Effect of Vascular Normalization by Antiangiogenic Therapy on Interstitial Hypertension, Peritumor Edema, and Lymphatic Metastasis: Insights from a Mathematical Model
Open accessPublished version of a preprint
Abstract
Preclinical and clinical evidence shows that antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with antiangiogenic therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that antiangiogenic therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies. [Cancer Res 2007;67(6):2729–35]
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Steep pressure gradients at the tumor periphery favor tumor growth and metastasis.
“The uniformly elevated IFP in tumor center is responsible for inhibiting drug delivery [172, 178, 186] while the steep pressure gradients at the periphery favors tumor growth and metastasis[154,[187][188][189][190].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [187]
The Introduction says pressure falls sharply at the tumor margin, creating fluid flow that transports molecules and cells facilitating angiogenesis and metastasis. The Mathematical model section says less steep gradients could potentially reduce lymphatic metastasis. The paper does not explicitly link the peripheral gradient to tumor growth, and presents its effect on metastasis as a proposed mechanism rather than an established outcome. (LLM, conf=0.84)
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- Authors
- Jain, R. K., Tong, R. T., & Munn, L. L.
- Affiliations
- Harvard University (US)
- ORCID
- Munn, Lance L.
- Venue
- Cancer Research
- Published
- 2007-03-15
- Volume
- 67
- Issue
- 6
- Pages
- 2729-2735
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3022341
- OpenAlex
- W2055009621
- Cited by
- 612
- References
- 53
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 24 · 2023: 28 · 2022: 42 · 2021: 28 · 2020: 38 · 2019: 31 · 2018: 34 · 2017: 20 · 2016: 27 · 2015: 42 · 2014: 33 · 2013: 33 · 2012: 46
- FWCI
- 14.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01 CA 85140, R01CA085140, P01CA080124)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- tumor vasculature normalization, anti-angiogenic therapy, interstitial fluid pressure, interstitial fluid velocity, lymph node metastasis, VEGF-C, VEGF-A, sentinel lymph node metastasis, brain tumors, ascites
- MeSH terms
- Animals, Capillary Permeability, Edema, Humans, Lymphatic Metastasis, Mathematical Computing, Models, Biological, Neoplasms, Neovascularization, Pathologic, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor C, Extracellular Fluid
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