Vascular endothelial growth factor/vascular permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma.
Kaposi sarcoma (KS) is the most common tumor associated with HIV-1 infection and develops in nearly 30% of cases. The principal features of this tumor are abnormal vascularization and the proliferation of endothelial cells and spindle (tumor) cells. KS-derived spindle cells induce vascular lesions and display enhanced vascular permeability when inoculated subcutaneously in the nude mouse. This finding suggests that angiogenesis and capillary permeability play a central role in the development and progression of KS. In this study, we show that AIDS-KS cell lines express higher levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VGF) than either human umbilical vein endothelial cells or human aortic smooth muscle cells. AIDS-KS cells and primary tumor tissues also expressed high levels of Flt-1 and KDR, the receptors for VEGF, while the normal skin of the same patients did not show any expression. We further demonstrate that VEGF antisense oligonucleotides AS-1 and AS-3 specifically block VEGF mRNA and protein production and inhibit KS cell growth in a dose-dependent manner. Furthermore, growth of KS cells in nude mice was specifically inhibited by VEGF antisense oligonucleotides. These results show that VEGF is an autocrine growth factor for AIDS-KS cells. To our knowledge, this is the first report that shows that VEGF acts as a growth stimulator in a human tumor. Inhibitors of VEGF or its cognate receptors may thus be candidates for therapeutic intervention.
Masood
R
R
University of Southern California, School of Medicine, Los Angeles 90033, USA.
Cai
J
J
Zheng
T
T
Smith
D L
DL
Naidu
Y
Y
Gill
P S
PS
D017088:AIDS-Related Opportunistic Infections / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016228:Endothelial Growth Factors / Q000235:genetics*; D004730:Endothelium, Vascular; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008222:Lymphokines / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009131:Muscle, Smooth, Vascular; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1