Abstract
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.
Highlights
side population (SP) cells were more metastatic in xenograft models and the invasive behavior of SP cells was driven by high Rac[1] activity.[10]
Using nonsmall cell lung adenocarcinoma (NSCLA) cell lines and primary patient samples, we demonstrate that the SP, CD133pos and ALDHhigh cells are phenotypically distinct subpopulations enriched for cancer stem/progenitor cells (CS/PC) activity
The conversion kinetics varied among the different marker-defined CS/PC subpopulations (Figure 4d, Supplementary Figure S2B). These results indicate that non-CS/PC and CS/PC populations are plastic and interconvertible in lung cancer cell lines and primary NSCLAs
Summary
SP cells were more metastatic in xenograft models and the invasive behavior of SP cells was driven by high Rac[1] activity.[10]. Gupta et al.[14] suggested that induced CSC differentiation by salinomycin can block mammary CSC activity and metastasis, the efficacy of such reagents remained untested in preclinical and clinical solid tumor models. Using NSCLA cell lines and primary patient samples, we demonstrate that the SP, CD133pos and ALDHhigh cells are phenotypically distinct subpopulations enriched for CS/PC activity. Rac[1], a Rho GTPase family member with known roles in metastasis and EMT, is activated during EMT, and Rac[1] inhibition blocks EMT and the dynamic plasticity between CS/PCs and Keywords: lung cancer; cancer stem cells; Rac[1]; EMT; self-renewal; plasticity
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