Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone

Sandy Liu; Radu M Cadaneanu; Baohui Zhang; Lihong Huo; Kevin Lai; Xinmin Li; Colette Galet; Tristan R Grogan; David Elashoff; Stephen J Freedland; Matthew Rettig; William J Aronson; Beatrice S Knudsen; Michael S Lewis; Isla P Garraway

doi:10.1371/journal.pone.0163232

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Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone

Journal article

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Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone

Sandy Liu, Radu M Cadaneanu, Baohui Zhang, Lihong Huo, Kevin Lai, Xinmin Li, Colette Galet, Tristan R Grogan, David Elashoff, Stephen J Freedland, …

PloS one, Vol.11(10), pp.e0163232-e0163232

10/06/2016

DOI: 10.1371/journal.pone.0163232

PMID: 27711225

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Abstract

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. 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. 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.

Adult

Animals

Biopsy, Needle

Bone Neoplasms - secondary

Cell Differentiation

Epithelial Cells - pathology

Gene Expression Regulation, Neoplastic

Humans

Keratin-13 - genetics

Keratin-13 - metabolism

Male

Mice

Neoplastic Stem Cells - pathology

Prostate - metabolism

Prostate - pathology

Prostate - surgery

Prostatectomy

Prostatic Neoplasms - genetics

Prostatic Neoplasms - metabolism

Prostatic Neoplasms - pathology

Prostatic Neoplasms - surgery

Survival Analysis

Details

Title: Subtitle: Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone
Creators: Sandy Liu - University of California, Los Angeles
Radu M Cadaneanu - University of California, Los Angeles
Baohui Zhang - University of California, Los Angeles
Lihong Huo - University of California, Los Angeles
Kevin Lai - University of California, Los Angeles
Xinmin Li - University of California, Los Angeles
Colette Galet - University of California, Los Angeles
Tristan R Grogan - University of California, Los Angeles
David Elashoff - University of California, Los Angeles
Stephen J Freedland - Durham VA Medical Center
Matthew Rettig - UCLA Jonsson Comprehensive Cancer Center
William J Aronson - University of California, Los Angeles
Beatrice S Knudsen - Cedars-Sinai Medical Center
Michael S Lewis - VA Greater Los Angeles Healthcare System
Isla P Garraway - VA Greater Los Angeles Healthcare System
Resource Type: Journal article
Publication Details: PloS one, Vol.11(10), pp.e0163232-e0163232
DOI: 10.1371/journal.pone.0163232
PMID: 27711225
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: P01 CA098912 / NCI NIH HHS R01 CA131255 / NCI NIH HHS UL1 TR001881 / NCATS NIH HHS P50 CA092131 / NCI NIH HHS P30 CA016042 / NCI NIH HHS P30 AI028697 / NIAID NIH HHS UL1 TR000124 / NCATS NIH HHS U54 CA143931 / NCI NIH HHS
Language: English
Date published: 10/06/2016
Academic Unit: Injury Prevention Research Center; University of Iowa Health Care
Record Identifier: 9985137928302771

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