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Annals of Oncology 28 (Supplement 5): v453–v456, 2017
doi:10.1093/annonc/mdx381
NSCLC, EARLY STAGE
1274PD
Analysis of immunoregulatory biomarkers in early stages of nonsmall cell lung cancer
A. Moreno Manuel1, S. Calabuig Fari~
nas2, A. Herreros Pomares1, S. Gallach Garcia3,
F. Aranda4, A. Blasco5, E. Carreras4, F. Lozano6, A. Cunquero Tomas7, M. Martorell8,
E. Jantus-Lewintre9, C. Camps Herrero10
1
Laboratorio de Oncologıa Molecular, Fundaci
on para la Investigaci
on, Hospital
General Universitario de Valencia, Valencia, Spain, 2Laboratorio de Oncologıa
Molecular, Fundacion para la Investigaci
on, Hospital General Universitario de ValenciaCIBERONC; Departamento de Patologıa, Universitat de València, Valencia, Spain,
3
Laboratorio de Oncologıa Molecular, Fundaci
on de Investigaci
on Hospital General
Universitario de Valencia-CIBERONC, Valencia, Spain, 4Immunoreceptors of the Innate
and Adaptative System, Institut d’Investigacions Biomèdiques August Pi i Sunyer,
Barcelona, Spain, 5Servicio de Oncologıa Médica, Hospital General Universitario de
ostic
Valencia-CIBERONC, Valencia, Spain, 6Servei d’Immunologia, Centre de Diagn
Biomèdic, Hospital Clınic de Barcelona, Immunoreceptors of the Innate and Adaptive
System, Institut d’Investigacions Biomèdiques August Pi i Sunyer; Departament de
Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain, 7Servicio
de Oncologıa Médica, Hospital General Universitario de Valencia, Valencia, Spain,
8
Servicio de Anatomıa Patol
ogica, Hospital General Universitario de Valencia, Spain;
Departamento de Patologıa, Universidad de Valencia, Valencia, Spain, 9Laboratorio de
Oncologıa Molecular, Fundaci
on para la Investigaci
on, Hospital General Universitario
de Valencia-CIBERONC, Spain; Departamento de Biotecnologıa, Universidad Politécnica
10
on para la
de Valencia, Valencia, Spain, Laboratorio de Oncologıa Molecular, Fundaci
Investigacion, Hospital General Universitario de Valencia-CIBERONC, Spain; Servicio de
Oncologıa Médica, Hospital General Universitario de Valencia, Spain; Departamento de
Medicina, Universidad de Valencia, Valencia, Spain
Background: The study of the tumour microenvironment is leading to a better understanding of the evasion of immune surveillance and the development of new therapies.
This research focuses on the analysis of immunoregulatory genes as potential prognostic biomarkers in resectable non-small cell lung cancer (NSCLC).
Methods: The expression of 8 genes involved in immune-regulation (PD-L1, PD-L2,
IDO-1, IDO-2, ICOS-LG, CD5, CD6 and CD200) was analysed by RTqPCR in 257
paired fresh frozen tumour and normal tissue samples of resected NSCLC. Relative expression was calculated by Pfaffl formulae using ACTB, CDKN1B and GUSB as endogenous controls. Non-parametric tests were used for correlations between clinicopathological and analytical variables and survival was assessed by Kaplan-Meier curves
(long rank-test), considering significant p < 0.05.
Results: Patients median age was 64 years, 82% were males, 88% were former or current
smokers, 47% were adenocarcinomas (ADC). Patients with higher expression of CD5
and IDO2 had a significant increase in overall survival (OS, 53.3 vs NR months,
p ¼ 0.032; 51.9 vs NR months, p ¼ 0.049, respectively). A signature combining the expression of CD5 and IDO2 was able to better prognosticate survival (40.4 vs NR
months, p ¼ 0.028). The multivariate analysis (including clinico-pathological and analytical variables) showed that this signature has independent prognostic information
OS (HR ¼ 0.553 [0.344-0.887], p ¼ 0.016). Moreover, in the subgroup of ADC
increased expression of CD5 and IDO2 was associated with longer OS as well as
increased relapse-free survival (RFS, 19.1 vs NR months, p ¼ 0.045; 18.8 and 67.0
months, p ¼ 0.029, respectively). The multivariate analysis established this gene signature as an independent prognostic biomarker for OS (HR ¼ 0.380 [0.166-0.872];
p ¼ 0.026) and RFS (HR ¼ 0.288 [0.139-0.597]; p ¼ 0.002).
Conclusions: The analyses revealed the prognostic value of CD5 and IDO2, being their
combination an independent prognostic marker in resectable NSCLC. Supported by
grants from FEDER and PI12-02838 and PI15-00753 from ISCIII.
Legal entity responsible for the study: Fundaci
on para la Investigaci
on del Hospital
General Universitario de Valencia
Funding: Supported by grants from FEDER and PI12-02838 and PI15-00753 from
ISCIII.
Disclosure: All authors have declared no conflicts of interest.
