title: Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer.
abstract: OBJECTIVE
  We have shown that the phenotypically undifferentiated (PSA(-/lo)) prostate cancer cell population harbors long-term self-renewing cancer stem cells (CSC) that resist castration, and a subset of the cells within the PSA(-/lo) population bearing the ALDH(hi)CD44(+)α2β1(+) phenotype (Triple Marker(+)/TM(+)) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biologic properties of TM(+) prostate cancer cell population, particularly in the context of initiating and propagating castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent and androgen-independent prostate cancer xenograft models. In vitro clonal, clonogenic, and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies.
  
  
  RESULTS
  By focusing on the LAPC9 model, we show that the TM(+) cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM(+) cells, which possess CSC activities in "castrated" culture conditions. Mechanistically, we find that (i) the phenotypic markers are causally involved in CRPC development; (ii) the TM(+) cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and (iii) the TM(+) cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir.
  
  
  CONCLUSIONS
  Our results define the TM(+) prostate cancer cells as a population of preexistent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM(+) cell population as a therapeutic target. Clin Cancer Res; 22(17); 4505-16. ©2016 AACR.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York. QLi3@mdanderson.org Dean.Tang@RoswellPark.org.
authors.forename: Qiuhui
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kiera
authors.initials: K
authors.lastname: Rycaj
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Dingxiao
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Bigang
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Collene
authors.initials: C
authors.lastname: Jeter
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Tammy
authors.initials: T
authors.lastname: Calhoun-Davis
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Hsueh-Ping
authors.initials: HP
authors.lastname: Chao
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York. Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China. Centers for Cancer Epigenetics, Stem Cell and Developmental Biology, RNA Interference and Non-coding RNAs, and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas. QLi3@mdanderson.org Dean.Tang@RoswellPark.org.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor; D002369:Castration; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D014408:Biomarkers, Tumor; D035683:MicroRNAs; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human