Cited by 1,605Angiogenesis and VEGF in CancerLymphatic System and DiseasesBarrier Structure and Function Studies

Normalization of the Vasculature for Treatment of Cancer and Other Diseases

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Goel, Shom, Duda, Dan G., Xu, Lei, Munn, Lance L., Boucher, Yves, Fukumura, Dai, Jain, Rakesh K.·2011·Physiological Reviews

Abstract

New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a “normalization” of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more “mature” or “normal” phenotype. This “vascular normalization” is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.

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  • High solid stress can increase drug resistance, influence tumor cell gene expression, compromise immune cells' ability to kill cancerous cells, turn macrophages to tumor-friendly cells, and thereby enhance the metastatic potential of cancer cells.

    “In addition to increasing drug resistance, a high SS could influence tumor cells' gene expression, comprise immune cells ability to kill cancerous cells or even turn macrophages to tumorfriendly cells, thereby enhancing the metastatic potential of cancer cells [180-184].”

    From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [182]

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  1. Emblem KE Polaskova P Jennings DL Gerstner E Batchelor TT Jain RK Sorensen AG Increased blood flow during anti-VEGF induced vascular normalization 2011 Proceedings of the 2011 Meeting of the International Soceity for Magnetic Resonance in Medicine Abstr. 247

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Authors
Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K.
Affiliations
Harvard University (US)
Corresponding author
Jain, Rakesh K.
Venue
Physiological Reviews
Published
2011-07
Volume
91
Issue
3
Pages
1071-1121
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
OpenAlex
W2104300873
Cited by
1,605
References
320
Citations by year
2026: 102 · 2025: 85 · 2024: 109 · 2023: 101 · 2022: 99 · 2021: 127 · 2020: 103 · 2019: 87 · 2018: 114 · 2017: 98 · 2016: 102 · 2015: 121 · 2014: 116 · 2013: 133 · 2012: 94
FWCI
10.36
Type
journal article
Language
en
Open access
Locations
  • Physiological Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA115767, T32CA073479, R01CA159258, R01CA085140, R01CA096915, R35CA056591, R24CA085140, P01CA080124, R01CA126642, R21CA139168)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
vascular normalization, tumor angiogenesis, anti-VEGF therapy, vascular endothelial growth factor, tumor vasculature, tumor hypoxia, interstitial fluid pressure, tumor microenvironment, pericyte coverage, basement membrane, PDGFRβ, PHD2, RGS5, TGF-beta, combination chemotherapy, radiotherapy, immunotherapy, metastasis, hyperpermeability
MeSH terms
Animals, Blood Vessels, Disease, Humans, Lymphatic System, Models, Cardiovascular, Neoplasms, Neovascularization, Pathologic, Disease Progression, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor A

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