ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors
Journal
Cancer Letters
Journal Volume
328
Journal Issue
1
Pages
144-151
Date Issued
2013
Author(s)
Huang C.-P.
Tsai M.-F.
Chang T.-H.
Tang W.-C.
Chen S.-Y.
Lai H.-H.
Lin T.-Y.
Lin S.-B.
Abstract
Molecular targeting therapeutics, such as EGFR tyrosine kinase inhibitors (TKIs), are important treatment strategies for lung cancer. Currently, the major challenge confronting targeted cancer therapies is the development of resistance. Cancer stem cells (CSCs) represent a rare population of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance and spreading. Resistance to conventional chemotherapeutic drugs is a common characteristic of CSCs. However, the issue of whether CSCs contribute to EGFR TKI resistance in lung cancer is yet to be established. In the current study, we explored the association of ALDH1A1 expression with EGFR TKI resistance in lung cancer stem cells. ALDH1A1-positive lung cancer cells displayed resistance to gefitinib, compared to ALDH1A1-negative lung cancer cells. Moreover, PC9/gef cells (gefitinib-resistant lung cancer cells) presented a higher proportion of ALDH1A1-positive cells, compared to PC9 cells (gefitinib-sensitive lung cancer cells). Clinical sample studies were consistent with results from cell culture model systems showing that lung cancer cells with resistance to EGFR TKI and chemotherapy drugs contain significantly increased proportions of ALDH1A1-positive cells. These findings collectively suggest that ALDH1A1 positivity in cancer stem cells confers resistance to EGFR TKI in lung cancer. ? 2012 Elsevier Ireland Ltd.
SDGs
Other Subjects
aldehyde dehydrogenase; aldehyde dehydrogenase 1a1; BMI1 protein; breast cancer resistance protein; cisplatin; epidermal growth factor receptor kinase inhibitor; etoposide; fluorouracil; gefitinib; kruppel like factor 4; messenger RNA; Myc protein; nestin; octamer transcription factor 4; transcription factor NANOG; transcription factor Sox2; unclassified drug; animal experiment; animal model; antineoplastic activity; article; cancer cell culture; cancer resistance; cancer stem cell; concentration response; controlled study; drug sensitivity; fluorescence activated cell sorting; gene expression; human; human cell; lung cancer; male; mouse; nonhuman; pleura effusion; priority journal; protein analysis; protein expression; reverse transcription polymerase chain reaction; Aldehyde Dehydrogenase; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Protein Kinase Inhibitors; Receptor, Epidermal Growth Factor
Type
journal article