Openings Between Defective Endothelial Cells Explain Tumor Vessel Leakiness
Open accessAbstract
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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Cites
Risau, W. (1997) · Nature · doi:10.1038/386671a0 · Cited by 5,727 · see citing works
Endostatin: an endogenous inhibitor of angiogenesis and tumor growth
O'Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., & Folkman, J. (1997) · Cell · doi:10.1016/s0092-8674(00)81848-6 · Cited by 4,486 · see citing works
Sallusto, F., Cella, M., Danieli, C., & Lanzavecchia, A. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.182.2.389 · Cited by 2,501 · see citing works
Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment
Hobbs, S. K., Monsky, W. L., Yuan, F., Roberts, W. G., Griffith, L., Torchilin, V. P., & Jain, R. K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.8.4607 · Cited by 2,438 · see citing works
Self-citationVessel Cooption, Regression, and Growth in Tumors Mediated by Angiopoietins and VEGF
Holash, J. A., Maisonpierre, P. C., Compton, D. L., Boland, P., Alexander, C., Zagzag, D., Yancopoulos, G. D., & Wiegand, S. J. (1999) · Science · doi:10.1126/science.284.5422.1994 · Cited by 2,181 · see citing works
Vascular Channel Formation by Human Melanoma Cells in Vivo and in Vitro: Vasculogenic Mimicry
Maniotis, A. J., Folberg, R., Hess, A. R., Seftor, E. A., Gardner, L. M. G., Pe’er, J., Trent, J. M., Meltzer, P. S., & Hendrix, M. J. C. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65173-5 · Cited by 2,049 · see citing works
Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size.
Yuan, F., Dellian, M., Fukumura, D., Leunig, M., Berk, D. A., Torchilin, V. P., & Jain, R. K. (1995) · PubMed · Cited by 1,706 · see citing works
Self-citationMajno, G., & Palade, G. E. (1961) · The Journal of Cell Biology · doi:10.1083/jcb.11.3.571 · Cited by 1,529 · see citing works
Leakage-Resistant Blood Vessels in Mice Transgenically Overexpressing Angiopoietin-1
Thurston, G., Suri, C., Smith, K., McClain, J., Sato, T. T., Yancopoulos, G. D., & McDonald, D. M. (1999) · Science · doi:10.1126/science.286.5449.2511 · Cited by 1,350 · see citing works
Self-citationDefinition of Two Angiogenic Pathways by Distinct α v Integrins
Friedlander, M., Brooks, P. C., Shaffer, R. W., Kincaid, C. M., Varner, J. A., & Cheresh, D. A. (1995) · Science · doi:10.1126/science.270.5241.1500 · Cited by 1,310 · see citing works
Ausprunk, D. H., & Folkman, J. (1977) · Microvascular Research · doi:10.1016/0026-2862(77)90141-8 · Cited by 1,290 · see citing works
Hanahan, D. (1985) · Nature · doi:10.1038/315115a0 · Cited by 1,267 · see citing works
Transport of molecules across tumor vasculature
Jain, R. K. (1987) · Cancer and Metastasis Reviews · doi:10.1007/bf00047468 · Cited by 869 · see citing works
Self-citationDvorak, H. F., Nagy, J. A., Feng, D., Brown, L. F., & Dvorak, A. M. (1999) · Current Topics in Microbiology and Immunology · doi:10.1007/978-3-642-59953-8_6 · Cited by 743 · see citing works
Dvorak, H. F., Nagy, J. A., Dvorák, J., & Dvořàk, A. M. (1988) · PubMed Central · Cited by 679 · see citing works
Microvascular permeability of normal and neoplastic tissues
Gerlowski, L. E., & Jain, R. K. (1986) · Microvascular Research · doi:10.1016/0026-2862(86)90018-x · Cited by 623 · see citing works
Self-citationVEGFR-3 and Its Ligand VEGF-C Are Associated with Angiogenesis in Breast Cancer
Valtola, R., Salvén, P., Heikkilä, P., Taipale, J., Joensuu, H., Rehn, M., Pihlajaniemi, T. A., Weich, H. A., deWaal, R. M., & Alitalo, K. K. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65392-8 · Cited by 536 · see citing works
Meis‐Kindblom, J. M., & Kindblom, L. (1998) · The American Journal of Surgical Pathology · doi:10.1097/00000478-199806000-00005 · Cited by 511 · see citing works
Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions.
