Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Cancer Cell. 2012 Sep 11;22(3):373-88. doi: 10.1016/j.ccr.2012.07.016.
Acquired resistance to Docetaxel precedes fatality in hormone-refractory prostate cancer (HRPC). However, strategies that target Docetaxel resistant cells remain elusive. Using in vitro and in vivo models, we identified a subpopulation of cells that survive Docetaxel exposure. This subpopulation lacks differentiation markers and HLA class I (HLAI) antigens, while overexpressing the Notch and Hedgehog signaling pathways. These cells were found in prostate cancer tissues and were related to tumor aggressiveness and poor patient prognosis. Notably, targeting Notch and Hedgehog signaling depleted this population through inhibition of the survival molecules AKT and Bcl-2, suggesting a therapeutic strategy for abrogating Docetaxel resistance in HRPC. Finally, these cells exhibited potent tumor-initiating capacity, establishing a link between chemotherapy resistance and tumor progression.
在激素难治性前列腺癌（HRPC）中，获得性多西紫杉醇耐药性先于死亡。然而，针对多西紫杉醇耐药细胞的策略仍然难以捉摸。通过体外和体内模型，我们鉴定出了在多西紫杉醇暴露下存活的细胞亚群。这群细胞缺乏分化标志物和 HLA Ⅰ类（HLAI）抗原，同时过度表达 Notch 和 Hedgehog 信号通路。这些细胞存在于前列腺癌组织中，与肿瘤侵袭性和患者预后不良有关。值得注意的是，通过抑制生存分子 AKT 和 Bcl-2 来靶向 Notch 和 Hedgehog 信号通路，耗尽了这一群体，这表明在 HRPC 中消除多西紫杉醇耐药性的一种治疗策略。最后，这些细胞表现出强大的肿瘤起始能力，在化疗耐药性和肿瘤进展之间建立了联系。
