Abstract
Malignant cancer may contain highly heterogeneous populations of cells, including stem-like cells which were resistant to chemotherapy agents, radiation, mechanical stress, and immune surveillance. The characterization of these specific subpopulations might be critical to develop novel strategy to remove malignant tumors.We selected and enriched small population of human melanoma A2058 cells by repetitive selection cycles (selection, restoration, and amplification). These subpopulation of melanoma cells persisted the characteristics of slower cell proliferation, enhanced drug-resistance, elevated percentage of side population as analyzed by Hoechst33342 exclusion, in vitro sphere formation, and in vivo xenograft tumor formation by small amount of tumor cells. The selected populations would be melanoma stem-like cells with high expression of stem cell markers and altered kinase activation. Microarray and bioinformatics analysis highlighted the high expression of angiopoietin-like 4 protein in drug-selected melanoma stem-like cells. Further validation by specific shRNA demonstrated the role of angiopoietin-like 4 protein in drug-selected subpopulation associated with enhanced drug-resistance, sphere formation, reduced kinase activation, in vitro tube-forming ability correlated with heparan-sulfate proteoglycans.Our finding would be applicable to explore the mechanism of melanoma stemness and use angiopoietin-like 4 as potential biomarkers to identify melanoma stem-like cells.
Highlights
Melanoma is the highly aggressive skin cancer with high morbidity, high mortality, and poor prognosis
Further validation by specific shRNA demonstrated the role of angiopoietin-like 4 protein in drug-selected subpopulation associated with enhanced drug-resistance, sphere formation, reduced kinase activation, in vitro tube-forming ability correlated with heparansulfate proteoglycans
Carmustine is one of alkylation agents to interfere DNA replication and RNA transcription. It had been included as one component in Dartmouth regimen in melanoma therapies [17,18,19]
Summary
Melanoma is the highly aggressive skin cancer with high morbidity, high mortality, and poor prognosis. Cancer cells are highly gene-mutated, heterogeneous, and more-resistant to chemicals, mechanical stress, and immune surveillance. Different subpopulations would be intrinsically generated by differentiation of cancer stem cells (CSCs) [3, 4] or acquired selection of mutation upon drug treatments [5, 6]. CSCs were recognized as tumor-initiating cells with the characteristics of self-renewal, cell quiescence, and drug resistance, by which derived by altered gene expression, www.aging-us.com altered cell signaling, or change in epithelialmesenchymal programming [7,8,9,10]. Many literatures suggested varieties of specific markers identified in melanoma cells to explain their cancer stemness, drug-resistance, and malignancy [7, 8, 11]. Since cancer therapies are to remove sensitive tumor cells while resistant cells remained survived, whether drug-selected subpopulation were presented as cancer stem-like cells remained of debut
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