Maitland Norman J
Department of Biology, University of York, Heslington, York YO10 5DD, UK.
Cancers (Basel). 2021 Jan 17;13(2):327. doi: 10.3390/cancers13020327.
Increasingly sophisticated therapies for chemical castration dominate first-line treatments for locally advanced prostate cancer. However, androgen deprivation therapy (ADT) offers little prospect of a cure, as resistant tumors emerge rather rapidly, normally within 30 months. Cells have multiple mechanisms of resistance to even the most sophisticated drug regimes, and both tumor cell heterogeneity in prostate cancer and the multiple salvage pathways result in castration-resistant disease related genetically to the original hormone-naive cancer. The timing and mechanisms of cell death after ADT for prostate cancer are not well understood, and off-target effects after long-term ADT due to functional extra-prostatic expression of the androgen receptor protein are now increasingly being recorded. Our knowledge of how these widely used treatments fail at a biological level in patients is deficient. In this review, I will discuss whether there are pre-existing drug-resistant cells in a tumor mass, or whether resistance is induced/selected by the ADT. Equally, what is the cell of origin of this resistance, and does it differ from the treatment-naïve tumor cells by differentiation or dedifferentiation? Conflicting evidence also emerges from studies in the range of biological systems and species employed to answer this key question. It is only by improving our understanding of this aspect of treatment and not simply devising another new means of androgen inhibition that we can improve patient outcomes.
日益复杂的化学去势疗法主导着局部晚期前列腺癌的一线治疗。然而，雄激素剥夺疗法（ADT）几乎没有治愈的希望，因为耐药肿瘤出现得相当迅速，通常在30个月内。细胞对即使是最复杂的药物治疗方案也有多种耐药机制，前列腺癌中的肿瘤细胞异质性和多种挽救途径都会导致与最初的激素未治疗癌症在基因上相关的去势抵抗性疾病。前列腺癌ADT后细胞死亡的时间和机制尚不清楚，由于雄激素受体蛋白在前列腺外功能性表达导致的长期ADT后的脱靶效应现在越来越多地被记录下来。我们对这些广泛使用的治疗方法在患者体内如何在生物学水平上失效的了解不足。在这篇综述中，我将讨论肿瘤块中是否存在预先存在的耐药细胞，或者耐药性是否由ADT诱导/选择。同样，这种耐药性的起源细胞是什么，它在分化或去分化方面是否与未接受治疗的肿瘤细胞不同？在用于回答这个关键问题的一系列生物系统和物种的研究中也出现了相互矛盾的证据。只有通过提高我们对治疗这一方面的理解，而不是简单地设计另一种新的雄激素抑制方法，我们才能改善患者的治疗效果。
