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Updated: May 29, 2026
Preparation Of Neovascular Tissues from Human Glioma Tissues for Quantitative Proteomics Analysis of Tumor Angiogenesis
Published on: March 20, 2026
Tumor-surrogate blood vessel subtypes exhibit differential susceptibility to anti-VEGF therapy
Basel Sitohy1, Janice A Nagy, Shou-Ching Shih Jaminet
1The Center for Vascular Biology Research and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
Antivascular therapy directed against VEGF or its receptors (VEGFR) 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-A(164). 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-A(164). Administering VEGF Trap treatment before or shortly after injection of a recombinant VEGF-A(164)-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.
Insights
Anti-VEGF therapy is effective against early-stage tumor vessels but less so against later-stage ones. Different blood vessel types exhibit varying sensitivities to anti-VEGF treatments like Aflibercept (VEGF Trap).
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Anti-VEGF/VEGFR therapies show success in early tumor vascularization but limited efficacy in later stages.
- Tumor blood vessels are heterogeneous, with distinct subpopulations potentially varying in VEGF dependence and therapy susceptibility.
- Human cancers harbor diverse vessel types (MV, GMP, VM, FA, DV) that can be modeled in mice using VEGF-A(164).
Purpose of the Study:
- To investigate the differential sensitivity of distinct blood vessel subtypes to anti-VEGF therapy.
- To determine if vessel type and VEGFR-2 expression levels correlate with susceptibility to VEGF Trap treatment.
- To provide a potential explanation for the clinical limitations of anti-VEGF therapy in advanced human cancers.
Main Methods:
- Generated distinct blood vessel types (MV, GMP, VM, FA, DV) in mice using VEGF-A(164) expression vectors.
- Administered Aflibercept (VEGF Trap) at various time points relative to neovasculature formation.
- Assessed the sensitivity of each vessel subtype to VEGF Trap by evaluating their response to treatment.
Main Results:
- Early-forming mother vessels (MV) and glomeruloid microvascular proliferations (GMP) expressing high VEGFR-2 were highly susceptible to VEGF Trap.
- Late-forming vascular malformations (VM), feeding arteries (FA), and draining veins (DV) expressing low VEGFR-2 were largely resistant to VEGF Trap.
- Treatment efficacy decreased progressively as therapy initiation was delayed after neovasculature formation.
Conclusions:
- Different blood vessel subtypes exhibit distinct sensitivities to anti-VEGF therapy, influenced by VEGFR-2 expression levels.
- Late-forming, VEGFR-2-low vessels (VMs, FAs, DVs) are resistant to VEGF Trap, potentially explaining limited clinical efficacy.
- Understanding vessel subtype susceptibility is crucial for improving anti-VEGF treatment strategies in human cancers.
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