Estrogen-initiated transformation of prostate epithelium derived from normal human prostate stem-progenitor cells.

The present study sought to determine whether estrogens with testosterone support are sufficient to transform the normal human prostate epithelium and promote progression to invasive adenocarcinoma using a novel chimeric prostate model. Adult prostate stem/early progenitor cells were isolated from normal human prostates through prostasphere formation in three-dimensional culture. The stem/early progenitor cell status and clonality of prostasphere cells was confirmed by immunocytochemistry and Hoechst staining. Normal prostate progenitor cells were found to express estrogen receptor α, estrogen receptor β, and G protein-coupled receptor 30 mRNA and protein and were responsive to 1 nm estradiol-17β with increased numbers and prostasphere size, implicating them as direct estrogen targets. Recombinants of human prostate progenitor cells with rat urogenital sinus mesenchyme formed chimeric prostate tissue in vivo under the renal capsule of nude mice. Cytodifferentiation of human prostate progenitor cells in chimeric tissues was confirmed by immunohistochemistry using epithelial cell markers (p63, cytokeratin 8/18, and androgen receptor), whereas human origin and functional differentiation were confirmed by expression of human nuclear antigen and prostate-specific antigen, respectively. Once mature tissues formed, the hosts were exposed to elevated testosterone and estradiol-17β for 1-4 months, and prostate pathology was longitudinally monitored. Induction of prostate cancer in the human stem/progenitor cell-generated prostatic tissue was observed over time, progressing from normal histology to epithelial hyperplasia, prostate intraepithelial neoplasia, and prostate cancer with local renal invasion. These findings provide the first direct evidence that human prostate progenitor cells are estrogen targets and that estradiol in an androgen-supported milieu is a carcinogen for human prostate epithelium.

[1]  G. Prins,et al.  Early-life estrogens and prostate cancer in an animal model , 2010, Journal of Developmental Origins of Health and Disease.

[2]  O. Witte,et al.  Primitive origins of prostate cancer: In vivo evidence for prostate‐regenerating cells and prostate cancer‐initiating cells , 2010, Molecular oncology.

[3]  A. N. Fullenkamp,et al.  Research resource: estrogen-driven prolactin-mediated gene-expression networks in hormone-induced prostatic intraepithelial neoplasia. , 2010, Molecular endocrinology.

[4]  Liang Cheng,et al.  Estrogen receptor β2 and β5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion , 2010, Endocrine-related cancer.

[5]  C. Genestie,et al.  Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors , 2010, Proceedings of the National Academy of Sciences.

[6]  Jiaoti Huang,et al.  Identification of a Cell of Origin for Human Prostate Cancer , 2010, Science.

[7]  R. Nolley,et al.  Metabolic , Endocrine and Genitourinary Pathobiology Tissue Slice Grafts An in Vivo Model of Human Prostate Androgen Signaling , 2010 .

[8]  C. Clarke,et al.  Progesterone induces adult mammary stem cell expansion , 2010, Nature.

[9]  J. Visvader,et al.  Control of mammary stem cell function by steroid hormone signalling , 2010, Nature.

[10]  I. Leav,et al.  ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. , 2010, Cancer cell.

[11]  O. Witte,et al.  Isolation, cultivation and characterization of adult murine prostate stem cells , 2010, Nature Protocols.

[12]  S. Ho,et al.  Activation of GPR30 inhibits growth of prostate cancer cells via sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G2 cell-cycle arrest , 2010, Cell Death and Differentiation.

[13]  S. Memarzadeh,et al.  Basal epithelial stem cells are efficient targets for prostate cancer initiation , 2010, Proceedings of the National Academy of Sciences.

[14]  M. Rubin,et al.  Human Prostate Sphere-Forming Cells Represent a Subset of Basal Epithelial Cells Capable of Glandular Regeneration in Vivo , 2009, The Prostate.

[15]  E. Cavalieri,et al.  Depurinating estrogen-DNA adducts in the etiology and prevention of breast and other human cancers. , 2010, Future oncology.

[16]  A. D. De Marzo,et al.  Dual‐label centromere and telomere FISH identifies human, rat, and mouse cell contribution to Multispecies recombinant urogenital sinus xenografts , 2009, The Prostate.

[17]  Vijayalakshmi Ananthanarayanan,et al.  Evidence for field cancerization of the prostate , 2009, The Prostate.

[18]  I. Bisson,et al.  WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics , 2009, Cell Research.

