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

Cell Death Dis. 2012 Jul 19;3(7):e352. doi: 10.1038/cddis.2012.93.


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), CD133(pos) and ALDH(high). 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 CD133(pos) or ALDH(high). The non-CS/PCs and CS/PCs of each subpopulation are interconvertible. Epithelial-mesenchymal transition (EMT) promotes the formation of CD133(pos) and ALDH(high) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AC133 Antigen
  • Aldehyde Dehydrogenase / metabolism
  • Antigens, CD / metabolism
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Epithelial-Mesenchymal Transition / drug effects
  • Glycoproteins / metabolism
  • Humans
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • Peptides / metabolism
  • Phenotype
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Transforming Growth Factor beta1 / pharmacology
  • Tumor Cells, Cultured
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism


  • AC133 Antigen
  • Antigens, CD
  • Glycoproteins
  • PROM1 protein, human
  • Peptides
  • RNA, Small Interfering
  • Transforming Growth Factor beta1
  • Aldehyde Dehydrogenase
  • rac1 GTP-Binding Protein