Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges
Open accessAbstract
Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents-originally developed to starve tumors-could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms. In parallel, we demonstrated that desmoplasia could also impair vascular function by compressing vessels, and that normalizing the extracellular matrix could improve vascular function and treatment outcome in both preclinical and clinical settings. Here, we summarize the progress made in understanding and applying the normalization concept to cancer and outline opportunities and challenges ahead to improve patient outcomes using various normalizing strategies.
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Anti-angiogenic agents are able to normalize malfunctioning tumoral blood vessels by improving tumor tissue perfusion and decreasing hypoxia.
“Later on, it was turned out that all these agents are able to normalize the malfunctioning tumoral blood vessels [67] by improving tumor tissue perfusion and decreasing hypoxia.”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [67]
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Self-citationModulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise
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Self-citationStromal disrupting effects of nab-paclitaxel in pancreatic cancer
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Self-citationOxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche
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Self-citationRole of vascular normalization in benefit from metronomic chemotherapy
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Self-citationInvestigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases
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Self-citationSmall GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels
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Self-citationEndothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization
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Self-citationCD4 + T Cell Activation and Vascular Normalization: Two Sides of the Same Coin?
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The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
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Wang, H., Yuan, S., & Wang, H. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70985 · Cited by 11 · see citing works
- Authors
- Martin, J. D., Seano, G., & Jain, R. K.
- Affiliations
- The University of Tokyo (JP)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Corresponding author
- Jain, Rakesh K.
- Venue
- Annual Review of Physiology
- Publisher
- Annual Reviews
- Published
- 2019-02-10
- Volume
- 81
- Issue
- 1
- Pages
- 505-534
- ISSN
- 0066-4278 (ISSN-L)
- 1545-1585
- PMC
- PMC6571025
- OpenAlex
- W2914098003
- Cited by
- 530
- References
- 155
- Citations by year
- 2026: 70 · 2025: 71 · 2024: 72 · 2023: 74 · 2022: 90 · 2021: 71 · 2020: 68 · 2019: 14
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Centre National de la Recherche Scientifique
- Japan Society for the Promotion of Science (P16731)
- National Cancer Institute (U01CA224348, P01CA080124, R35CA197743, R01CA208205, R01CA129371, P50CA165962)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- tumor vasculature normalization, anti-angiogenic therapy, tumor microenvironment, tumor hypoxia, desmoplasia, extracellular matrix, vascular function, interstitial fluid pressure, tumor immunosuppression, treatment resistance, anticancer drug delivery
- MeSH terms
- Animals, Hypoxia, Humans, Neoplasms, Neovascularization, Pathologic, Tumor Microenvironment
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
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