Inoue Takahiro, Kobayashi Takashi, Terada Naoki, Shimizu Yosuke, Kamoto Toshiyuki, Ogawa Osamu, Nakamura Eijiro
a Department of Urology, University Graduate School of Medicine, Kyoto, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
b Department of Urology, University Graduate School of Medicine, Kyoto, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Expert Rev Endocrinol Metab. 2007 Sep;2(5):689-704. doi: 10.1586/17446651.2.5.689.
Prostate cancer is one of the most frequently diagnosed cancers in the western world and this malignant neoplasm is the second-leading cause of cancer death among men in the USA. In the early 1940s, Huggins and Hodges demonstrated that growth and survival of prostate cancer depends on androgens. The mainstay of treatment for advanced prostate cancer is currently androgen ablation. Over the past few decades, several compounds, such as luteinizing hormone-releasing hormone analogues and anti-androgens, were developed and widely used in clinics. Then, the new treatment strategy, maximum androgen blockade (MAB) was introduced. In fact, MAB improved the prognosis of patients with advanced prostate cancer to some extent; however, most of those patients finally relapse after a period of initial response to this therapy, developing androgen-independent prostate cancer (AIPC). Once patients develop AIPC, effective therapeutic modalities are extremely limited and, therefore, the prognosis of this disease is very poor. It is strongly desirable to explore novel therapeutic concepts for AIPC, based on detailed molecular mechanisms for progression to androgen independency. As for the molecular mechanisms involved in the emergence of AIPC, mutations in the androgen receptor have been examined most extensively. These days, evidence is accumulating that demonstrates activation of signal transduction pathways, such as Src, PI3K and mTOR/S6K, are involved in the acquisition of the androgen-independent cell proliferation of prostate cancer cells. In addition, animal models using transgenic and gene-knockout techniques have confirmed these results. The development of therapies targeting against the signal transduction pathways is critical for the improvement of the prognosis of patients with AIPC. In this article, we review recent understandings on molecular mechanisms of androgen-dependent proliferation of prostate cancer cells, whose aberrant activation is proposed as a critical event for progression to AIPC.
前列腺癌是西方世界最常被诊断出的癌症之一，这种恶性肿瘤是美国男性癌症死亡的第二大原因。20世纪40年代初，哈金斯和霍奇斯证明前列腺癌的生长和存活依赖于雄激素。目前，晚期前列腺癌治疗的主要方法是雄激素去除。在过去几十年中，开发了几种化合物，如促黄体激素释放激素类似物和抗雄激素，并在临床上广泛使用。然后，引入了新的治疗策略——最大限度雄激素阻断（MAB）。事实上，MAB在一定程度上改善了晚期前列腺癌患者的预后；然而，大多数患者在对这种疗法产生初始反应一段时间后最终会复发，发展为去势抵抗性前列腺癌（AIPC）。一旦患者发展为AIPC，有效的治疗方式极其有限，因此，这种疾病的预后非常差。基于向去势抵抗进展的详细分子机制，迫切需要探索针对AIPC的新治疗理念。至于AIPC出现所涉及的分子机制，雄激素受体的突变已得到最广泛的研究。如今，越来越多的证据表明，信号转导通路如Src、PI3K和mTOR/S6K的激活参与了前列腺癌细胞去势抵抗性细胞增殖的获得。此外，使用转基因和基因敲除技术的动物模型证实了这些结果。针对信号转导通路开发治疗方法对于改善AIPC患者的预后至关重要。在本文中，我们综述了关于前列腺癌细胞雄激素依赖性增殖分子机制的最新认识，其异常激活被认为是向AIPC进展的关键事件。
