TGF-beta immunoreactivity in the glandular epithelial cells, while the stromal component was totally negative. There was a significant increase in the levels of TGF-beta in primary prostatic tumors compared to the normal prostate. Bcl-2 expression was detected among certain populations of tumor epithelial cells in a mutually exclusive topological distribution pattern for apoptosis. In marked contrast, neither TGF-beta1 nor bcl-2 immunoreactivity was detected in metastatic prostate tumor cells, despite their high proliferative and apoptotic rates. Balancing the prostatic growth equation for the prostatic tumor epithelial cell populations revealed a substantial net increase in cell number in both primary and metastatic prostate cancers. This loss of apoptotic control in favor of cell proliferation may be responsible for prostate cancer initiation and progression.
为明确程序性细胞死亡（凋亡）和细胞增殖在人类前列腺癌中潜在失调的意义，我们对正常和恶性人类前列腺组织中的这两种现象进行了研究。我们采用原位末端标记法检测核小体DNA片段化，分析了40例不同肿瘤分级的原发性前列腺腺癌、17例前列腺癌转移阳性淋巴结及9例正常前列腺标本中“自发性”凋亡的发生率，以及调节凋亡的两种蛋白TGF-β1和bcl-2的表达模式及拓扑定位。利用Ki-67核抗原测定相同标本中不同前列腺细胞群体的基础细胞增殖水平。局限性前列腺癌细胞的凋亡率相对较低，显著低于正常前列腺腺上皮细胞的凋亡指数。然而，与局限性前列腺癌细胞相比，转移性前列腺肿瘤细胞的凋亡指数显著更高。与正常腺体相比，前列腺肿瘤的增殖指数显著增加（5倍），与正常前列腺上皮细胞相比，转移性前列腺肿瘤细胞的增殖指数升高更为明显（约24倍）。对正常和恶性前列腺标本的免疫组织化学分析显示，腺上皮细胞中TGF-β免疫反应性占主导，而基质成分完全阴性。与正常前列腺相比，原发性前列腺肿瘤中TGF-β水平显著升高。在某些肿瘤上皮细胞群体中检测到bcl-2表达，其凋亡的拓扑分布模式相互排斥。与之形成鲜明对比的是，尽管转移性前列腺肿瘤细胞具有高增殖率和凋亡率，但未检测到TGF-β1和bcl-2免疫反应性。对前列腺肿瘤上皮细胞群体的前列腺生长平衡方程进行分析发现，原发性和转移性前列腺癌中的细胞数量均有显著净增加。这种有利于细胞增殖的凋亡控制丧失可能是前列腺癌发生和进展的原因。