Less, J. R., Skalak, T. C., Sevick, E., & Jain, R. K. (1991) · PubMed · Cited by 508 · see citing works
Self-citationNeovasculature induced by vascular endothelial growth factor is fenestrated.
Roberts, W. G., & Palade, G. E. (1997) · PubMed · Cited by 446 · see citing works
Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice.
Thurston, G., McLean, J. W., Rizen, M., Bałuk, P., Haskell, A., Murphy, T. J., Hanahan, D., & McDonald, D. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci965 · Cited by 417 · see citing works
Self-citationThe next frontier of molecular medicine: Delivery of therapeutics
Jain, R. K. (1998) · Nature Medicine · doi:10.1038/nm0698-655 · Cited by 411 · see citing works
Self-citationJain, R. K., Safabakhsh, N., Sckell, A., Chen, Y., Jiang, P., Benjamin, L., Yuan, F., & Keshet, E. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10820 · Cited by 374 · see citing works
Self-citationLeunig, M., Yuan, F., Menger, M. D., Boucher, Y., Goetz, A. E., Meßmer, K., & Jain, R. K. (1992) · PubMed · Cited by 370 · see citing works
Self-citationTransgenic Mice as Probes into Complex Systems
Hanahan, D. (1989) · Science · doi:10.1126/science.2686032 · Cited by 356 · see citing works
Dvorak, H. F., Detmar, M. J., Claffey, K. P., et al. (2009) · International Archives of Allergy and Immunology · doi:10.1159/000236988 · Cited by 336 · see citing works
Ellis, L. M., & Fidler, I. J. (1996) · European Journal of Cancer · doi:10.1016/s0959-8049(96)00389-9 · Cited by 307 · see citing works
Sieczkiewicz, G. J., Hussain, M. M., & Kohn, E. C. (2002) · Springer eBooks · doi:10.1007/978-1-4757-3587-1_17 · Cited by 294 · see citing works
Nagy, J. A., Masse, E., Herzberg, K. T., Meyers, M., Yeo, K. T., Yeo, T.-K., Sioussat, T. M., & Dvorak, H. F. (1995) · PubMed · Cited by 281 · see citing works
Delivery of molecular and cellular medicine to solid tumors
Jain, R. K. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(97)00027-6 · Cited by 272 · see citing works
Self-citationDvořàk, A. M., Kohn, S., Morgan, E. S., Fox, P., Nagy, J. A., & Dvorak, H. F. (1996) · Journal of Leukocyte Biology · doi:10.1002/jlb.59.1.100 · Cited by 271 · see citing works
Patan, S., Munn, L. L., & Jain, R. K. (1996) · Microvascular Research · doi:10.1006/mvre.1996.0025 · Cited by 267 · see citing works
Self-citationDaldrup-Link, H. E., Shames, D. M., Wendland, M. F., Okuhata, Y., Link, T. M., Rosenau, W., Lü, Y., & Brasch, R. C. (1998) · American Journal of Roentgenology · doi:10.2214/ajr.171.4.9762973 · Cited by 265 · see citing works
Delivery of Molecular and Cellular Medicine to Solid Tumors
Jain, R. K. (1997) · Microcirculation · doi:10.3109/10739689709148314 · Cited by 262 · see citing works
Self-citationCancer Cell Invasion and Metastasis
Liotta, L. A. (1992) · Scientific American · doi:10.1038/scientificamerican0292-54 · Cited by 259 · see citing works
Cheng, S., Nagane, M., Huang, H., & Cavenee, W. K. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.22.12081 · Cited by 224 · see citing works
Endothelial gaps and permeability of venules in rat tracheas exposed to inflammatory stimuli
McDonald, D. M. (1994) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1994.266.1.l61 · Cited by 222 · see citing works
Self-citationEndothelial Gaps as Sites for Plasma Leakage in Inflammation
McDonald, D. M., Thurston, G., & Bałuk, P. (1999) · Microcirculation · doi:10.1111/j.1549-8719.1999.tb00084.x · Cited by 218 · see citing works
Self-citationPham, C. D., Roberts, T. P. L., van Bruggen, N., Melnyk, O. O., Mann, J. S., Ferrara, N., Cohen, R. L., & Brasch, R. C. (1998) · Cancer Investigation · doi:10.3109/07357909809039771 · Cited by 208 · see citing works
(2020) · CRC Press eBooks · doi:10.1201/9780429283024 · Cited by 202 · see citing works
Endothelial fenestral diaphragms: a quick-freeze, deep-etch study.
