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

Abstract

BackgroundBenign 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.ResultsGene 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.ConclusionsThe 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.

Keratin Profiling by Single-Cell RNA-Sequencing Identifies Human Prostate Stem Cell Lineage Hierarchy and Cancer Stem-Like Cells

“…Several distinct keratins have been identified in stem cells and cancers where they may play unique roles [ 28 , 29 , 30 , 31 ]. Previous studies had identified KRT13 as a marker for leading edge prostate cancer regional invasion in organ-confined disease [ 32 , 33 ], and our findings confirmed it as a specific human prostate stem cell marker regulating its self-renewal [ 23 , 24 ].…”

Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution

“…Selective expression of KRT13 and PRAC1 was also documented in prostate stem cells relative to progenitors and knockdown experiments confirmed their critical role in maintaining stemness properties. A recent study similarly identified KRT13 as enriched in human fetal prostate epithelial cells and confirmed it as a marker for the stem/progenitor population in adult prostate tissue (Liu et al, 2016). Of note, KRT13 plays a directive role in prostate cancer metastasis and its expression in primary prostate tumors is predictive of metastasis and lower survival (Li et al, 2016).…”

A Cellular Anatomy of the Normal Adult Human Prostate and Prostatic Urethra

“…Cells with KRT13 expression were previously shown to be rare in the adult prostate but abundant in fetal prostate, although it is unclear whether hillock cells populate the fetal urogenital sinus. KRT13 + cells are enriched in localized prostate tumors and in stem-like cells that display androgen resistance and a capacity for branching morphogenesis ( Liu et al, 2016a ). The top genes associated with the KRT13 + cell type are members of the androgen metabolism pathway (AKR1C1 and AKR1C2), which have been implicated in the development of castrate-resistant prostate cancer ( Zhang et al, 2016a ).…”