Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation
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The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.
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Accumulating evidence shows that antiangiogenic drugs normalize the overall function of tumor vessels before disrupting tumor vessels to improve tumor blood supply and increase tissue oxygen content.
“With the proposal of the “vascular normalization” theory, accumulating evidence has shown that antiangiogenic drugs normalize the overall function of tumor vessels before disrupting tumor vessels to improve tumor blood supply and increase the tissue oxygen content.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [259]
Antiangiogenic drugs have a synergistic antitumor effect in combination with radiotherapy and chemotherapy in clinical practice.
“Therefore, antiangiogenic drugs have a synergistic antitumor effect in combination with radiotherapy and chemotherapy in clinical practice.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [259]
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- Authors
- Winkler, F., Kozin, S. V., Tong, R. T., Chae, S.-S., Booth, M. F., Garkavtsev, I., Xu, L., Hicklin, D. J., Fukumura, D., di Tomaso, E., Munn, L. L., & Jain, R. K.
- Affiliations
- Harvard University (US)
- Corresponding author
- Jain, Rakesh K.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 6
- Issue
- 6
- Pages
- 553-563
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2028437938
- Cited by
- 1,170
- References
- 52
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 19 · 2023: 28 · 2022: 26 · 2021: 51 · 2020: 47 · 2019: 55 · 2018: 35 · 2017: 72 · 2016: 60 · 2015: 53 · 2014: 56 · 2013: 69 · 2012: 85
- FWCI
- 18.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Cancer Institute (P01CA080124)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- vascular normalization, brain tumors, radiotherapy, anti-angiogenic therapy, tumor oxygenation, pericyte coverage, angiopoietin-1, basement membrane degradation, matrix metalloproteinases, tumor vasculature
- MeSH terms
- Chondroitin Sulfate Proteoglycan 4, Animals, Antibodies, Monoclonal, Antigens, Basement Membrane, Blood Vessels, Brain Neoplasms, Cell Movement, Combined Modality Therapy, Dipeptides, Fluorescein Angiography, Gamma Rays, Glioma, Humans, Immunohistochemistry, Male, Mice, Nude, Models, Biological, Neovascularization, Pathologic, Oxygen, Proteoglycans, Time Factors, Transfection, Blotting, Western, Up-Regulation, Gene Expression Regulation, Neoplastic, Apoptosis, Pericytes, Oligonucleotide Array Sequence Analysis, Angiogenesis Inhibitors, Matrix Metalloproteinases, Xenograft Model Antitumor Assays, Collagen Type IV, Ephrin-B2, Vascular Endothelial Growth Factor Receptor-2, Angiopoietin-1, Receptor, TIE-2, Cell Line, Tumor, Mice, Matrix Metalloproteinase Inhibitors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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