Background: Lung adenocarcinomas are proposed to originate from the malignant transformation of bronchioalveolar stem cells (BASC). This hypothesis, however, has not been confirmed in humans yet. In the present study, we determined to analyze the BASC properties in human lung adenocarcinoma stem cells.
Methods: The human lung adenocarcinoma stem cells were obtained by flow cytometry (FCM) and induced with the sphereforming assay. The markers associated with BASC were measured by immunofluorescent staining, and their metastatic capacity was evaluated by injecting into NOD/SCID mice via tail vein.
Results: The majority of A549 and SPC-A1 human lung adenocarcinoma cells expressed the type II alveolar cell-specific marker SP-C. However, a minority of cells also expressed the bronchiolar Clara cell-specific marker CCSP and the embryonic stem cell marker OCT4, suggesting that these cells may belong to cancer stem cells with BASC properties. The CD24(+)CD221(+) human lung adenocarcinoma stem cells were purified by FCM and then subjected to the immunofluorescent staining. The results documented that these cells had the phenotype of CCSP(+)SP-C(+)OCT4(+), with the same phenotype as mouse BASC. Furthermore, the floatgrowing spheres (named pulmospheres) were developed after 2-week incubation of cancer cells in the serum-free medium containing EGF, IGF-1, and FGF-10. Again, the resultant pulmosphere cells had the phenotype of BASC. These cells were able to differentiate when incubated for two weeks in serum-containing conditions, exhibiting the loss of CCSP and OCT4 markers. Animal studies indicated that the pulmosphere cells had the highly metastatic capacity.
Conclusions: The human lung adenocarcinoma stem cells may originate from the transformation of BASC, as their mouse counterparts. These primitive cancer cells are characterized to express the BASC markers as well as the embryonic stem cell gene OCT4.
Prognostic significance of OCT4 expression in adenocarcinoma of the lung.Jpn J Clin Oncol. 2010 Oct;40(10):961-6. doi: 10.1093/jjco/hyq066. Epub 2010 May 12. Jpn J Clin Oncol. 2010. PMID: 20462980
Human lung cancer cell line SPC-A1 contains cells with characteristics of cancer stem cells.Neoplasma. 2012;59(6):685-92. doi: 10.4149/neo_2012_087. Neoplasma. 2012. PMID: 22862169
SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity.Lab Invest. 2011 Dec;91(12):1796-804. doi: 10.1038/labinvest.2011.140. Epub 2011 Sep 19. Lab Invest. 2011. PMID: 21931300
Antagonistic growth regulation of cell lines derived from human lung adenocarcinomas of Clara cell and aveolar type II cell lineage: Implications for chemoprevention.Int J Oncol. 2004 Jun;24(6):1467-72. Int J Oncol. 2004. PMID: 15138589
Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell. 2005 Jun 17;121(6):823-35. doi: 10.1016/j.cell.2005.03.032. Cell. 2005. PMID: 15960971
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