Tumor-Surrogate Blood Vessel Subtypes Exhibit Differential Susceptibility to Anti-VEGF Therapy

Abstract

Anti-vascular therapy directed against VEGF or its receptors has been successful when administered at early stages of tumor vessel growth, but is less effective when administered later. Tumor blood vessels are heterogeneous, so vessel subpopulations may differ in their requirements for tumor cell-secreted VEGF and in their susceptibility to anti-VEGF/VEGFR therapy. Human cancers contain several distinct blood vessel types, including mother vessels (MV), glomeruloid microvascular proliferations (GMP), vascular malformations (VM), feeding arteries (FA) and draining veins (DV), all of which can be generated in mice in the absence of tumor cells using expression vectors for VEGF-A164. In this study, we investigated the sensitivity of each of these vessel types to anti-VEGF therapy with aflibercept ® (VEGF Trap), a potent inhibitor of VEGF-A164. Administering VEGF Trap treatment before or shortly after injection of a recombinant VEGF-A164 expressing adenovirus could prevent or regress tumor-free neovasculature, but it was progressively less effective if initiated at later times. Early-forming MVs and GMPs in which the lining endothelial cells expressed high levels of VEGFR-2 were highly susceptible to blockade by VEGF Trap. In contrast, late-forming VMs, FAs, and DVs that expressed low levels of VEGFR-2 were largely resistant. Together, our findings define the susceptibility of different blood vessel subtypes to anti-VEGF therapy, offering a possible explanation for the limited effectiveness of anti-VEGF-A/VEGFR treatment of human cancers, which are typically present for months to years before discovery and are largely populated by late-forming blood vessels.

Molecular Mechanisms of Preeclampsia

“…There is compelling evidence that the growth of some tumors is dependent on VEGF-induced angiogenesis (Sitohy et al 2011). VEGF inhibitor therapy caused early striking vascular changes in islet cell tumors.…”

Antiangiogenic Therapy for Glioblastoma: Current Status and Future Prospects

“…Notwithstanding a better understanding of the potential benefits of utilizing an optimal dose, schedule and drug combination, data from phase 3 clinical trials(19, 20)of bevacizumab suggest that some glioblastomas may be intrinsically resistant to antiangiogenic therapy. Inherent vessel insensitivity to the effect of VEGF inhibition could partially mediate this intrinsic resistance(21). Several adaptive resistance mechanisms may counteract any potential, initial benefit afforded by antiangiogenic therapy.…”

The Effects of All-Trans Retinoic Acid on Vasculogenic Mimicry Formation Ability in CD133+ Glioma Stem Cells and Its Mechanisms

“…Thus, ATRA may make a contribution to blocking the PLCγ-PKC-MAPK pathway in glioma stem cells to inhibit VM. In the meantime, recent therapies [47] demonstrated that only "early" vessels were highly responsive to anti-VEGF/VEGFR therapy, VM thereby might be consigned to the "early" vessels and ATRA might be an effective drug for anti-VEGF/VEGFR. However, further studies are still needed.…”