Lung tumorspheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-09-10

AUTHORS

Alejandro Herreros-Pomares, Juan Diego de-Maya-Girones, Silvia Calabuig-Fariñas, Rut Lucas, Alicia Martínez, José Miguel Pardo-Sánchez, Sergio Alonso, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Eva Escorihuela, María Dolores Chiara, Elena Duréndez, Carolina Gandía, Jerónimo Forteza, Rafael Sirera, Eloísa Jantus-Lewintre, Rosa Farràs, Carlos Camps

ABSTRACT

The high resistance against current therapies found in non-small-cell lung cancer (NSCLC) has been associated to cancer stem-like cells (CSCs), a population for which the identification of targets and biomarkers is still under development. In this study, primary cultures from early-stage NSCLC patients were established, using sphere-forming assays for CSC enrichment and adherent conditions for the control counterparts. Patient-derived tumorspheres showed self-renewal and unlimited exponential growth potentials, resistance against chemotherapeutic agents, invasion and differentiation capacities in vitro, and superior tumorigenic potential in vivo. Using quantitative PCR, gene expression profiles were analyzed and NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 were selected to distinguish tumorspheres from adherent cells. Immunoblot and immunofluorescence analyses confirmed that proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The prognostic role of genes significantly overexpressed in tumorspheres was evaluated in a NSCLC cohort (N = 661) from The Cancer Genome Atlas. Based on a Cox regression analysis, CDKN1A, SNAI1, and ITGA6 were found to be associated with prognosis and used to calculate a gene expression score, named CSC score. Kaplan–Meier survival analysis showed that patients with high CSC score have shorter overall survival (OS) in the entire cohort [37.7 vs. 60.4 months (mo), p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo, p = 0.003], but not in the squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score is an independent biomarker of prognosis for OS in both the entire cohort [hazard ratio (HR): 1.498; 95% confidence interval (CI), 1.167–1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275–2.738; p = 0.001]. This score was also analyzed in an independent cohort of 114 adenocarcinoma patients, confirming its prognostic value [42.90 vs. not reached (NR) mo, p = 0.020]. In conclusion, our findings provide relevant prognostic information for lung adenocarcinoma patients and the basis for developing novel therapies. Further studies are required to identify suitable markers and targets for lung squamous cell carcinoma patients. More... »

PAGES

660

References to SciGraph publications

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  • Journal

    TITLE

    Cell Death & Disease

    ISSUE

    9

    VOLUME

    10

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41419-019-1898-1

    DOI

    http://dx.doi.org/10.1038/s41419-019-1898-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1120955211

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31506430


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