The role of the androgen receptor in the development and progression of prostate cancer.
The role of the androgen receptor in the development and progression of prostate cancer.
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作者：
G. Jenster
雄激素对前列腺的发育、生长和维持至关重要。它们通过细胞内雄激素受体（AR）发挥作用，雄激素受体是一种依赖配体的转录激活因子。与正常前列腺发育的情况一样，原发性前列腺癌在很大程度上依赖于雄激素的生长和生存。大多数患者对雄激素消融和抗雄激素治疗反应良好，这已成为转移性疾病的标准治疗方法。然而，几乎所有的患者都会复发为临床定义的雄激素非依赖性癌症。这一现象提出了一个问题：癌细胞是如何在低雄激素环境下存活和生长的？细胞可以采取的两种适应途径是：(1)绕过AR途径和(2)使AR途径敏感。在接受激素治疗的前列腺肿瘤患者中观察到的大量AR异常表明，许多细胞使AR通路敏感或改变。为了在低雄激素环境下继续激活这一途径，细胞可以(1)使AR发生突变，使其被不同的类固醇混合激活，(2)放大AR，(3)通过生长因子和细胞因子以不依赖配体的方式激活AR，或(4)放大共激活因子。或者，失去AR表达的前列腺癌细胞必须绕过AR途径。癌基因的激活和自分泌生长因子的刺激是可能导致完全雄激素独立的两种机制。从所有关于前列腺癌中AR功能的研究来看，AR在癌症的发生发展中起着重要的作用。此外，AR通路在临床上定义的雄激素非依赖型前列腺癌患者的大多数细胞中仍然很重要。
Androgens are essential for the development, growth, and maintenance of the prostate. They exert their effects via the intracellular androgen receptor (AR), which is a ligand-dependent transcription activator. As is the case with normal prostate development, primary prostatic cancers are largely dependent on androgens for growth and survival. Most patients respond favorably to androgen ablation and antiandrogen therapy, which has become a standard treatment of metastatic disease. However, virtually all patients will relapse with clinically defined androgen-independent cancer. This phenomenon raises the question of how cancer cells survive and grow in the low androgen environment? Two of the routes cells can take to adapt are (1) bypassing and (2) sensitizing the AR pathway. The vast numbers of AR abnormalities observed in prostate tumors from patients treated with hormonal therapy suggest that many cells sensitize or change the AR pathway. To continue to activate this pathway in a low androgen environment, cells can (1) mutate the AR to become promiscuously activated by different steroids, (2) amplify the AR, (3) activate the AR in a ligand-independent manner by growth factors and cytokines, or (4) amplify coactivators. Alternatively, prostate cancer cells that have lost AR expression must have bypassed the AR pathway. Activation of oncogenes and autocrine growth factor stimulation are two mechanisms that likely contribute to becoming completely androgen-independent. From all the studies on AR function in prostate cancer, it is clear that the AR plays an important role in cancer development and progression. Moreover, the AR pathway remains important in most cells from patients with clinically defined androgen-independent prostate cancer.