文章：

雄激素非依赖性前列腺癌的发展

The development of androgen-independent prostate cancer

原文发布日期：2001-10-01

DOI: 10.1038/35094009

类型: Review Article

开放获取: 否

要点：

1. Androgen-independent prostate cancer (AIPC) is an untreatable form of prostate cancer in which the normal dependence on androgens for growth and survival has been bypassed. AIPC is selected for by androgen ablation therapy.
2. The potential mechanisms by which AIPC develops can be divided into five categories.
3. In the hypersensitive pathway, sensitivity to low circulating levels of androgen is increased by amplification of the androgen receptor (AR), mutations in the AR, increased levels of co-activators, or increased production of the potent androgen dihydrotestosterone. Tumours that use this mechanism continue to depend on both androgen and the AR.
4. By contrast, the promiscuous pathway bypasses the need for androgen (but not for AR) by broadening the specificity of the AR so that other steroid hormones — and even AR antagonists — can activate it.
5. Outlaw receptor pathways also bypass the need for androgen. In prostate cancer, outlaw receptors can be produced by crosstalk with growth factor signalling pathways, which lead to phosphorylation and activation of the AR in the absence of androgen.
6. Unlike the three pathways above, the bypass pathway is independent of AR. In this pathway, the pro-apoptotic mechanisms that are normally blocked by androgen are, instead, inhibited by a parallel mechanism such as upregulation of BCL2.
7. In the lurker cell pathway, it is proposed that malignant androgen- and AR-independent epithelial stem cells 'lurking' in the normal prostate become selected for by therapy.
8. By understanding which of these pathways is responsible for AIPC in individual patients, it might be possible to tailor therapies to each patient's needs, thereby outwitting the mechanisms that, so far, have made this disease intractable.

要点翻译：

1. 雄激素非依赖性前列腺癌（AIPC）是一种无法治愈的前列腺癌类型，其生长和存活不再依赖雄激素，这种特性是通过雄激素剥夺疗法筛选而来的。
2. AIPC的形成机制可分为五类。
3. 超敏通路中，通过雄激素受体（AR）扩增、AR突变、共激活因子水平升高或强效雄激素二氢睾酮产量增加，使癌细胞对低循环雄激素水平的敏感性增强。采用此机制的肿瘤仍依赖雄激素及AR。
4. 混杂通路则通过拓宽AR特异性，使其他类固醇激素甚至AR拮抗剂都能激活受体，从而规避对雄激素的需求（但仍需AR）。
5. 叛逆受体通路同样规避雄激素需求。在前列腺癌中，叛逆受体可通过生长因子信号通路串扰产生，导致AR在无雄激素状态下被磷酸化激活。
6. 与上述三种通路不同，旁路通路完全独立于AR。该通路中，原本由雄激素阻断的凋亡机制被平行机制（如BCL2上调）所抑制。
7. 潜藏细胞通路假说认为，正常前列腺中潜伏的恶性不依赖雄激素与AR的上皮干细胞，通过治疗被筛选激活。
8. 通过明确个体患者AIPC的具体通路机制，或可为其量身定制治疗方案，从而破解这一至今仍难以治愈疾病的耐药机制。

英文摘要：

The normal prostate and early-stage prostate cancers depend on androgens for growth and survival, and androgen ablation therapy causes them to regress. Cancers that are not cured by surgery eventually become androgen independent, rendering anti-androgen therapy ineffective. But how does androgen independence arise? We predict that understanding the pathways that lead to the development of androgen-independent prostate cancer will pave the way to effective therapies for these, at present, untreatable cancers.

摘要翻译： 

正常前列腺和早期前列腺癌的生长与存活依赖于雄激素，雄激素剥夺疗法可使其消退。未经手术治愈的癌症最终会转变为雄激素非依赖型，从而使抗雄激素治疗失效。但雄激素非依赖性是如何产生的？我们预测，理解导致雄激素非依赖性前列腺癌发展的信号通路，将为目前无法治愈的这类癌症开辟有效治疗途径。

原文链接：

The development of androgen-independent prostate cancer