Human prostate sphere-forming cells represent a subset of basal epithelial cells capable of glandular regeneration in vivo.
BACKGROUND
Prostate stem/progenitor cells function in glandular development and maintenance. They may be targets for tumor initiation, so characterization of these cells may have therapeutic implications. Cells from dissociated tissues that form spheres in vitro often represent stem/progenitor cells. A subset of human prostate cells that form prostaspheres were evaluated for self-renewal and tissue regeneration capability in the present study.


METHODS
Prostaspheres were generated from 59 prostatectomy specimens. Lineage marker expression and TMPRSS-ERG status was determined via immunohistochemistry and fluorescence in situ hybridization (FISH). Subpopulations of prostate epithelial cells were isolated by cell sorting and interrogated for sphere-forming activity. Tissue regeneration potential was assessed by combining sphere-forming cells with rat urogenital sinus mesenchyme (rUGSM) subcutaneously in immunocompromised mice.


RESULTS
Prostate tissue specimens were heterogeneous, containing both benign and malignant (Gleason 3-5) glands. TMPRSS-ERG fusion was found in approximately 70% of cancers examined. Prostaspheres developed from single cells at a variable rate (0.5-4%) and could be serially passaged. A basal phenotype (CD44+CD49f+CK5+p63+CK8-AR-PSA-) was observed among sphere-forming cells. Subpopulations of prostate cells expressing tumor-associated calcium signal transducer 2 (Trop2), CD44, and CD49f preferentially formed spheres. In vivo implantation of sphere-forming cells and rUGSM regenerated tubular structures containing discreet basal and luminal layers. The TMPRSS-ERG fusion was absent in prostaspheres derived from fusion-positive tumor tissue, suggesting a survival/growth advantage of benign prostate epithelial cells.


CONCLUSIONS
Human prostate sphere-forming cells self-renew, have tissue regeneration capability, and represent a subpopulation of basal cells.
Garraway
Isla P
IP
Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. igarraway@mednet.ucla.edu
Sun
Wenyi
W
Tran
Chau P
CP
Perner
Sven
S
Zhang
Bao
B
Goldstein
Andrew S
AS
Hahm
Scott A
SA
Haider
Maahum
M
Head
Christian S
CS
Reiter
Robert E
RE
Rubin
Mark A
MA
Witte
Owen N
ON
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D019070:Cell Lineage; D004847:Epithelial Cells / Q000502:physiology*; D015321:Gene Rearrangement; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007150:Immunohistochemistry; D039503:Integrin alpha6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics; D010455:Peptides / Q000032:analysis; D011467:Prostate / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000473:pathology; D012038:Regeneration; D013234:Stem Cells / Q000502:physiology*
D000071916:AC133 Antigen; D015703:Antigens, CD; C497483:CD44 protein, human; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D039503:Integrin alpha6; D015514:Oncogene Proteins, Fusion; D010455:Peptides; C515553:TMPRSS2-ERG fusion protein, human