Amler L C, Agus D B, LeDuc C, Sapinoso M L, Fox W D, Kern S, Lee D, Wang V, Leysens M, Higgins B, Martin J, Gerald W, Dracopoli N, Cordon-Cardo C, Scher H I, Hampton G M
Genos Biosciences Incorporated, La Jolla, California 92037, USA.
Cancer Res. 2000 Nov 1;60(21):6134-41.
Treatment of metastatic prostate cancer with androgen-ablation often elicits dramatic tumor regressions, but the response is rarely complete, making clinical recurrence inevitable with time. To gain insight into therapy-related progression, changes in gene expression that occurred following androgen-deprivation of an androgen-dependent prostate tumor xenograft, CWR22, and the emergence of an androgen-independent tumor, CWR22-R, were monitored using microarray analysis. Androgen-deprivation resulted in growth arrest of CWR22 cells, as evidenced by decreased expression of genes encoding cell cycle components and basal cell metabolism, respiration and transcription, and the induced expression of putative negative regulatory genes that may act to sustain cells in a nonproliferative state. Evolution of androgen-independent growth and proliferation, represented by CWR22-R, was associated with a reentry into active cell cycle and the up-regulation of several genes that were expressed at low levels or absent in the androgen-dependent tumor. Androgen repletion to mice bearing androgen-independent CWR22-R tumors induced, augmented, or repressed the expression of a number of genes. Expression of two of these genes, the calcium-binding protein S100P and the FK-506-binding protein FKBP51, was decreased following androgen-deprivation, subsequently reexpressed in CWR22-R at levels comparable with CWR22, and elevated further upon treatment with androgens. The dysregulated behavior of these genes is analogous to other androgen-dependent genes, e.g., prostate-specific antigen and human kallikrein 2, which are commonly reexpressed in androgen-independent disease in the absence of androgens. Other androgen-responsive genes whose expression decreased during androgen-deprivation and whose expression remained decreased in CWR22 were also identified in CWR22-R. These results imply that evolution to androgen-independence is due, in part, to reactivation of the androgen-response pathway in the absence of androgens, but that this reactivation is probably incomplete.
用雄激素剥夺疗法治疗转移性前列腺癌通常会引发显著的肿瘤消退，但反应很少是完全的，随着时间的推移，临床复发不可避免。为了深入了解与治疗相关的进展，使用微阵列分析监测了雄激素依赖性前列腺肿瘤异种移植瘤CWR22雄激素剥夺后发生的基因表达变化以及雄激素非依赖性肿瘤CWR22-R的出现。雄激素剥夺导致CWR22细胞生长停滞，这表现为编码细胞周期成分以及基础细胞代谢、呼吸和转录的基因表达减少，以及可能作用于使细胞维持在非增殖状态的假定负调控基因的诱导表达。以CWR22-R为代表的雄激素非依赖性生长和增殖的演变与重新进入活跃细胞周期以及一些在雄激素依赖性肿瘤中低表达或不表达的基因的上调有关。给携带雄激素非依赖性CWR22-R肿瘤的小鼠补充雄激素会诱导、增强或抑制许多基因的表达。其中两个基因，即钙结合蛋白S100P和FK-506结合蛋白FKBP51，在雄激素剥夺后表达降低，随后在CWR22-R中重新表达，其水平与CWR22相当，并在用雄激素治疗后进一步升高。这些基因的失调行为类似于其他雄激素依赖性基因，例如前列腺特异性抗原和人激肽释放酶2，它们在雄激素非依赖性疾病中通常在没有雄激素的情况下重新表达。在CWR22-R中也鉴定出了其他在雄激素剥夺期间表达降低且在CWR22中表达仍降低的雄激素反应性基因。这些结果表明，向雄激素非依赖性的演变部分归因于在没有雄激素的情况下雄激素反应途径的重新激活，但这种重新激活可能是不完全的。
