Gingrich J R, Barrios R J, Kattan M W, Nahm H S, Finegold M J, Greenberg N M
Scott Department of Urology, Texas Children's Hospital, Houston 77030, USA.
Cancer Res. 1997 Nov 1;57(21):4687-91.
We previously established the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model to facilitate characterization of molecular mechanisms involved in the initiation and progression of prostate cancer. TRAMP mice display high grade prostatic intraepithelial neoplasia or well-differentiated prostate cancer by 10-12 weeks of age. To test the hypothesis that molecular events leading to androgen independence and metastasis can occur early in the natural history of prostate cancer yet remain silent until selective pressures such as androgen deprivation are applied, we have examined the consequences of castration on the initiation and progression to metastatic prostate cancer in TRAMP mice. Cohorts were castrated at 12 weeks of age and sacrificed at 18 (T12/18) or 24 (T12/24) weeks of age, and the development of primary cancer and metastatic disease was compared to noncastrated (T18 and T24) controls. Median T12/18 and T12/24 genitourinary (GU) weight was significantly less than T18 and T24, respectively. In addition, T12/24 GU weight was significantly greater than T12/18. Histological prostate tumors developed in 3 of 7 T12/18 and 8 of 10 T12/24 mice. All tumors that developed in castrated mice were poorly differentiated in contrast to 27% in noncastrated controls. Although castration significantly decreased GU tumor burden, overall progression to poorly differentiated and metastatic disease was not ultimately delayed. These results demonstrate that prostate cancer in the TRAMP model is heterogeneous with respect to androgen dependence as early as 12 weeks of age; therefore, early androgen ablation may have a variable impact on progression in an individual mouse. Further analysis of this prostate cancer model to identify specific molecular mechanisms that determine androgen sensitivity may facilitate future initiation of appropriate individualized hormonal therapy for the management of human prostate cancer.
我们先前建立了自发性转基因腺癌小鼠前列腺（TRAMP）模型，以促进对前列腺癌发生和发展过程中涉及的分子机制的表征。TRAMP小鼠在10至12周龄时会出现高级别前列腺上皮内瘤变或高分化前列腺癌。为了验证导致雄激素非依赖性和转移的分子事件可能在前列腺癌自然病程早期就已发生，但在诸如雄激素剥夺等选择性压力施加之前仍保持沉默这一假设，我们研究了去势对TRAMP小鼠前列腺癌发生和发展至转移性前列腺癌的影响。将小鼠在12周龄时去势，并在18周龄（T12/18）或24周龄（T12/24）时处死，将原发性癌和转移性疾病的发展情况与未去势（T18和T24）对照组进行比较。T12/18和T12/24组泌尿生殖系统（GU）的中位重量分别显著低于T18和T24组。此外，T12/24组的GU重量显著大于T12/18组。7只T12/18小鼠中有3只以及10只T12/24小鼠中有8只出现了组织学前列腺肿瘤。与未去势对照组的27%相比，去势小鼠中发生的所有肿瘤均为低分化。尽管去势显著降低了GU肿瘤负荷，但最终并未延迟至低分化和转移性疾病的总体进展。这些结果表明，TRAMP模型中的前列腺癌早在12周龄时就雄激素依赖性而言具有异质性；因此，早期雄激素消融对个体小鼠的进展可能产生可变影响。对该前列腺癌模型进行进一步分析以确定决定雄激素敏感性的特定分子机制，可能有助于未来启动适当的个体化激素疗法来治疗人类前列腺癌。
