Cited by 1,689Angiogenesis and VEGF in CancerBarrier Structure and Function StudiesLymphatic System and Diseases

Openings Between Defective Endothelial Cells Explain Tumor Vessel Leakiness

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Hashizume, Hiroya, Baluk, Peter, Morikawa, Shunichi, McLean, John W., Thurston, Gavin, Roberge, Sylvie, Jain, Rakesh K., McDonald, Donald M.·2000·The American Journal of Pathology

Abstract

Leakiness of blood vessels in tumors may contribute to disease progression and is key to certain forms of cancer therapy, but the structural basis of the leakiness is unclear. We sought to determine whether endothelial gaps or transcellular holes, similar to those found in leaky vessels in inflammation, could explain the leakiness of tumor vessels. Blood vessels in MCa-IV mouse mammary carcinomas, which are known to be unusually leaky (functional pore size 1.2-2 microm), were compared to vessels in three less leaky tumors and normal mammary glands. Vessels were identified by their binding of intravascularly injected fluorescent cationic liposomes and Lycopersicon esculentum lectin and by CD31 (PECAM) immunoreactivity. The luminal surface of vessels in all four tumors had a defective endothelial monolayer as revealed by scanning electron microscopy. In MCa-IV tumors, 14% of the vessel surface was lined by poorly connected, overlapping cells. The most superficial lining cells, like endothelial cells, had CD31 immunoreactivity and fenestrae with diaphragms, but they had a branched phenotype with cytoplasmic projections as long as 50 microm. Some branched cells were separated by intercellular openings (mean diameter 1.7 microm; range, 0.3-4.7 microm). Transcellular holes (mean diameter 0.6 microm) were also present but were only 8% as numerous as intercellular openings. Some CD31-positive cells protruded into the vessel lumen; others sprouted into perivascular tumor tissue. Tumors in RIP-Tag2 mice had, in addition, tumor cell-lined lakes of extravasated erythrocytes. We conclude that some tumor vessels have a defective cellular lining composed of disorganized, loosely connected, branched, overlapping or sprouting endothelial cells. Openings between these cells contribute to tumor vessel leakiness and may permit access of macromolecular therapeutic agents to tumor cells.

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  1. [16]16. Peterson H-I: Vascular and extravascular spaces in tumors: tumor vascular permeability. Tumor Blood Circulation: Angiogenesis, Vas- cular Morphology and Blood Flow of Experimental and Human Tu- mors. Edited by Peterson H-I. Boca Raton, CRC Press, Inc., 1979, pp 77-85
  2. [39]39. Duke-Elder S, Perkins ES: Cysts and tumours of the uveal tract. System of Ophthalmology, chapter VI. Edited by Duke-Elder S. St. Louis, CV Mosby Company, 1966, pp 754 -937

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Authors
Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K., & McDonald, D. M.
Affiliations
  • University of California, San Francisco (US)
  • Harvard University (US)
Corresponding author
McDonald, Donald M.
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2000-04
Volume
156
Issue
4
Pages
1363-1380
ISSN
0002-9440 (ISSN-L)
OpenAlex
W2025036947
Cited by
1,689
References
85
Citations by year
2026: 30 · 2025: 37 · 2024: 62 · 2023: 58 · 2022: 68 · 2021: 99 · 2020: 100 · 2019: 70 · 2018: 71 · 2017: 63 · 2016: 76 · 2015: 64 · 2014: 82 · 2013: 89 · 2012: 83
FWCI
13.49
Type
journal article
Language
en
Open access
Locations
  • American Journal Of Pathology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (HL24136)
  • National Heart, Lung, and Blood Institute (R01HL059157, HL 24136, HL 59157, P01HL024136)
  • National Cancer Institute (R35CA056591, R35-CA-56591)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords
tumor vasculature, CD31, fenestrae, tumor angiogenesis, macromolecular drug delivery
MeSH terms
Animals, Blood Vessels, Capillary Permeability, Endothelium, Vascular, Extracellular Space, Female, Male, Microscopy, Electron, Microscopy, Electron, Scanning, Microscopy, Fluorescence, Neoplasm Transplantation, Mammary Neoplasms, Animal, Mice

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