title: Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone.
abstract: BACKGROUND
  Benign human prostate tubule-initiating cells (TIC) and aggressive prostate cancer display common traits, including tolerance of low androgen levels, resistance to apoptosis, and microenvironment interactions that drive epithelial budding and outgrowth. TIC can be distinguished from epithelial and stromal cells that comprise prostate tissue via cell sorting based upon Epcam, CD44, and CD49f antigenic profiles. Fetal prostate epithelial cells (FC) possess a similar antigenic profile to adult TIC and are capable of inducing tubule formation. To identify the TIC niche in human prostate tissue, differential keratin (KRT) expression was evaluated.
  
  
  RESULTS
  Gene expression data generated from Affymetrix Gene Chip human U133 Plus 2.0 array of sorted adult and fetal epithelial cells revealed KRT13 to be significantly enriched in FC and TIC compared to basal cells (BC) and luminal cells (LC) (p<0.001). Enriched KRT13 expression was confirmed by RT-PCR and cytospin immunostaining. Immunohistochemical analysis of KRT13 expression revealed rare KRT13+ epithelia throughout prostatic ducts/acini in adult tissue specimens and differentiated tubules in 24-week recombinant grafts, In contrast, abundant KRT13 expression was observed in developing ducts/acini in fetal prostate and cord-like structures composing 8-week recombinant grafts. Immunostaining of a prostate tissue microarray revealed KRT13+ tumor foci in approximately 9% of cases, and this subset displayed significantly shorter time to recurrence (p = 0.031), metastases (p = 0.032), and decreased overall survival (p = 0.004). Diagnostic prostate needle biopsies (PNBX) from untreated patients with concurrent bone metastases (clinical stage M1) displayed KRT13+ tumor foci, as did bone metastatic foci.
  
  
  CONCLUSIONS
  The expression profile of KRT13 in benign fetal and adult prostate tissue and in recombinant grafts, as well as the frequency of KRT13 expression in primary and metastatic prostate cancer indicates that it may be a marker of a stem/progenitor-like cell state that is co-opted in aggressive tumor cells. KRT13 is enriched in benign stem-like cells that display androgen-resistance, apoptosis-resistance, and branching morphogenesis properties. Collectively our data demonstrate that KRT13 expression is associated with poor prognosis at multiple stages of disease progression and may represent an important biomarker of adverse outcome in patients with prostate cancer.
authors.affiliation: Department of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Sandy
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Radu M
authors.initials: RM
authors.lastname: Cadaneanu
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Baohui
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Lihong
authors.initials: L
authors.lastname: Huo
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lai
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Colette
authors.initials: C
authors.lastname: Galet
authors.affiliation: Department of Medicine Statistics Core, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: Tristan R
authors.initials: TR
authors.lastname: Grogan
authors.affiliation: Department of Medicine Statistics Core, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.affiliation: Urologic Section, Department of Surgery, Durham VA Medical Center, Durham, North Carolina, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rettig
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, United States of America.|Urology Section, Department of Surgery, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Aronson
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Knudsen
authors.affiliation: Department of Pathology, Greater Los Angeles Veterans Affairs Health System, Los Angeles, California, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lewis
authors.affiliation: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, United States of America.|Urology Section, Department of Surgery, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California, United States of America.
authors.forename: Isla P
authors.initials: IP
authors.lastname: Garraway
mesh_terms: D000328:Adult; D000818:Animals; D001707:Biopsy, Needle; D001859:Bone Neoplasms / Q000556:secondary*; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053535:Keratin-13 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D011467:Prostate / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D016019:Survival Analysis
chemical_list: D053535:Keratin-13