Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype
Article first published online: 5 FEB 2014
© 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 4, pages 539–550, April 2014
How to Cite
EMBO Mol Med (2014) 6, 539–550
- Issue published online: 2 APR 2014
- Article first published online: 5 FEB 2014
- Manuscript Accepted: 27 DEC 2013
- Manuscript Revised: 20 DEC 2013
- Manuscript Received: 21 JUN 2013
- UTE project CIMA
- European Union. Grant Number: HEALTH-F2-2010-258677
- Sara Borrell Program
- Spanish Government, Instituto de Salud Carlos III. Grant Numbers: PI11/00618, PI10/00166, PI13/00806
- Red Temática de Investigación Cooperativa en Cáncer. Grant Number: RD12/0036/0040
- Spanish Ministry of Economy and Competitiveness & European Regional Development Fund
- Una manera de hacer Europa
- Government of Navarra, Department of Health. Grant Number: 39/2007
- lung cancer;
- mouse models;
- squamous cell carcinoma
The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC.
Antiangiogenic therapies induce contrasting responses in non-small cell lung cancer (NSCLC) depending on the histological subtype. Anti-VEGFR2 therapies stabilize adenocarcinomas (ADCs) but induce tumor cell hyperproliferation in squamous cell carcinomas (SCCs).
- Antiangiogenic therapies induce contrasting responses in NSCLC depending on the histological subtype
- Anti-VEGFR2 therapies (sunitinib and DC101) stabilize ADC tumors
- VEGFR2 blockade induces hyperproliferation of tumor cells and increases cell survival in SCC of the lung
- Antiangiogenic therapies induce the expression of stem cell markers in SCC, independently of intratumoral hypoxia.