Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature.
Development of metastasis is a leading cause of cancer-induced death. Acquisition of an invasive tumor cell phenotype suggests loss of cell adhesion and basement membrane breakdown during a process termed epithelial-to-mesenchymal transition (EMT). Recently, cancer stem cells (CSC) were discovered to mediate solid tumor initiation and progression. Prostate CSCs are a subpopulation of CD44(+) cells within the tumor that give rise to differentiated tumor cells and also self-renew. Using both primary and established prostate cancer cell lines, we tested the assumption that CSCs are more invasive. The ability of unsorted cells and CD44-positive and -negative subpopulations to undergo Matrigel invasion and EMT was evaluated, and the gene expression profiles of these cells were analyzed by microarray and a subset confirmed using QRT-PCR. Our data reveal that a subpopulation of CD44(+) CSC-like cells invade Matrigel through an EMT, while in contrast, CD44(-) cells are non-invasive. Furthermore, the genomic profile of the invasive cells closely resembles that of CD44(+)CD24(-) prostate CSCs and shows evidence for increased Hedgehog signaling. Finally, invasive cells from DU145 and primary prostate cancer cells are more tumorigenic in NOD/SCID mice compared with non-invasive cells. Our data strongly suggest that basement membrane invasion, an early and necessary step in metastasis development, is mediated by these potential cancer stem cells.
Klarmann
George J
GJ
Cancer Stem Cell Section, Laboratory of Cancer Prevention, SAIC-Frederick Inc., National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Hurt
Elaine M
EM
Mathews
Lesley A
LA
Zhang
Xiaohu
X
Duhagon
Maria A
MA
Mistree
Tashan
T
Thomas
Suneetha B
SB
Farrar
William L
WL
D000818:Animals; D051927:CD24 Antigen / Q000096:biosynthesis; D004848:Epithelium / Q000473:pathology; D023281:Genomics; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism
D051927:CD24 Antigen; D018960:Hyaluronan Receptors