Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?
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Ana Luísa Coelho1,2, Mónica Patrícia Gomes1,3, Raquel Jorge Catarino1,2, Christian Rolfo4,5, Agostinho Marques Lopes2,6, Rui Manuel Medeiros1,3,7 and António Manuel Araújo3,8
1 Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal
2 Faculdade de Medicina, University of Porto, Porto, Portugal
3 Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
4 Phase I, Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium
5 Centre of Oncological Research (CORE), Antwerp University, Edegem, Belgium
6 Centro Hospitalar de S. João, Pulmonology Department, Porto, Portugal
7 Liga Portuguesa Contra o Cancro (NRNorte), Research Department, Porto, Portugal
8 Centro Hospitalar do Porto, Medical Oncology Department, Porto, Portugal
Christian Rolfo, email:
Keywords: NSCLC, angiogenesis, anti-angiogenic strategies, vessel co-option, angiopoietin-2
Received: January 25, 2016 Accepted: February 09, 2016 Published: February 29, 2016
The critical role of angiogenesis in tumor development makes its inhibition a valuable new approach in therapy, rapidly making anti-angiogenesis a major focus in research. While the VEGF/VEGFR pathway is the main target of the approved anti-angiogenic molecules in NSCLC treatment, the results obtained are still modest, especially due to resistance mechanisms. Accumulating scientific data show that vessel co-option is an alternative mechanism to angiogenesis during tumor development in well-vascularized organs such as the lungs, where tumor cells highjack the existing vasculature to obtain its blood supply in a non-angiogenic fashion. This can explain the low/lack of response to current anti-angiogenic strategies. The same principle applies to lung metastases of other primary tumors. The exact mechanisms of vessel co-option need to be further elucidated, but it is known that the co-opted vessels regress by the action of Angiopoietin-2 (Ang-2), a vessel destabilizing cytokine expressed by the endothelial cells of the pre-existing mature vessels. In the absence of VEGF, vessel regression leads to tumor cell loss and hypoxia, with a subsequent switch to a neoangiogenic phenotype by the remaining tumor cells. Unravelling the vessel co-option mechanisms and involved players may be fruitful for numerous reasons, and the particularities of this form of vascularization should be carefully considered when planning anti-angiogenic interventions or designing clinical trials for this purpose. In view of the current knowledge, rationale for therapeutic approaches of dual inhibition of Ang-2 and VEGF are swiftly gaining strength and may serve as a launchpad to more successful NSCLC anti-vascular treatments.
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