Berges R R, Vukanovic J, Epstein J I, CarMichel M, Cisek L, Johnson D E, Veltri R W, Walsh P C, Isaacs J T
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Clin Cancer Res. 1995 May;1(5):473-80.
The daily percentage of cells proliferating and dying were determined for normal, premalignant, and cancerous prostatic cells within the prostate as well as for prostatic cancer cells in lymph node, soft tissue, and bone metastases from untreated and hormonally failing patients. These data demonstrate that normal prostatic glandular cells have an extremely low but balanced rate of cell proliferation and death (i.e., both <0.20%/day). This results in a steady-state, self-renewing condition in which there is no net growth, although the glandular cells are continuously being replaced (i.e., turnover) every 500 +/- 79 days. Transformation of these cells into high-grade prostatic intraepithelial neoplastic cells initially involves an unbalanced increase in the daily percentage of cells proliferating versus dying, such that net continuous growth occurs (i.e., mean doubling time, 154 +/- 22 days). As these early proliferation lesions continue to grow into late stage high-grade prostatic intraepithelial neoplastic cells, the daily percentage of cells dying increases further to a point equaling the daily percentage of proliferation. This results in cessation of net growth while inducing a 6-fold increase in the turnover time of these cells (i.e., 56 +/- 12 days), increasing their risk of further genetic changes. The transition of late stage high-grade prostatic intraepithelial neoplastic cells into localized prostatic cancer cells involves no further increase in proliferation but a decrease in death resulting in net continuous growth of localized prostatic cancers with a mean doubling time of >/=475 days. As compared to localized prostatic cancer cells, metastatic prostatic cancer cells within lymph nodes or bones of untreated patients have an increase in daily rate of proliferation coupled with a reduction in their daily percentage of cell death, producing net growth rates with a mean doubling time of 33 +/- 4 days and 54 +/- 5 days, respectively. Remarkably, there is no further increase in proliferation in hormonally failing patients, but instead an increase in the daily percentage of androgen-independent prostatic cancer cells dying within soft tissue or bone metastases. These changes result in doubling times which are two to three times longer (i.e., 126 +/- 21 and 94 +/- 15 days) in these lymph node and bone metastatic sites, respectively, compared to similar sites in hormonally untreated patients. These data demonstrate that the daily percentage of proliferation for either androgen-dependent or -independent metastatic prostatic cancer cells is remarkably low (i.e., <3. 0%/day), consistent with why antiproliferative chemotherapy has been of such limited value against such metastatic cells. These results also suggest that prostatic carcinogenesis starts in the second to third decade of life and may require over 50 years for progression to pathologically detectable metastatic disease.
测定了前列腺内正常、癌前和癌性前列腺细胞以及未经治疗和激素治疗失败患者的淋巴结、软组织和骨转移灶中前列腺癌细胞的每日增殖和死亡细胞百分比。这些数据表明，正常前列腺腺细胞的细胞增殖和死亡率极低但保持平衡（即均<0.20%/天）。这导致一种稳态的自我更新状态，尽管腺细胞每500±79天持续更新（即周转），但没有净生长。这些细胞转化为高级别前列腺上皮内瘤变细胞最初涉及增殖细胞与死亡细胞的每日百分比失衡增加，从而发生持续净生长（即平均倍增时间为154±22天）。随着这些早期增殖性病变继续发展为晚期高级别前列腺上皮内瘤变细胞，每日死亡细胞百分比进一步增加至与每日增殖百分比相等的程度。这导致净生长停止，同时这些细胞的周转时间增加6倍（即56±12天），增加了它们发生进一步基因变化的风险。晚期高级别前列腺上皮内瘤变细胞向局限性前列腺癌细胞的转变不涉及增殖的进一步增加，而是死亡减少，导致局限性前列腺癌持续净生长，平均倍增时间≥475天。与局限性前列腺癌细胞相比，未经治疗患者的淋巴结或骨中的转移性前列腺癌细胞每日增殖率增加，同时每日细胞死亡率百分比降低，产生的净生长率平均倍增时间分别为33±4天和54±5天。值得注意的是，激素治疗失败患者的增殖没有进一步增加，而是软组织或骨转移灶中雄激素非依赖性前列腺癌细胞的每日死亡百分比增加。这些变化导致这些淋巴结和骨转移部位的倍增时间分别比未经激素治疗患者的相似部位长两到三倍（即126±21天和94±15天）。这些数据表明，雄激素依赖性或非依赖性转移性前列腺癌细胞的每日增殖百分比极低（即<3.0%/天），这与抗增殖化疗对这类转移细胞价值有限的原因一致。这些结果还表明，前列腺癌发生始于生命的第二个至第三个十年，可能需要超过50年才能进展为病理上可检测到的转移性疾病。
