Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells

被引：360

作者：

Domingo-Domenech, Josep ^{[1
]}

Vidal, Samuel J. ^{[1
]}

Rodriguez-Bravo, Veronica ^{[1
]}

Castillo-Martin, Mireia ^{[1
]}

Quinn, S. Aidan ^{[1
]}

Rodriguez-Barrueco, Ruth ^{[1
]}

Bonal, Dennis M. ^{[1
]}

Charytonowicz, Elizabeth ^{[1
]}

Gladoun, Nataliya ^{[1
]}

de la Iglesia-Vicente, Janis ^{[1
]}

Petrylak, Daniel P. ^{[1
,2
]}

Benson, Mitchell C. ^{[1
,3
]}

Silva, Jose M. ^{[1
,4
]}

Cordon-Cardo, Carlos ^{[1
,3
,4
]}

机构：

[1] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Columbia Univ Coll Phys & Surg, New York, NY 10032 USA

[2] Columbia Univ, Dept Med, Div Hematol Oncol, Columbia Univ Coll Phys & Surg, New York, NY 10032 USA

[3] Columbia Univ, Dept Urol, Columbia Univ Coll Phys & Surg, New York, NY 10032 USA

[4] Columbia Univ, Dept Pathol & Cell Biol, Columbia Univ Coll Phys & Surg, New York, NY 10032 USA

来源：

CANCER CELL | 2012年 / 22卷 / 03期

关键词：

STEM-CELLS; CHEMOTHERAPY RESISTANCE; SIGNALING PATHWAY; INHIBITION; MITOXANTRONE; PREDNISONE; ACTIVATION; APOPTOSIS;

D O I：

10.1016/j.ccr.2012.07.016

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：373 / 388

页数：16

共 34 条

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