Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy.
We have characterized a murine IgM monoclonal antibody, TEC-11, that recognizes endoglin and may be suitable for targeting cytotoxic agents to human tumor vasculature. TEC-11 strongly stains endothelial cells in a broad range of solid human tumors while staining endothelial cells in the majority of normal, healthy adult tissues relatively weakly. Human umbilical vein endothelial cells (HUVECs) in sections of the umbilical vein react weakly with TEC-11, whereas proliferating HUVECs in tissue culture react strongly and uniformly. HUVEC cultures grown to confluence and then rested contain two subpopulations having high and low levels of endoglin expression. Flow cytometry revealed that a significant proportion of cells with high endoglin expression are cycling, having markedly increased levels of cellular protein, RNA, and DNA by comparison to low endoglin-expressing cells, which appear to be noncycling. Taken together, the increased binding of TEC-11 to tumor vasculature and to dividing as opposed to noncycling HUVECs in vitro suggests that endoglin is an endothelial cell proliferation-associated marker. An immunotoxin [TEC-11.deglycosylated ricin A chain (dgA)] composed of TEC-11 and dgA was 3000-fold more potent at inhibiting protein synthesis in proliferating HUVEC cultures than in confluent cultures. The confluent cells were no more sensitive to TEC-11.dgA than they were to an isotype-matched immunotoxin of irrelevant specificity. These findings suggest that TEC-11.dgA might have therapeutic value in the treatment of solid tumors in humans by selectively killing dividing endothelial cells which are prevalent in such tumors.
Burrows
F J
FJ
Simmons Cancer Center, Department of Pharmacology, Cancer Immunobiology Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-8593, USA.
Derbyshire
E J
EJ
Tazzari
P L
PL
Amlot
P
P
Gazdar
A F
AF
King
S W
SW
Letarte
M
M
Vitetta
E S
ES
Thorpe
P E
PE
D000328:Adult; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000918:Antibody Specificity; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism; D009928:Organ Specificity; D011956:Receptors, Cell Surface; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D007075:Immunoglobulin M; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1