Lung tumorspheres reveal cancer stem cell-like properties and a score with prognostic impact in resected non-small-cell lung cancer
Por:
Herreros-Pomares, A, de-Maya-Girones, JD, Calabuig-Farinas, S, Lucas, R, Martinez, A, Pardo-Sanchez, JM, Alonso, S, Blasco, A, Guijarro, R, Martorell, M, Escorihuela, E, Chiara, MD, Durendez, E, Gandia, C, Forteza, J, Sirera, R, Jantus-Lewintre, E, Farras, R and Camps, C
Publicada:
10 sep 2019
Ahead of Print:
10 sep 2019
Resumen:
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), 1.1671.922; 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.
Filiaciones:
Herreros-Pomares, A:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
de-Maya-Girones, JD:
Ctr Invest Principe Felipe, Oncogen Signalling Lab, Valencia, Spain
Calabuig-Farinas, S:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Univ Valencia, Dept Pathol, Valencia, Spain
Lucas, R:
Univ Valencia, Dept Hist Sci & Documentat, Valencia, Spain
Martinez, A:
Ctr Invest Principe Felipe, Cytom Core Facil, Valencia, Spain
Pardo-Sanchez, JM:
Ctr Invest Principe Felipe, Oncogen Signalling Lab, Valencia, Spain
:
Inst Reserca Germans Trias & Pujol PMPPC IGTP, Program Predict & Personalized Med Canc, Badalona, Spain
Blasco, A:
Hosp Gen Univ Valencia, Dept Med Oncol, Valencia, Spain
Guijarro, R:
Hosp Gen Univ Valencia, Dept Thorac Surg, Valencia, Spain
Martorell, M:
Hosp Gen Univ Valencia, Dept Pathol, Valencia, Spain
Escorihuela, E:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Chiara, MD:
CIBERONC, Valencia, Spain
Univ Oviedo, Hosp Cent Asturias, Inst Sanitary Res Asturias, Oviedo, Spain
Durendez, E:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Gandia, C:
Ctr Invest Principe Felipe, Oncogen Signalling Lab, Valencia, Spain
Forteza, J:
Univ Catolica Valencia, Ctr Invest Principe Felipe, Unidad Mixta Patol Mol, Inst Valenciano Patol, Valencia, Spain
Sirera, R:
CIBERONC, Valencia, Spain
Univ Politecn Valencia, Dept Biotechnol, Valencia, Spain
Jantus-Lewintre, E:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Univ Politecn Valencia, Dept Biotechnol, Valencia, Spain
Farras, R:
Ctr Invest Principe Felipe, Oncogen Signalling Lab, Valencia, Spain
Camps, C:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Hosp Gen Univ Valencia, Dept Med Oncol, Valencia, Spain
Hosp Gen Univ Valencia, Dept Med, Valencia, Spain
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