Primary patient-derived lung adenocarcinoma cell culture challenges the association of cancer stem cells with epithelial-to-mesenchymal transition

Sci Rep. 2017 Aug 30;7(1):10040. doi: 10.1038/s41598-017-09929-0.

Abstract

The cancer stem cell (CSC) and epithelial-to-mesenchymal transition (EMT) models have been closely associated and used to describe both the formation of metastasis and therapy resistance. We established a primary lung cell culture from a patient in a clinically rare and unique situation of primary resistant disease. This culture consisted of two biologically profoundly distinct adenocarcinoma cell subpopulations, which differed phenotypically and genotypically. One subpopulation initiated and sustained in spheroid cell culture (LT22s) whereas the other subpopulation was only capable of growth and proliferation under adherent conditions (LT22a). In contrast to our expectations, LT22s were strongly associated with the epithelial phenotype, and expressed additionally CSC markers ALDH1 and CD133, whereas the LT22a was characterized as mesenchymal with lack of CSC markers. The LT22s cells also demonstrated an invasive behavior and mimicked gland formation. Finally, LT22s were more resistant to Cisplatin than LT22a cells. We demonstrate a primary lung adenocarcinoma cell culture derived from a patient with resistant disease, with epithelial aggressive subpopulation of cells associated with stem cell features and therapy resistance. Our findings challenge the current model associating CSC and disease resistance mainly to mesenchymal cells and may have important clinical implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / genetics
  • AC133 Antigen / metabolism
  • Adenocarcinoma / pathology*
  • Adult
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Chickens
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition*
  • Female
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Retinal Dehydrogenase / genetics
  • Retinal Dehydrogenase / metabolism
  • Tumor Cells, Cultured

Substances

  • AC133 Antigen
  • Biomarkers, Tumor
  • Isoenzymes
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • Cisplatin