PMID- 10751361
OWN - NLM
STAT- MEDLINE
DCOM- 20000629
LR  - 20220316
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 156
IP  - 4
DP  - 2000 Apr
TI  - Openings between defective endothelial cells explain tumor vessel leakiness.
PG  - 1363-80
AB  - 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.
FAU - Hashizume, H
AU  - Hashizume H
AD  - Cardiovascular Research Institute and Department of Anatomy, University of 
      California, San Francisco, California 94143-0130, USA.
FAU - Baluk, P
AU  - Baluk P
FAU - Morikawa, S
AU  - Morikawa S
FAU - McLean, J W
AU  - McLean JW
FAU - Thurston, G
AU  - Thurston G
FAU - Roberge, S
AU  - Roberge S
FAU - Jain, R K
AU  - Jain RK
FAU - McDonald, D M
AU  - McDonald DM
LA  - eng
GR  - R35-CA-56591/CA/NCI NIH HHS/United States
GR  - HL-24136/HL/NHLBI NIH HHS/United States
GR  - P01 HL024136/HL/NHLBI NIH HHS/United States
GR  - R01 HL059157/HL/NHLBI NIH HHS/United States
GR  - HL-59157/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
SB  - IM
MH  - Animals
MH  - Blood Vessels/metabolism/pathology
MH  - *Capillary Permeability
MH  - Endothelium, Vascular/*pathology
MH  - Extracellular Space/*physiology
MH  - Female
MH  - Male
MH  - Mammary Neoplasms, Animal/*blood supply/*metabolism/pathology/physiopathology
MH  - Mice
MH  - Microscopy, Electron
MH  - Microscopy, Electron, Scanning
MH  - Microscopy, Fluorescence
MH  - Neoplasm Transplantation
PMC - PMC1876882
EDAT- 2000/04/07 09:00
MHDA- 2000/07/06 11:00
PMCR- 2000/10/01
CRDT- 2000/04/07 09:00
PHST- 2000/04/07 09:00 [pubmed]
PHST- 2000/07/06 11:00 [medline]
PHST- 2000/04/07 09:00 [entrez]
PHST- 2000/10/01 00:00 [pmc-release]
AID - S0002-9440(10)65006-7 [pii]
AID - 2150 [pii]
AID - 10.1016/S0002-9440(10)65006-7 [doi]
PST - ppublish
SO  - Am J Pathol. 2000 Apr;156(4):1363-80. doi: 10.1016/S0002-9440(10)65006-7.