| Autor: |
Herreros-Pomares A; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.; CIBERONC, Valencia, Spain., de-Maya-Girones JD; Oncogenic Signalling Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain., Calabuig-Fariñas S; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.; CIBERONC, Valencia, Spain.; Department of Pathology, Universitat de València, Valencia, Spain., Lucas R; Department of History of Science and Documentation, Universitat de València, Valencia, Spain., Martínez A; Cytomic Core Facility, Centro de Investigación Príncipe Felipe, Valencia, Spain., Pardo-Sánchez JM; Oncogenic Signalling Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain., Alonso S; Program of Predictive and Personalized Medicine of Cancer, Institut de Reserca Germans Trias i Pujol (PMPPC-IGTP), Badalona, Spain., Blasco A; Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain., Guijarro R; Department of Thoracic Surgery, Hospital General Universitario de Valencia, Valencia, Spain., Martorell M; Department of Pathology, Hospital General Universitario de Valencia, Valencia, Spain., Escorihuela E; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.; CIBERONC, Valencia, Spain., Chiara MD; CIBERONC, Valencia, Spain.; Institute of Sanitary Research of Asturias, Hospital Central de Asturias, Universidad de Oviedo, Oviedo, Spain., Duréndez E; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.; CIBERONC, Valencia, Spain., Gandía C; Oncogenic Signalling Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain., Forteza J; Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular, Centro Investigación Príncipe Felipe/Universidad Católica de Valencia, Valencia, Spain., Sirera R; CIBERONC, Valencia, Spain.; Department of Biotechnology, Universidad Politécnica de Valencia, Valencia, Spain., Jantus-Lewintre E; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain. jantus_elo@gva.es.; CIBERONC, Valencia, Spain. jantus_elo@gva.es.; Department of Biotechnology, Universidad Politécnica de Valencia, Valencia, Spain. jantus_elo@gva.es., Farràs R; Oncogenic Signalling Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain. rfarras@cipf.es., Camps C; Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Valencia, Spain.; CIBERONC, Valencia, Spain.; Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain.; Department of Medicine, Hospital General Universitario de Valencia, Valencia, Spain. |
| Abstrakt: |
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. |