[19]  G. Prins,et al.  The role of Wnt5a in prostate gland development. , 2009, Developmental biology.

[20]  S. Hayward,et al.  Development of a three‐dimensional culture model of prostatic epithelial cells and its use for the study of epithelial‐mesenchymal transition and inhibition of PI3K pathway in prostate cancer , 2009, The Prostate.

[21]  P. Schultz,et al.  The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations , 2009, Proceedings of the National Academy of Sciences.

[22]  O. Witte,et al.  Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics , 2008, Proceedings of the National Academy of Sciences.

[23]  K. Leong,et al.  Generation of a prostate from a single adult stem cell , 2008, Nature.

[24]  A. DeMarzo,et al.  The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. , 2008, Cancer research.

[25]  N. Maitland,et al.  Prostate cancer stem cells: a new target for therapy. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  P. Nelson,et al.  Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. , 2008, Cancer research.

[27]  W. Hahn,et al.  The current state of preclinical prostate cancer animal models , 2008, The Prostate.

[28]  K. Korach,et al.  The role of estrogens and estrogen receptors in normal prostate growth and disease , 2008, Steroids.

[29]  J. Rhim,et al.  Prostate cell cultures as in vitro models for the study of normal stem cells and cancer stem cells , 2008, Prostate Cancer and Prostatic Diseases.

[30]  B. Leiby,et al.  Transcription Factor Signal Transducer and Activator of Transcription 5 Promotes Growth of Human Prostate Cancer Cells In vivo , 2008, Clinical Cancer Research.

[31]  S. Kasper.  Exploring the Origins of the Normal Prostate and Prostate Cancer Stem Cell , 2008, Stem Cell Reviews.

[32]  O. Witte,et al.  Self‐Renewal and Multilineage Differentiation In Vitro from Murine Prostate Stem Cells , 2007, Stem cells.

[33]  G. Carruba.  Estrogen and prostate cancer: An eclipsed truth in an androgen‐dominated scenario , 2007, Journal of cellular biochemistry.

[34]  Shuk-Mei Ho,et al.  Sex hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the noble rat. , 2007, The American journal of pathology.

[35]  F. Hamdy,et al.  Combination of polymorphisms from genes related to estrogen metabolism and risk of prostate cancers: the hidden face of estrogens. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  G. Risbridger,et al.  Treating prostate cancer: a rationale for targeting local oestrogens , 2007, Nature Reviews Cancer.

[37]  S. Teitelbaum,et al.  Adult Versus Embryonic Stem Cells: Treatments , 2007, Science.

[38]  Jialing Yuan,et al.  Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. , 2007, Cancer research.

[39]  G. Prins,et al.  Developmental estrogen exposures predispose to prostate carcinogenesis with aging. , 2007, Reproductive toxicology.

[40]  N. Maitland,et al.  Differentiation of prostate epithelial cellcultures by materigel/stromal cell glandular reconstruction , 2006, In Vitro Cellular & Developmental Biology - Animal.

[41]  R. Dahiya,et al.  Establishment and characterization of an immortalized but non-transformed human prostate epithelial cell line: BPH-1 , 2007, In Vitro Cellular & Developmental Biology - Animal.

[42]  D. Bostwick,et al.  Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. , 2006, The Journal of urology.

[43]  Shuk-Mei Ho,et al.  4 Epigenetically Regulates Phosphodiesterase Type 4 Variant Increases Susceptibility to Prostate Carcinogenesis and Developmental Exposure to Estradiol and Bisphenol A , 2006 .

[44]  Yuzhuo Wang,et al.  Steroid hormones stimulate human prostate cancer progression and metastasis , 2006, International journal of cancer.

[45]  A. Trounson,et al.  Formation of human prostate tissue from embryonic stem cells , 2006, Nature Methods.

[46]  Guojun Wu,et al.  A novel knock-in prostate cancer model demonstrates biology similar to that of human prostate cancer and suitable for preclinical studies. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[47]  G. Prins,et al.  The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland: lobe-specific suppression by neonatal estrogens. , 2005, Developmental biology.

[48]  M. Sadar,et al.  Cell lines used in prostate cancer research: a compendium of old and new lines--part 1. , 2005, The Journal of urology.

[49]  David M. Berman,et al.  Tissue repair and stem cell renewal in carcinogenesis , 2004, Nature.

[50]  D. Neal,et al.  CD133, a novel marker for human prostatic epithelial stem cells , 2004, Journal of Cell Science.

