title: Developing a Novel Two-Dimensional Culture System to Enrich Human Prostate Luminal Progenitors that Can Function as a Cell of Origin for Prostate Cancer.
abstract: Elucidating the cell of origin of cancer has great significance in stratifying patients into appropriate treatment groups and for developing novel targeted therapies. Early studies demonstrate that only stem-like basal cells in the normal human prostate (NHP) can function as the cell of origin for prostate cancer (PCa). Here, we show that the organoids derived from bulk NHP luminal cells can also be tumorigenically transformed. We further show that the WIT medium, which is used to culture human mammary epithelial progenitor cells, when combined with the ROCK inhibitor, can readily propagate a population of progenitor-like cells from the primary NHP luminal cell isolates. Such functionally defined luminal progenitors can be transformed by distinct sets of genetic perturbations (i.e., AR+AKT/ERG or c-MYC+PTEN knockout) to form tumor glands. Genome-wide RNA-Seq analysis of freshly purified unperturbed human benign prostatic basal and luminal cells and culture-expanded lineage-specific stem/progenitor populations reveals that the luminal progenitors possess a distinct gene expression profile that is greatly enriched in advanced, castration-resistant, and metastatic PCa, and it associates with poor patient survival. The ability of the simple two-dimensional culture system reported herein to greatly enrich NHP progenitor-like cells should facilitate biological and biochemical studies as well as high-throughput screening in these cells and in progenitor-like PCa cells. Stem Cells Translational Medicine 2017;6:748-760.
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Dingxiao
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Kiera
authors.initials: K
authors.lastname: Rycaj
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Hsueh-Ping
authors.initials: HP
authors.lastname: Chao
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Calhoun-Davis
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA.|Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Center for Stem Cell and Developmental Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Center for RNA Interference and Non-Coding RNAs, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Center for Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University, Shanghai, People's Republic of China.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D002369:Castration; D018929:Cell Culture Techniques / Q000379:methods*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D002478:Cells, Cultured; D003470:Culture Media; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009940:Organoids / Q000473:pathology; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D012038:Regeneration; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D016019:Survival Analysis; D059467:Transcriptome / Q000235:genetics
chemical_list: D003470:Culture Media
keywords: Cancer cell of origin; Prostate cancer; Prostate epithelial progenitor cells; Stem cells