Bearer, E. L., & Orci, L. (1985) · The Journal of Cell Biology · doi:10.1083/jcb.100.2.418 · Cited by 200 · see citing works
Organ-specific endothelial cell uptake of cationic liposome-DNA complexes in mice
McLean, J. W., Fox, E. A., Bałuk, P., Bolton, P. B., Haskell, A., Pearlman, R., Thurston, G., Umemoto, E. Y., & McDonald, D. M. (1997) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1997.273.1.h387 · Cited by 199 · see citing works
Self-citationKohn, S., Nagy, J. A., Dvorak, H. F., & Dvořàk, A. M. (1992) · PubMed · Cited by 190 · see citing works
The use of fluorescent probes to identify regions of transient perfusion in murine tumors
Trotter, M. J., Chaplin, D. J., Durand, R. E., et al. (1989) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/0360-3016(89)90889-4 · Cited by 171 · see citing works
Nagy, J. A., Morgan, E. S., Herzberg, K. T., Manseau, E. J., Dvořàk, A. M., & Dvorak, H. F. (1995) · PubMed · Cited by 163 · see citing works
Thurston, G., Bałuk, P., Hirata, A., & McDonald, D. M. (1996) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1996.271.6.h2547 · Cited by 159 · see citing works
Self-citationMicrovascular corrosion casting in the study of tumor vascularity: a review.
Konerding, M. A., Miodoński, A. J., & Lametschwandtner, A. (1995) · PubMed · Cited by 144 · see citing works
Endothelial gaps: time course of formation and closure in inflamed venules of rats
Bałuk, P., Hirata, A., Thurston, G., et al. (1997) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.1997.272.1.l155 · Cited by 143 · see citing works
Self-citationVascular Endothelial Growth Factor and Microvascular Permeability
Bates, D. O., Lodwick, D., & Williams, B. (1999) · Microcirculation · doi:10.1111/j.1549-8719.1999.tb00091.x · Cited by 136 · see citing works
Endothelial Gaps as Sites for Plasma Leakage in Inflammation
McDonald, D. M., Thurston, G., & Bałuk, P. (1999) · Microcirculation · doi:10.1080/713773924 · Cited by 130 · see citing works
Self-citationCavallo, T., Sade, R. M., Folkman, J., et al. (1972) · The Journal of Cell Biology · doi:10.1083/jcb.54.2.408 · Cited by 129 · see citing works
Feng, D., Nagy, J. A., Hipp, J. A., Pyne, K., Dvorak, H. F., & Dvořàk, A. M. (1997) · The Journal of Physiology · doi:10.1111/j.1469-7793.1997.747bd.x · Cited by 115 · see citing works
The relationship between the capillary structure and hemorrhage in gliomas
Liwnicz, B. H., Wu, S. Z., & Tew, J. M. (1987) · Journal of neurosurgery · doi:10.3171/jns.1987.66.4.0536 · Cited by 112 · see citing works
Geometric Resistance and Microvascular Network Architecture of Human Colorectal Carcinoma
Less, J. R., Mc, P., Skalak, T. C., Wolmark, N., & Jain, R. K. (1997) · Microcirculation · doi:10.3109/10739689709148315 · Cited by 110 · see citing works
Self-citationHost Microvasculature Influence on Tumor Vascular Morphology and Endothelial Gene Expression
Roberts, W. G., Delaat, J. L., Nagane, M., et al. (1998) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65668-4 · Cited by 107 · see citing works
Schwickert, H. C., Stiskal, M., Roberts, T. P. L., van Dijke, C. F., Mann, J. S., Mühler, A., Shames, D. M., Demšar, F., Disston, A. R., & Brasch, R. C. (1996) · Radiology · doi:10.1148/radiology.198.3.8628889 · Cited by 99 · see citing works
Bergers, G., Hanahan, D., & Coussens, L. M. (1998) · The International Journal of Developmental Biology · doi:10.1387/ijdb.9853830 · Cited by 89 · see citing works
Tang, D. G., Chen, Y. Q., Newman, P. J., et al. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41609-2 · Cited by 88 · see citing works
Hammersen, F., Endrich, B., & Meßmer, K. (1985) · PubMed · Cited by 80 · see citing works
Ultrastructural changes in the capillary bed of human pituitary tumors.