[51]  R. Vessella,et al.  LuCaP 35: A new model of prostate cancer progression to androgen independence , 2003, The Prostate.

[52]  G. Prins,et al.  The role of prolactin in the prostatic inflammatory response to neonatal estrogen. , 2003, Endocrinology.

[53]  B. Petersen,et al.  Stem cells in adult tissues. , 2002, Seminars in cell & developmental biology.

[54]  J. Thomson,et al.  Surface antigens of human embryonic stem cells: changes upon differentiation in culture * , 2002, Journal of anatomy.

[55]  J. Kaufman,et al.  Estradiol in elderly men , 2002, The aging male : the official journal of the International Society for the Study of the Aging Male.

[56]  N. Maitland,et al.  Experimental prostate epithelial morphogenesis in response to stroma and three-dimensional matrigel culture. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[57]  S. Hayward,et al.  Malignant transformation in a nontumorigenic human prostatic epithelial cell line. , 2001, Cancer research.

[58]  C. Bieberich,et al.  Influence of neonatal estrogens on rat prostate development. , 2001, Reproduction, fertility, and development.

[59]  B. Katzenellenbogen,et al.  Estrogen Imprinting of the Developing Prostate Gland Is Mediated through Stromal Estrogen Receptor α Studies with αERKO and βERKO Mice , 2001 .

[60]  K. Imaida,et al.  Prostate carcinomas developing in transgenic rats with SV40 T antigen expression under probasin promoter control are strictly androgen dependent. , 2001, Cancer research.

[61]  L. Speroff.  Postmenopausal estrogen therapy and ovarian cancer , 2001 .

[62]  K. Imaida,et al.  Experimental prostate carcinogenesis - rodent models. , 2000, Mutation research.

[63]  D. S. Coffey,et al.  New concepts in tissue specificity for prostate cancer and benign prostatic hyperplasia. , 1999, Urology.

[64]  G. Prins,et al.  Estrogen Receptor-b Messenger Ribonucleic Acid Ontogeny in the Prostate of Normal and Neonatally Estrogenized Rats , 1998 .

[65]  W. Rand,et al.  Suppression of testosterone and estradiol-17beta-induced dysplasia in the dorsolateral prostate of Noble rats by bromocriptine. , 1997, Carcinogenesis.

[66]  G. Prins,et al.  Neonatal estrogen exposure up-regulates estrogen receptor expression in the developing and adult rat prostate lobes. , 1997, Endocrinology.

[67]  M. Bosland,et al.  Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol. , 1995, Carcinogenesis.

[68]  M. Sporn,et al.  Histogenesis of induced prostate and seminal vesicle carcinoma in Lobund-Wistar rats: a system for histological scoring and grading. , 1994, Cancer research.

[69]  M. Gleave,et al.  Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. , 1992, Cancer research.

[70]  A. Levine,et al.  Effect of the addition of estrogen to medical castration on prostatic size, symptoms, histology and serum prostate specific antigen in 4 men with benign prostatic hypertrophy. , 1991, The Journal of urology.

[71]  P. Walsh,et al.  Clinical and experimental studies of benign prostatic hyperplasia. , 1990, The Urologic clinics of North America.

[72]  D. S. Coffey,et al.  Etiology and disease process of benign prostatic hyperplasia , 1989, The Prostate. Supplement.

[73]  I. Leav,et al.  Androgen‐supported estrogen‐enhanced epithelial proliferation in the prostates of intact noble rats , 1989, The Prostate.

[74]  M. Pollard,et al.  Production of autochthonous prostate cancer in Lobund-Wistar rats by treatments with N-nitroso-N-methylurea and testosterone. , 1986, Journal of the National Cancer Institute.

[75]  R. Noble.  Production of Nb rat carcinoma of the dorsal prostate and response of estrogen-dependent transplants to sex hormones and tamoxifen. , 1980, Cancer research.

[76]  G. Cunha,et al.  Glandular epithelial induction by embryonic mesenchyme in adult bladder epithelium of BALB/c mice. , 1980, Investigative urology.

[77]  R. Noble.  The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. , 1977, Cancer research.

[78]  Dunning Wf.  PROSTATE CANCER IN THE RAT. , 1963 .

[79]  W. F. Dunning.  PROSTATE CANCER IN THE RAT. , 1963, National Cancer Institute monograph.

[80]  D. Price.  Normal development of the prostate and seminal vesicles of the rat with a study of experimental postnatal modifications , 1936 .