title: Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?
abstract: 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.
authors.affiliation: Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.|Faculdade de Medicina, University of Porto, Porto, Portugal.
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Coelho
authors.affiliation: Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.
authors.forename: Mónica Patrícia
authors.initials: MP
authors.lastname: Gomes
authors.affiliation: Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.|Faculdade de Medicina, University of Porto, Porto, Portugal.
authors.forename: Raquel Jorge
authors.initials: RJ
authors.lastname: Catarino
authors.affiliation: Phase I, Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium.|Centre of Oncological Research (CORE), Antwerp University, Edegem, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Faculdade de Medicina, University of Porto, Porto, Portugal.|Centro Hospitalar de S. João, Pulmonology Department, Porto, Portugal.
authors.forename: Agostinho Marques
authors.initials: AM
authors.lastname: Lopes
authors.affiliation: Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.|Liga Portuguesa Contra o Cancro (NRNorte), Research Department, Porto, Portugal.
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Medeiros
authors.affiliation: Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.|Centro Hospitalar do Porto, Medical Oncology Department, Porto, Portugal.
authors.forename: António Manuel
authors.initials: AM
authors.lastname: Araújo
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000473:pathology*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*
keywords: NSCLC; angiogenesis; angiopoietin-2; anti-angiogenic strategies; vessel co-option