Genomic profiling of tumor initiating prostatospheres.
BACKGROUND
The cancer stem cell (CSC) hypothesis proposes that a population of tumor cells bearing stem cell properties is responsible for the origin and maintenance of tumors. Normal and cancer stem cells possess the ability to grow in vitro as self-renewing spheres, but the molecular basis of this phenotype remains largely unknown. We intended to establish a comprehensive culture system to grow prostatospheres (PSs) from both cancer cell lines and patient tumors. We then used gene expression microarrays to gain insight on the molecular pathways that sustain the PS tumor initiating cell (TIC) phenotype.


RESULTS
Traditional stem cell medium (SCM) supplemented with KnockoutSR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.


CONCLUSIONS
We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.
Duhagon
Maria Ana
MA
Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA. mduhagon@fcien.edu.uy
Hurt
Elaine M
EM
Sotelo-Silveira
Jose R
JR
Zhang
Xiaohu
X
Farrar
William L
WL
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
D015703:Antigens, CD; D051880:Receptors, Notch