Non-small cell lung cancer stem/progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity

TLDR

Cancer stem cells, which self‑renew, differentiate, and resist chemotherapy, can be identified in lung tumors by markers such as side‑population, CD133⁺, and ALDHhigh. The study used human non‑small‑cell lung adenocarcinoma cell lines and patient‑derived primary tumor cells to demonstrate that side‑population cells constitute a distinct subpopulation from CD133⁺ or ALDHhigh cancer stem/progenitor cells. The authors found that non‑stem/progenitor and stem/progenitor cells interconvert, that epithelial‑mesenchymal transition drives CD133⁺ and ALDHhigh subpopulations while suppressing side‑population cells, and that Rac1 inhibition blocks this dynamic conversion and stem‑cell activity, suggesting a more effective therapeutic strategy.

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.