Schechter, J. (1972) · PubMed · Cited by 79 · see citing works
Determinants of Endothelial Cell Phenotype in Venules
Thurston, G., Bałuk, P., & McDonald, D. M. (2000) · Microcirculation · doi:10.1111/j.1549-8719.2000.tb00743.x · Cited by 79 · see citing works
Self-citationOpenings Through Endothelial Cells Associated with Increased Microvascular Permeability
Michel, C. C., & Neal, C. R. (1999) · Microcirculation · doi:10.1111/j.1549-8719.1999.tb00086.x · Cited by 78 · see citing works
Microvessel quantification in primary colorectal carcinoma: an immunohistochemical study
Vermeulen, P., Verhoeven, D., Fierens, H., et al. (1995) · British Journal of Cancer · doi:10.1038/bjc.1995.68 · Cited by 77 · see citing works
Debbage, P. L., Griebel, J., Ried, M., Gneiting, T., DeVries, A., & Hutzler, P. (1998) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215549804600508 · Cited by 76 · see citing works
Parangi, S., Dietrich, W., Christofori, G., Lander, E. S., & Hanahan, D. (1995) · PubMed · Cited by 73 · see citing works
Structural and functional characteristics of the microcirculation in neoplasms
Papadimitriou, J. M., & Woods, A. E. (1975) · The Journal of Pathology · doi:10.1002/path.1711160202 · Cited by 71 · see citing works
Hewitt, R. E., Powe, D. G., Morrell, K., Balley, E., LEACH, I. H., Ellis, I. O., & Turner, D. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.37 · Cited by 69 · see citing works
Endrich, B., Hammersen, F., Götz, A., et al. (1982) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/68.3.475 · Cited by 69 · see citing works
Perfusion of Single Tumor Microvessels: Application to Vascular Permeability Measurement
Lichtenbeld, H. C., Yuan, F., Michel, C. C., et al. (1996) · Microcirculation · doi:10.3109/10739689609148307 · Cited by 63 · see citing works
Cox, D. J., PILKINGTON, G., & Lantos, P. L. (1976) · PubMed · Cited by 53 · see citing works
Berger, R., Albelda, S. Μ., Berd, D., et al. (1993) · Journal of Cutaneous Pathology · doi:10.1111/j.1600-0560.1993.tb00661.x · Cited by 50 · see citing works
Openings Through Endothelial Cells Associated with Increased Microvascular Permeability
MICHEL, C. C., & Neal, C. R. (1999) · Microcirculation · doi:10.1080/713773926 · Cited by 46 · see citing works
Steinberg, F., Konerding, M. A., & Streffer, C. (1990) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/bf01613005 · Cited by 43 · see citing works
Estrogen‐induced tumors: Changes in the vasculature in two strains of rat
Schechter, J., Ahmad, N., Elias, K. A., et al. (1987) · American Journal of Anatomy · doi:10.1002/aja.1001790402 · Cited by 42 · see citing works
Expression of PECAM-1/CD31 Isoforms in Human Brain Gliomas
Aroca, F., Renaud, W., Bartoli, C., Bouvier-Labit, C., & Figarella-Branger, D. F. (1999) · Journal of Neuro-Oncology · doi:10.1023/a:1006233816724 · Cited by 41 · see citing works
Pituitary tumorigenesis in aging female C57BL/6J mice: A light and electron microscopic study
Schechter, J., Felicio, L. S., Nelson, J. F., & Finch, C. E. (1981) · The Anatomical Record · doi:10.1002/ar.1091990310 · Cited by 35 · see citing works
Tumour angiogenesis: ultrastructure of endothelial cells in mitosis.
Warren, B. A., Greenblatt, M., & Kommineni, V. (1972) · PubMed · Cited by 32 · see citing works
The vascular system of xenotransplanted tumors--scanning electron and light microscopic studies.
Konerding, M. A., Steinberg, F., & Budach, V. (1989) · PubMed · Cited by 32 · see citing works
The microvasculature of the 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumour
Kaidoh, T., Yasugi, T., & Uehara, Y. (1991) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/bf01600286 · Cited by 23 · see citing works
The significance of free blood in liquid and solid tumours.
van den Brenk, H. A., Crowe, M. C., Kelly, H. D. B., & Stone, M. G. (1977) · PubMed Central · Cited by 17 · see citing works
HEMANGIOSARCOMA OF THE BREAST—CASE REPORT WITH SCANNING ELECTRON MICROSCOPIC STUDY—
Hamazaki, M., & Tanaka, T. (1978) · Acta Pathologica Japonica · doi:10.1111/j.1440-1827.1978.tb00899.x · Cited by 16 · see citing works
Tóth, B., & Malick, L. E. (1976) · The Journal of Pathology · doi:10.1002/path.1711180109 · Cited by 14 · see citing works
Tumour vessel permeability and transcapillary exchange of large molecules of different size.
