Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells.
Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells.
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DOI：
10.1016/j.ccr.2012.07.016
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发表时间：
2012-09-11
期刊：
影响因子：
50.3
通讯作者：
Cordon-Cardo C
中科院分区：
文献类型：
--
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
多西他赛获得性耐药先于激素难治性前列腺癌（HRPC）的死亡。然而，针对多西他赛耐药细胞的策略仍然难以捉摸。通过体外和体内模型，我们确定了多西他赛暴露后存活的细胞亚群。该亚群缺乏分化标记和HLAI类（HLAI）抗原，而过表达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，靶向Notch和Hedgehog信号通路通过抑制存活分子AKT和Bcl-2来减少这一群体，这表明一种消除HRPC中多西他赛耐药的治疗策略。最后，这些细胞表现出强大的肿瘤启动能力，建立了化疗耐药性和肿瘤进展之间的联系。
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.
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