Clinical evidence suggests an increased CSC in tumor mass may contribute to the failure of conventional therapies since 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.
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The stemness of prostate cancer cells was determined by a prostasphere assay, and dye exclusion assay. To find critical stem cell marker and reveal regulation mechanism, basic biochemical and molecular biological methods such as qRT-PCR, Western blot, reporter gene assay and chromatin immunoprecipitation assay were employed. 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.
We demonstrate immortalized normal human prostate epithelial cells, appeared non-tumorigenic 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 anti-cancer 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 mice model bearing xenografts showed a robust inhibition of tumor growth after combination therapy.
Overall, this study provides strong evidence of CSC in CRPC. This new combination therapy strategy targeting CSC could significantly enhance therapeutic efficacy of current chemotherapy regimen only targeting non-CSC cells.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 Oct 21 [Epub ahead of print]
Eun-Jin Yun, Jiancheng Zhou, Chun-Jung Lin, Elizabeth Hernandez, Ladan Fazli, Martin E Gleave, Jer-Tsong Hsieh
Urology, UT Southwestern Medical Center. , Urology, University of Texas Southwestern Medical Center. , Urology, University of Texas Southwestern Medical Center. , Urology, University of Texas Southwestern Medical Center. , Urological Sciences, Vancouver Prostate Centre, University of British Columbia. , Vancouver Prostate Centre, University of British Columbia. , Urology, University of Texas Southwestern Medical Center