Peterson, H. I., & Appelgren, L. (1977) · PubMed · Cited by 11 · see citing works
Ultrastructure of the Lewis lung carcinoma
Sato, T., Takusagawa, K., Asoö, N., et al. (1982) · European Journal of Cancer and Clinical Oncology · doi:10.1016/0277-5379(82)90008-6 · Cited by 6 · see citing works
Traumatic Enucleation for Posterior Uveal Melanoma
Specht, C. S., McLean, I. W., & Biscoe, B. W. (1990) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(14)77875-4 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [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
- [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
Cited by
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Drug Delivery Systems: Entering the Mainstream
Allen, T. M., & Cullis, P. R. (2004) · Science · doi:10.1126/science.1095833 · Cited by 4,552 · see citing works
The extracellular matrix: A dynamic niche in cancer progression
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Greish, K. (2010) · Methods in Molecular Biology · doi:10.1007/978-1-60761-609-2_3 · Cited by 841 · see citing works
Hypoxia and Metabolic Adaptation of Cancer Cells
Eales, K. L., Hollinshead, K. E. R., & Tennant, D. A. (2016) · Oncogenesis · doi:10.1038/oncsis.2015.50 · Cited by 724 · see citing works
The brain tumor microenvironment
Charles, N. A., Holland, E. C., Gilbertson, R., Glass, R., & Kettenmann, H. (2011) · Glia · doi:10.1002/glia.21136 · Cited by 718 · see citing works
Jain, R. K., Tong, R. T., & Munn, L. L. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4102 · Cited by 612 · see citing works
Self-citationRecent Advances in Tumor Targeting via EPR Effect for Cancer Treatment
Subhan, M. A., Yalamarty, S. S. K., Filipczak, N., Parveen, F., & Torchilin, V. P. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11060571 · Cited by 623 · see citing works
Delivery of Molecular and Nanoscale Medicine to Tumors: Transport Barriers and Strategies
Chauhan, V. P., Stylianopoulos, T., Boucher, Y., & Jain, R. K. (2011) · Annual Review of Chemical and Biomolecular Engineering · doi:10.1146/annurev-chembioeng-061010-114300 · Cited by 597 · see citing works
Self-citationLiver sinusoidal endothelial cells — gatekeepers of hepatic immunity
Shetty, S., Lalor, P. F., & Adams, D. H. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0020-y · Cited by 523 · see citing works
Abnormalities of Basement Membrane on Blood Vessels and Endothelial Sprouts in Tumors
Baluk, P., Morikawa, S., Haskell, A., Mancuso, M., & McDonald, D. M. (2003) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63540-7 · Cited by 528 · see citing works
Self-citationPolymeric nanomedicine for cancer therapy
Park, J. H., Lee, S., Kim, J.-H., Park, K., Kim, K., & Kwon, I. C. (2008) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2007.09.003 · Cited by 506 · see citing works
Anti-angiogenic therapy: current challenges and future perspectives
Lopes-Coelho, F., Martins, F., Pereira, S. A., & Serpa, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073765 · Cited by 416 · see citing works
Dudley, A. C. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006536 · Cited by 424 · see citing works
Vascular normalization as a therapeutic strategy for malignant and nonmalignant disease.
