Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy.
OBJECTIVE
(1) To determine whether exposure of phosphatidylserine (PS) occurs on vascular endothelium in solid tumors in mice. (2) To determine whether PS exposure can be induced on viable endothelial cells in tissue culture by conditions present in the tumor microenvironment.


METHODS
Externalized PS in vivo was detected by injecting mice with a monoclonal anti-PS antibody and examining frozen sections of tumors and normal tissues for anti-PS antibody bound to vascular endothelium. Apoptotic cells were identified by anti-active caspase-3 antibody or by TUNEL assay. PS exposure on cultured endothelial cells was determined by 125I-annexin V binding.


RESULTS
Anti-PS antibody bound specifically to vascular endothelium in six tumor models. The percentage of PS-positive vessels ranged from 4% to 40% in different tumor types. Vascular endothelium in normal organs was unstained. Very few tumor vessels expressed apoptotic markers. Hypoxia/reoxygenation, acidity, inflammatory cytokines, thrombin, or hydrogen peroxide induced PS exposure on cultured endothelial cells without causing loss of viability.


CONCLUSIONS
Vascular endothelial cells in tumors, but not in normal tissues, externalize PS. PS exposure might be induced by tumor-associated oxidative stress and activating cytokines. PS is an abundant and accessible marker of tumor vasculature and could be used for tumor imaging and therapy.
Ran
Sophia
S
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8594, USA. sophia.ran@utsouthwestern.edu
Thorpe
Philip E
PE
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000906:Antibodies / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D000860:Hypoxia; D020287:In Situ Nick-End Labeling; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000628:therapy; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010718:Phosphatidylserines / Q000096:biosynthesis*; D017382:Reactive Oxygen Species
D017304:Annexin A5; D000906:Antibodies; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen