Abstract
BackgroundRecently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown.ResultsIn this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors.ConclusionOur study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.
Highlights
A small population of cancer stem cells in adult and pediatric brain tumors has been identified
After screening thirty glioblastoma patients' primary cultured cells, we found that three glioblastoma patients' tumor cells (No 66, No 377 and No 1049) could form separate colonies in 10% FBS/DMEM/F-12 culture medium for 3– 6 passages (Fig 1A), which in turn became floating neurospheres when switching to serum-free medium containing EGF/FGF (NSC medium)
We found Bmi-1, phosphoserine phosphatase (PSP), SHH, OCT4 and Snail mRNA expressed in CD133 positive cells derived from above three cell lines, none of the five genes were detectable on CD133 negative cells
Summary
A small population of cancer stem cells in adult and pediatric brain tumors has been identified. We and other groups have identified a small population of cancer stem cells in adult and pediatric brain tumors [1,2,3,4] These cancer stem cells form neurospheres and possess the capacity for self-renewal. Bearing properties of normal neural stem cells, we inferred that these cancer stem-like cells may give us insight into oncogenesis of glioblastoma and explain clinical resistance of these tumors to conventional chemotherapeutic agents. We show that CD133 gene expression is significantly higher in the recurrent GBM tumor tissue from five patients as compared to their respective newly diagnosed tumors These data suggest that CD133 positive cancer stem cells are resistant to current chemotherapy and may represent a cell target for novel glioblastoma therapies
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