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S. Landreville, O. A. Agapova, J. W. Harbour; The Cell Surface Glycoprotein ABCB1 Identifies a Highly Aggressive Subpopulation of Uveal Melanoma Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):732.
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© ARVO (1962-2015); The Authors (2016-present)
The main challenge in the treatment of uveal melanoma is the occurrence of liver metastases in half of all patients and the notorious chemoresistance of this cancer. Recently, a subpopulation of cancer stem cells representing more aggressive cells responsible for tumor growth, chemoresistance and metastasis has been identified in different types of tumors. The purpose of this study was to determine in uveal melanoma whether a similar subpopulation of more aggressive cells could be identified.
Flow cytometry was performed using Hoechst dye exclusion, ALDEFLUOR and ABCB1 shift assays to sort out side population, ALDH+ and ABCB1+ cells in OCM-1A uveal melanoma cell line and primary tumor samples. ABCB1+ subpopulation behavior was then analyzed by soft agar and migration assays and by subcutaneous flank injection in 8 week-old SCID mice (500 cells). Gene expression profiling with Illumina HumanRef-8 Expression BeadChip array and subsequent validation by real-time PCR were achieved with ABCB1+ and ABCB1- populations.
A side population representing 0.2% of cells was detected in OCM-1A cells and in all 3 primary tumor samples tested. Subpopulations that were ALDH1+ (0.4%) and ABCB1+ (0.5-1.0%) were also identified. The ABCB1+ subpopulation showed the most enrichment in the side population, the highest expression of the stem cell markers OCT4 and NANOG, the greatest migration capacity (P=0.007) and the most robust colony formation in soft agar (P=0.02) compared to side population (P=0.25) and ALDH1+ (P=0.60) subpopulations. ABCB1+ cells formed significantly larger tumors than ABCB1- cells in flank injection experiments (P=0.03). Gene expression profile analysis showed that ABCB1+ cells were up-regulated for the expression of genes involved in mitochondrial respiration.
Uveal melanomas contain a subpopulation of highly aggressive cells with stem-like properties. The aggressiveness of these cells may be due, at least in part, to enhanced adaptation for hypoxia by up-regulating the mitochondrial respiration transcriptional program. These findings may provide new direction for the development of targeted therapies against this cell population.
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