Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer

Eun Jin Yun, Jiancheng Zhou, Chun Jung Lin, Elizabeth Hernandez, Ladan Fazli, Martin Gleave, Jer Tsong Hsieh

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)670-679
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number3
DOIs
StatePublished - Feb 1 2016

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Neoplastic Stem Cells
Castration
Prostatic Neoplasms
Stem Cells
Heterografts
Therapeutics
Neoplasms
Chromatin Immunoprecipitation
Tumor Suppressor Genes
Reporter Genes
Real-Time Polymerase Chain Reaction
Prostate
Research Design
Coloring Agents
Western Blotting
Epithelial Cells
Phenotype
Drug Therapy
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer. / Yun, Eun Jin; Zhou, Jiancheng; Lin, Chun Jung; Hernandez, Elizabeth; Fazli, Ladan; Gleave, Martin; Hsieh, Jer Tsong.

In: Clinical Cancer Research, Vol. 22, No. 3, 01.02.2016, p. 670-679.

Research output: Contribution to journalArticle

Yun, EJ, Zhou, J, Lin, CJ, Hernandez, E, Fazli, L, Gleave, M & Hsieh, JT 2016, 'Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer', Clinical Cancer Research, vol. 22, no. 3, pp. 670-679. https://doi.org/10.1158/1078-0432.CCR-15-0190
Yun EJ, Zhou J, Lin CJ, Hernandez E, Fazli L, Gleave M et al. Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer. Clinical Cancer Research. 2016 Feb 1;22(3):670-679. https://doi.org/10.1158/1078-0432.CCR-15-0190
Yun, Eun Jin ; Zhou, Jiancheng ; Lin, Chun Jung ; Hernandez, Elizabeth ; Fazli, Ladan ; Gleave, Martin ; Hsieh, Jer Tsong. / Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 3. pp. 670-679.
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