Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions.
BACKGROUND
The tumor-initiating capacity of many cancers is considered to reside in a small subpopulation of cells (cancer stem cells). We have previously shown that rare prostate epithelial cells with a CD133+/alpha2beta1hi phenotype have the properties of prostate cancer stem cells. We have compared gene expression in these cells relative to their normal and differentiated (CD133-/alpha2beta1low) counterparts, resulting in an informative cancer stem cell gene-expression signature.


RESULTS
Cell cultures were generated from specimens of human prostate cancers (n = 12) and non-malignant control tissues (n = 7). Affymetrix gene-expression arrays were used to analyze total cell RNA from sorted cell populations, and expression changes were selectively validated by quantitative RT-PCR, flow cytometry and immunocytochemistry. Differential expression of multiple genes associated with inflammation, cellular adhesion, and metastasis was observed. Functional studies, using an inhibitor of nuclear factor kappaB (NF-kappaB), revealed preferential targeting of the cancer stem cell and progenitor population for apoptosis whilst sparing normal stem cells. NF-kappaB is a major factor controlling the ability of tumor cells to resist apoptosis and provides an attractive target for new chemopreventative and chemotherapeutic approaches.


CONCLUSIONS
We describe an expression signature of 581 genes whose levels are significantly different in prostate cancer stem cells. Functional annotation of this signature identified the JAK-STAT pathway and focal adhesion signaling as key processes in the biology of cancer stem cells.
Birnie
Richard
R
Pro-Cure Therapeutics Ltd, The Biocentre, Innovation Way, York Science Park, Heslington, York, UK. richard.birnie@pro-cure.uk.com
Bryce
Steven D
SD
Roome
Claire
C
Dussupt
Vincent
V
Droop
Alastair
A
Lang
Shona H
SH
Berry
Paul A
PA
Hyde
Catherine F
CF
Lewis
John L
JL
Stower
Michael J
MJ
Maitland
Norman J
NJ
Collins
Anne T
AT
D000368:Aged; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology
D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide