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Keywords:

  • angiogenesis;
  • lung cancer;
  • mouse models;
  • N-nitroso-tris-chloroethylurea;
  • squamous cell carcinoma

Abstract

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.

Synopsis

Thumbnail image of graphical abstract

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.