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Non-small cell lung cancer stem/progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity | Cell Death & Disease
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Cancer stem cells (CSCs) represent a population of cancer cells that possess unique self-renewal and differentiation characteristics required for tumorigenesis and are resistant to chemotherapy-induced apoptosis. Lung CSCs can be enriched by several markers including drug-resistant side population (SP), CD133pos and ALDHhigh. Using human non-small cell lung adenocarcinoma cell lines and patient-derived primary tumor cells, we demonstrate that SP cells represent a subpopulation distinct from other cancer stem/progenitor cell (CS/PC) populations marked by CD133pos or ALDHhigh. The non-CS/PCs and CS/PCs of each subpopulation are interconvertible. Epithelial-mesenchymal transition (EMT) promotes the formation of CD133pos and ALDHhigh CS/PC subpopulations while suppressing the SP CS/PC subpopulation. Rac1 GTPase activity is significantly increased in cells that have undergone EMT, and targeting Rac1 is effective in inhibiting the dynamic conversion of non-CS/PCs to CS/PCs, as well as the CS/PC activity. These results imply that various subpopulations of CS/PCs and non-CS/PCs may achieve a stochastic equilibrium in a defined microenvironment, and eliminating multiple subpopulations of CS/PCs and effectively blocking non-CS/PC to CS/PC transition, by an approach such as targeting Rac1, can be a more effective therapy.
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nature portfolio hospital research foundation privacy policy liver tumor development bead-immobilized p21-binding domain advertising immune compromised nod/scid/γc−/− cancer stem/progenitor cell small-cell lung cancer social media author information authors dynamic nature marker-defined cs/pc subpopulations transient nature 0/ reprints figure 1b middle full size image nature nature 1994 nature 2004 nature 2007 nature 2010 nature 2005 aldh1a1-/cd133-/mutant p53 slow-cycling melanoma cells creative commons attribution-noncommercial cobble-stone epithelial morphology tumor-initiating cell propagation distinct cs/pc subpopulations author correspondence primary resected early-stage therapy-resistant tumor cells cs/pc subpopulations vary liver-lodged cancer cells drug-resistant side population cs/pc transition dynamically distinct cs/pc subpopulation anti-rac1 western blotting adherent sphere-forming conditions cancer stem cell middle panel multiple cs/pc subpopulations nscla cs/pc subpopulations single cs/pc subpopulations reveal relative rac1-gtp cytokine-induced killer cells stem cell marker regulate nf-κβ activity tumour cell growth initiating tumour growth
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