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Clinical Cancer Research
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Cancer Therapy: Preclinical

Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer

Eun-Jin Yun, Jiancheng Zhou, Chun-Jung Lin, Elizabeth Hernandez, Ladan Fazli, Martin Gleave and Jer-Tsong Hsieh
Eun-Jin Yun
1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
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Jiancheng Zhou
1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
2Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
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Chun-Jung Lin
1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
3Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
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Elizabeth Hernandez
1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
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Ladan Fazli
4Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada.
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Martin Gleave
4Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada.
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Jer-Tsong Hsieh
1Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
5Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung, Taiwan, Republic of China.
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  • For correspondence: jt.hsieh@utsouthwestern.edu
DOI: 10.1158/1078-0432.CCR-15-0190 Published February 2016
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Abstract

Purpose: Clinical evidence suggests increased cancer stem cells (CSCs) in a tumor mass may contribute to the failure of conventional therapies because CSCs seem to be more resistant than differentiated tumor cells. Thus, unveiling the mechanism regulating CSCs and candidate target molecules will provide new strategy to cure the patients.

Experimental design: The stem-like cell properties were determined by a prostasphere assay and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biologic methods, such as quantitative real-time PCR, Western blot, reporter gene assay, and chromatin immunoprecipitation assay, were used. In addition, to determine the effect of combination therapy targeting both CSCs and its progeny, in vitro MTT assay and in vivo xenograft model was used.

Results: We demonstrate immortalized normal human prostate epithelial cells, appeared nontumorigenic in vivo, become tumorigenic, and acquire stem cell phenotype after knocking down a tumor suppressor gene. Also, those stem-like cells increase chemoresistance to conventional anticancer reagent. Mechanistically, we unveil that Wnt signaling is a key pathway regulating well-known stem cell marker CD44 by directly interacting to the promoter. Thus, by targeting CSCs using Wnt inhibitors synergistically enhances the efficacy of conventional drugs. Furthermore, the in vivo mouse model bearing xenografts showed a robust inhibition of tumor growth after combination therapy.

Conclusions: Overall, this study provides strong evidence of CSC in castration-resistant prostate cancer. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells. Clin Cancer Res; 22(3); 670–9. ©2015 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received January 28, 2015.
  • Revision received August 20, 2015.
  • Accepted October 11, 2015.
  • ©2015 American Association for Cancer Research.
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Clinical Cancer Research: 22 (3)
February 2016
Volume 22, Issue 3
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Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer
Eun-Jin Yun, Jiancheng Zhou, Chun-Jung Lin, Elizabeth Hernandez, Ladan Fazli, Martin Gleave and Jer-Tsong Hsieh
Clin Cancer Res February 1 2016 (22) (3) 670-679; DOI: 10.1158/1078-0432.CCR-15-0190

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Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer
Eun-Jin Yun, Jiancheng Zhou, Chun-Jung Lin, Elizabeth Hernandez, Ladan Fazli, Martin Gleave and Jer-Tsong Hsieh
Clin Cancer Res February 1 2016 (22) (3) 670-679; DOI: 10.1158/1078-0432.CCR-15-0190
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