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.

Keywords: NSCLC; angiogenesis; angiopoietin-2; anti-angiogenic strategies; vessel co-option.

Figure 1. Vessel co-option and Ang-2 regulation in cancer development in vessel dense tissues

A. In well vascularized organs, such as the lung, tumor cells grow and migrate along quiescent normal vessels (vessel co-option). B. Over time, tumor cells induce extreme changes in the co-opted vessels and ECs start to express Ang-2, leading to vascular disruption and vessel regression. C. Regression of the co-opted vessel associated with regression of the ECs generates a hypoxic core in the tumor centre, with massive tumor cell loss. This triggers the angiogenic switch, with the remaining tumor cells expressing high amounts of VEGF. D. VEGF expression induces a robust angiogenic response that ultimately rescues the tumor and allows its growth and progression.