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Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches?
Ana Luísa Coelho1,2, Mónica Patrícia Gomes1,3, Raquel Jorge Catarino1,2
1Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.
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.
Insights
Tumor cells can hijack existing blood vessels via vessel co-option, bypassing anti-angiogenesis therapies. Dual inhibition of Angiopoietin-2 (Ang-2) and VEGF shows promise for improving non-small cell lung cancer (NSCLC) treatment.
Area of Science:
- Oncology
- Vascular Biology
- Cancer Therapeutics
Background:
- Anti-angiogenesis targeting the VEGF/VEGFR pathway is a key strategy in non-small cell lung cancer (NSCLC) therapy.
- Current anti-angiogenic therapies show modest efficacy in NSCLC, partly due to resistance mechanisms.
- Tumor vessel co-option, where tumors utilize existing vasculature, is an alternative to angiogenesis, particularly in well-vascularized organs like the lungs.
Purpose of the Study:
- To investigate the role of vessel co-option as a resistance mechanism to anti-angiogenesis in NSCLC.
- To explore the mechanisms of vessel co-option, including the involvement of Angiopoietin-2 (Ang-2).
- To evaluate the potential of dual inhibition of Ang-2 and VEGF as a therapeutic strategy for NSCLC.
Main Methods:
- Review of accumulating scientific data on tumor vascularization mechanisms.
- Analysis of the role of Ang-2 in the regression of co-opted vessels.
- Exploration of the implications of vessel co-option for anti-angiogenic therapy design.
Main Results:
- Vessel co-option allows tumors to bypass anti-angiogenic treatments by hijacking pre-existing vasculature.
- Ang-2 promotes the regression of co-opted vessels in the absence of VEGF, potentially leading to tumor cell loss and hypoxia.
- Tumor cells may switch to a neoangiogenic phenotype following vessel regression induced by Ang-2 inhibition.
Conclusions:
- Vessel co-option is a significant factor contributing to the limited response to current anti-angiogenic therapies in NSCLC.
- Understanding vessel co-option mechanisms is crucial for developing more effective anti-vascular treatments.
- Dual inhibition of Ang-2 and VEGF presents a promising therapeutic approach to overcome resistance and improve outcomes in NSCLC.
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