Transcriptomic Compositions And Therapeutic Target Of Non-Small Cell Lung Cancer Stem Cells
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Date
2017-08
Authors
Zakaria, Norashikin
Journal Title
Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
Recent evidence indicates that tumours contain a small population of cancer stem cells (CSCs) which may be the responsible factor that post significant challenges in treating the lung cancer. This is due to their ability to self-renew, resistance towards chemotherapy and leading to the formation and development of the new cancer population. However the identification of lung CSCs in non-small cell lung cancer (NSCLC) remains challenging due to its highly heterogeneous cell population and no universal markers to distinguish the lung CSCs. By properly identifying and characterising lung CSCs, their transcriptomic compositions can be further analysed. This may help in finding potential molecular target for future targeted therapy in lung cancer. The objective of this study was to identify and characterise the CSCs population in NSCLC, determine their transcriptomic composition and identify the possible molecular candidate for CSCs targeted therapy. In this study, lung CSCs was isolated using CD166/CD44 and CD166/EpCAM marker combination from NSCLC cell lines (A549 and H2170) and normal lung stem cells were isolated from normal bronchial epithelial cells (PHBEC). In A549 cells, 62.5% of CD166+CD44+ and 9.8% of CD166+EpCAM+ were identified, and only CD166+EpCAM+ (3.1%) was found in H2170 cells. CD166+CD44+ and CD166+EpCAM+ show multipotent characteristics, including differentiation into osteogenic and adipogenic, self-renewal and expression of stem cell transcription factors such as SOX2, OCT4 and KLF4. The populations were also able to form higher colonies and spheres numbers in comparison to non-CSCs indicating their self-renewal capability. Moreover, the populations have formed
xenograft tumour after transplants into nude mice indicating their tumourigenic capability. Using Affymetrix microarray, 379 lung CSCs genes signature (FC>2.0, p<0.05) were found. Transcriptomic analysis shows that these genes are related to cancer and stem cells related biological pathways. Among all, the pathway analysis showed that NF-κB pathway is the most suitable candidate for targeted lung CSCs therapy. Inhibiting the NF-κB pathway using kinase inhibitor BMS-345541 reduced sphere forming capability, lowering their self-renewal and reduce SOX2, OCT4, KLF4 and SCA-1 expression. It also down regulates EMT transcription factors (SNAI1 and TWIST1), down-regulates mesenchymal marker (N-cadherin and Vimentin) and lowering CSCs migration capability. This study has shown that multipotent and tumorigenic CSCs populations from NSCLC cell lines were successfully isolated and characterized using novel combinations of CD166/CD44 and CD166/EpCAM markers. The analysis of transcriptomic composition of this cells has help in finding a potential molecular target that shows promising results to be used in future targeted therapy in lung cancer.
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Keywords
The identification of lung cancer stem cells , in non-small cell lung cancer