Goel, S., Wong, A. H.-K., & Jain, R. K. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006486 · Cited by 352 · see citing works
Self-citationPericytes limit tumor cell metastasis
Xian, X. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25705 · Cited by 345 · see citing works
Liao, D., Corle, C., Seagroves, T. N., & Johnson, R. S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2701 · Cited by 339 · see citing works
Current Challenges of Cancer Anti-angiogenic Therapy and the Promise of Nanotherapeutics
Abdalla, A. M. E., Xiao, L., Ullah, M. W., Yu, M., Ouyang, C., & Yang, G. (2018) · Theranostics · doi:10.7150/thno.21674 · Cited by 240 · see citing works
Diagaradjane, P., Shetty, A., Wang, J. C., Elliott, A. M., Schwartz, J., Shentu, S., Park, H. C., Deorukhkar, A., Stafford, R. J., Cho, S. H., et al. (2008) · Nano Letters · doi:10.1021/nl080496z · Cited by 215 · see citing works
Blanco, E., Bey, E. A., Dong, Y., Weinberg, B. D., Sutton, D. M., Boothman, D. A., & Gao, J. (2007) · Journal of Controlled Release · doi:10.1016/j.jconrel.2007.04.014 · Cited by 165 · see citing works
Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor Accumulation
Wang, H.-F., Ran, R., Liu, Y., Hui, Y., Zeng, B., Chen, D., Weitz, D. A., & Zhao, C.-X. (2018) · ACS Nano · doi:10.1021/acsnano.8b06846 · Cited by 161 · see citing works
A review of polypeptide-based polymersomes
Zhao, L., Li, N., Wang, K., Shi, C., Zhang, L., & Luan, Y. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2013.10.063 · Cited by 149 · see citing works
The Multifaceted Role of Heme in Cancer
Fiorito, V., Chiabrando, D., Petrillo, S., Bertino, F., & Tolosano, E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01540 · Cited by 129 · see citing works
Leung, C. S., Yeung, T.-L., Yip, K.-P., Wong, K.-K., Ho, S. Y., Mangala, L. S., Sood, A. K., Lopez-Berestein, G., Sheng, J., Wong, S. T. C., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci95200 · Cited by 132 · see citing works
The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver
Wilkinson, A. L., Qurashi, M., & Shetty, S. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00990 · Cited by 121 · see citing works
Policastro, L. L., Ibañez, I. L., Notcovich, C., Duran, H. A., & Podhajcer, O. L. (2013) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.4367 · Cited by 120 · see citing works
Tang, Y., Soroush, F., Sheffield, J. B., Wang, B., Prabhakarpandian, B., & Kiani, M. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-09815-9 · Cited by 102 · see citing works
Füredi, A., Szebényi, K., Tóth, S., Cserepes, M., Hámori, L., Nagy, V., Karai, E., Vajdovich, P., Imre, T., Szabó, P., et al. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.07.010 · Cited by 100 · see citing works
Elimination of Neoangiogenesis for Plaque Stabilization
Kolodgie, F. D., Narula, J., Yuan, C., Burke, A. P., Finn, A. V., & Virmani, R. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.10.083 · Cited by 96 · see citing works
Datta, N. R., Krishnan, S., Speiser, D. E., Neufeld, E., Kuster, N., Bodis, S., & Hofmann, H. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.09.016 · Cited by 92 · see citing works
Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature
Hooglugt, A., van der Stoel, M. M., Boon, R. A., & Huveneers, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.612802 · Cited by 82 · see citing works
Tissue factor expression and prognosis in patients with metastatic prostate cancer
Akashi, T., Furuya, Y., Ohta, S., & Fuse, H. (2003) · Urology · doi:10.1016/s0090-4295(03)00768-4 · Cited by 75 · see citing works
Synthetic tumor networks for screening drug delivery systems
Prabhakarpandian, B., Shen, M.-C., Nichols, J. B., Garson, C. J., Mills, I. R., Matar, M. M., Fewell, J. G., & Pant, K. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.01.018 · Cited by 57 · see citing works
Rapid Assessment of Nanoparticle Extravasation in a Microfluidic Tumor Model
Vu, M. N., Rajasekhar, P., Poole, D. P., Khor, S. Y., Truong, N. P., Nowell, C. J., Quinn, J. F., Whittaker, M., Veldhuis, N. A., & Davis, T. P. (2019) · ACS Applied Nano Materials · doi:10.1021/acsanm.8b02056 · Cited by 52 · see citing works
Application of High-Z Nanoparticles to Enhance Current Radiotherapy Treatment
Jackson, N., Cecchi, D., Beckham, W., & Chithrani, D. B. (2024) · Molecules · doi:10.3390/molecules29112438 · Cited by 52 · see citing works
The Potential Role of Sildenafil in CancerManagement Through EPR Augmentation
Haider, M., Elsherbeny, A., Pittalà, V., Fallica, A. N., Alghamdi, M. A., & Greish, K. (2021) · doi:10.20944/preprints202104.0679.v1 · Cited by 42 · see citing works
Casanovas, O., Hager, J. H., Chun, M. G. H., & Hanahan, D. (2005) · Oncogene · doi:10.1038/sj.onc.1208823 · Cited by 31 · see citing works
- 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)
- PMC
- PMC1876882
- 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
- bronze
- doi.org
- 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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