Department of Urology and Cancer Center, University of California School of Medicine at Davis, Sacramento, CA 95817, USA.
Future Oncol. 2009 Nov;5(9):1403-13. doi: 10.2217/fon.09.117.
Hormone-refractory prostate cancer is the result of regrowth of prostate cancer cells that have adapted to the hormone-deprived environment of the prostate. The process by which castration-resistant prostate cancer (CRPC) cells are generated appears to be varied. The complex mechanism of hormone resistance has been the topic of research in most laboratories that have analyzed the process from different angles. This review compiles research findings that explain the methods of development of hormone resistance in prostate cancer. Research data show many different processes to be involved in the acquisition of hormone resistance. Interestingly, one observes interdependence between these processes, indicating a complex network at play in the development of hormone resistance. Cytokines such as IL-6 have been shown to initiate an alternative signaling pathway, compared with the androgen receptor signaling pathway, in CRPC. IL-6 has been proposed to be the effector of the intracrine signaling pathway by influencing the levels of metabolic enzymes. Neuroendocrine cells are present at low levels in normal prostate, and signify the transitory phase of normal hormone-sensitive cells to hormone-refractory cells. IL-6 induces growth of neuroendocrine cells or neuroendocrine-like features in cells in CRPC. The increased presence of neuroendocrine cells in CRPC signifies a change in the prostate cell microenvironment. The stromal microenvironment also influences the development of CRPC in the hormone-refractory stage. In addition, intracrine androgen metabolic enzymes play a significant role in the development of the hormone refractory process. Despite hormone ablation, there is a residual level of hormones in cells due to active intracrine metabolic pathways. It is acknowledged that the androgen receptor plays the most influential role in development of prostate cancer. In addition to mutation and amplification, the androgen receptor has been characterized and shown to differ in sequence in CRPC compared with the androgen-sensitive prostate cancer cells. These variants of the androgen receptor through sequence changes may preserve the basic function of the molecule, but have far-reaching consequences on the cell as a whole. A multicombinatorial drug treatment approach has been suggested to target these multiple pathways in an effort to reduce the possibility of recurrence of CRPC.
激素难治性前列腺癌是前列腺癌细胞在去势环境中适应的结果。产生去势抵抗性前列腺癌（CRPC）细胞的过程似乎多种多样。大多数分析该过程的实验室都从不同角度研究了激素抵抗的复杂机制，这是研究的主题。这篇综述汇编了一些研究结果，这些结果解释了前列腺癌中激素抵抗发展的方法。研究数据表明，许多不同的过程参与了激素抵抗的获得。有趣的是，人们观察到这些过程之间存在相互依存关系，这表明在激素抵抗的发展过程中存在着复杂的网络。研究表明，细胞因子如白细胞介素 6（IL-6）与雄激素受体信号通路相比，在 CRPC 中启动了另一种信号通路。IL-6 被提议通过影响代谢酶的水平成为细胞内信号通路的效应物。神经内分泌细胞在正常前列腺中含量较低，标志着正常激素敏感细胞向激素抵抗细胞的过渡阶段。IL-6 诱导 CRPC 中神经内分泌细胞或神经内分泌样特征的生长。CRPC 中神经内分泌细胞的增加表明前列腺细胞微环境发生了变化。基质微环境也会影响激素抵抗阶段 CRPC 的发展。此外，细胞内雄激素代谢酶在激素抵抗过程的发展中起着重要作用。尽管进行了激素消融，但由于活跃的细胞内代谢途径，细胞中仍存在残留的激素水平。人们认识到雄激素受体在前列腺癌的发展中起着最具影响力的作用。除了突变和扩增之外，雄激素受体在 CRPC 中与雄激素敏感的前列腺癌细胞相比，其序列也有所不同。这些雄激素受体的变体通过序列改变可能保留了分子的基本功能，但对整个细胞产生了深远的影响。有人建议采用多组合药物治疗方法，针对这些多个途径，以降低 CRPC 复发的可能性。
