Targeting Cancer Stem Cells in Castration-Resistant Prostate Cancer.
OBJECTIVE
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.


METHODS
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.
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
Eun-Jin
EJ
Yun
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, China.
Jiancheng
J
Zhou
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Chun-Jung
CJ
Lin
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
Elizabeth
E
Hernandez
Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada.
Ladan
L
Fazli
Vancouver Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada.
Martin
M
Gleave
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung, Taiwan, Republic of China. jt.hsieh@utsouthwestern.edu.
Jer-Tsong
JT
Hsieh
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D043823:Taxoids / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D060449:Wnt Signaling Pathway; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics
D000970:Antineoplastic Agents; D015415:Biomarkers; D051927:CD24 Antigen; C462952:DAB2IP protein, human; D018960:Hyaluronan Receptors; D043823:Taxoids; D020703:ras GTPase-Activating Proteins; D000077143:Docetaxel