1275PD
Stemness characterization of tumorspheres from non-small cell
lung cancer: Differential expression in CSC-related markers and
signaling pathways
nas2, E. Escorihuela3, H. Amado1, R. Guijarro4,
A. Herreros Pomares1, S. Calabuig Fari~
S. Gallach Garcia3, A. Navarro5, E. Jantus-Lewintre6, C. Camps Herrero7
1
Laboratorio de Oncologıa Molecular, Fundaci
on de Investigaci
on fc, Valencia, Spain,
2
Laboratorio de Oncologıa Molecular; Fundaci
on de Investigaci
on Hospital General
Universitario de Valencia-CIBERONC, Spain; Departamento de Patologıa, Universitat de
3
on de
València, Valencia, Spain, Laboratorio de Oncologıa Molecular, Fundaci
Investigaci
on Hospital General Universitario de Valencia-CIBERONC, Valencia, Spain,
4
Departamento de Cirugıa, Universidad de Valencia, Servicio de Cirugıa Tor
acica,
Hospital General Universitario de Valencia-CIBERONC, Valencia, Spain, 5Servicio de
Anatomıa Patol
ogica, Hospital General Universitario de Valencia, Valencia, Spain,
6
Laboratorio de Oncologıa Molecular, Fundaci
on para la Investigaci
on, Hospital
General Universitario de Valencia-CIBERONC, Spain; Departamento de Biotecnologıa,
7
Universidad Politécnica de Valencia, Valencia, Spain, Laboratorio de Oncologıa
Molecular, Fundaci
on para la Investigaci
on, Hospital General Universitario de ValenciaCIBERONC, Spain; Departamento de Medicina, Universidad de Valencia, Spain; Servicio de
Oncologıa Médica, Hospital Hospital General Universitario de Valencia, Valencia, Spain
Background: Treatment resistance and relapse have been associated to cancer stem cells
(CSCs), a highly tumorigenic subpopulation of cells with self-renewal properties and
the ability to grow forming tumorspheres in non-adherent conditions. The aim of this
study was to isolate and characterize CSCs from lung cancer cell lines and tumor-tissue
from resectable non-small cell lung cancer (NSCLC).
Methods: The study was performed on tumour cells from 8 resected NSCLC patients and
12 NSCLC cell lines grown in monolayer and as spheroids. The expression of 60 genes,
including CSC-markers, pluripotency inducers, cell cycle regulators, invasion promoters
and components of Notch, Wnt and Hedgehog pathways was analysed by RTqPCR. In
addition, protein levels of CSC-markers (ALDH1A1, CD133, CD166, CD44 and
EpCAM), pluripotency inducers (Nanog, Oct-4 and Sox2), Wnt components (Wnt3 and
b-catenin) and Notch1 were assessed by western blot and immunofluorescence.
Results: Lung tumorspheres had significantly higher expression levels of CSC-related
genes EPCAM1, CD44, ALDH1A1, CDKN1A, CCND1, and KLF4 compared to their
paired-adherent cells. Similarly, epithelial to mesenquimal transition (EMT) inducer
SNAI1 and integrins ITGA2, ITGA6 and ITGB1 were overexpressed in lungspheres.
Notch pathway ligands, JAG1 and DLL4, receptors, NOTCH1, NOTCH2 and
NOTCH3, and the effector factor HES1 showed increased expression in spheroids. In
Wnt, higher expression levels of WNT3, CTNNB1 and GSK3B were found in tumorspheres. No significant differences were found for the rest of genes analyzed. Western
blot and immunofluorescence analyses revealed that CD44, CD133, Sox2 and b-catenin
were highly expressed in spheroids from cell lines and patients’ samples. The expression
of the rest of proteins evaluated differed among specimens.
Conclusions: Our results suggest four molecules which could act as markers for CSCs
in NSCLC. Genes related to Notch and Wnt signaling pathways were more expressed in
spheroids compared to the cells grown in adherence, suggesting that both pathways
could be interesting targets against lung CSCs. Supported by grants RD12/0036/0025
from RTICC-FEDER, and PI12-02838 and PI15-00753 from ISCIII.
Legal entity responsible for the study: Fundaci
on de Investigaci
on Hospital General
Universitario de Valencia.
Funding: Supported by grants RD12/0036/0025 from RTICC-FEDER, and PI12-02838
and PI15-00753 from ISCIII.
Disclosure: All authors have declared no conflicts of interest.
Keywords: Cancer stem cells, Non - small cell lung cancer, gene expression analysis.
1277PD
A phase II randomized trial of adjuvant chemotherapy for the
patients completely resected pathological stage IB (T > 5cm), II, IIIA
non-small cell lung cancer comparing S-1 versus S-1 with cisplatin
T. Okamoto1, T. Yano2, M. Shimokawa3, S. Takeo4, K. Yamazaki4, K. Sugio5,
M. Takenoyama6, A. Nagashima7, T. Tagawa1, Y. Emi8, Y. Maehara1
1
Department of Surgery and Science, Kyushu University, Graduate School of Medical
Sciences, Fukuoka, Japan, 2Department of Thoracic Surgery, National Hospital
Organization Beppu Medical Center, Beppu, Japan, 3Clinical Research Institute,
National Kyushu Cancer Center, Fukuoka, Japan, 4Department of Thoracic Surgery and
Clinical Research Institute, National Kyushu Medical Center Hospital, Fukuoka, Japan,
5
Department of Thoracic and Breast Surgery, Oita University, Faculty of Medicine, Yufu,
Japan, 6Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka,
Japan, 7Department of Thoracic Surgery and Clinical Research Institute, Kitakyushu
Municipal Medical Center, Kitakyushu, Japan, 8Department of Surgery, Saiseikai
Fukuoka General Hospital, Fukuoka, Japan
Background: Platinum-based combination chemotherapy is a standard postoperative
adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC).
C European Society for Medical Oncology 2017. Published by Oxford University Press.
V
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