Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1738, USA.
Prostate. 2013 Sep;73(13):1378-90. doi: 10.1002/pros.22685. Epub 2013 May 31.
Prostate cancer stem cells (PCSC) offer theoretical explanations to many clinical and biological behaviors of the disease in human. In contrast to approaches of using side populations and cell-surface markers to isolate and characterize the putative PCSC, we hypothesize that androgen deprivation leads to functional enrichment of putative PCSC.
Human prostate cancer lines LNCaP, LAPC4 and LAPC9 were depleted of androgen in cell cultures and in castrated SCID mice. The resultant androgen deprivation-resistant or castration-resistant populations, in particular in LNCaP and its derivative cell lines, displayed increased expression of pluripotency transactivators and significantly higher tumorigenicity. Individual tumor cell clones were isolated from castration-resistant bulk cultures of LNCaP (CR-LNCaP) and tested for tumorigenicity in male SCID mice under limiting dilution conditions. As few as 200 cells were able to form spheres in vitro, and generate tumors with similar growth kinetics as 10(6) LNCaP or 10(4) CR-LNCaP cells in vivo. These putative PCSC were CD44(+) /CD24(-) and lack the expression of prostate lineage proteins. When transplanted into the prostate of an intact male SCID mouse, these putative PCSC seemed to show limited differentiation into Ck5(+) , Ck8(+) , Ck5(+) /Ck8(+) , and AR(+) cells. On the other hand, stable transduction of LNCaP with retrovirus encoding Sox2 led to androgen-deprivation resistant growth and down-regulation of major prostate lineage gene products in vitro.
Concurrence of overexpression of pluripotency transactivators and resistance to androgen deprivation supported the role of putative PCSC in the emergence of prostate cancer resistant to androgen deprivation.
前列腺癌干细胞（PCSC）为人类前列腺癌的许多临床和生物学行为提供了理论解释。与使用侧群和细胞表面标志物来分离和鉴定推测的 PCSC 的方法不同，我们假设雄激素剥夺导致推测的 PCSC 的功能富集。
在细胞培养和去势 SCID 小鼠中，人前列腺癌细胞系 LNCaP、LAPC4 和 LAPC9 被耗尽雄激素。由此产生的雄激素剥夺抗性或去势抗性群体，特别是在 LNCaP 及其衍生细胞系中，显示出多能转录因子的表达增加，并具有明显更高的致瘤性。从去势抗性 LNCaP （CR-LNCaP）的 bulk 培养物中分离单个肿瘤细胞克隆，并在雄性 SCID 小鼠中进行致瘤性测试，采用有限稀释条件。在体外，少至 200 个细胞能够形成球体，并在体内产生与 10（6）个 LNCaP 或 10（4）个 CR-LNCaP 细胞相似生长动力学的肿瘤。这些推测的 PCSC 是 CD44（+）/CD24（-），缺乏前列腺谱系蛋白的表达。当将这些推测的 PCSC 移植到完整雄性 SCID 小鼠的前列腺中时，它们似乎显示出向 Ck5（+）、Ck8（+）、Ck5（+）/Ck8（+）和 AR（+）细胞的有限分化。另一方面，逆转录病毒编码 Sox2 稳定转导 LNCaP 导致体外雄激素剥夺抗性生长和主要前列腺谱系基因产物的下调。
多能转录因子的过度表达和对雄激素剥夺的抗性的并存支持了推测的 PCSC 在雄激素剥夺抵抗的前列腺癌发生中的作用。
