Platelet activating factor produced in vitro by Kaposi's sarcoma cells induces and sustains in vivo angiogenesis.
Imbalance in the network of soluble mediators may play a pivotal role in the pathogenesis of Kaposi's sarcoma (KS). In this study, we demonstrated that KS cells grown in vitro produced and in part released platelet activating factor (PAF), a powerful lipid mediator of inflammation and cell-to-cell communication. IL-1, TNF, and thrombin enhanced the synthesis of PAF. PAF receptor mRNA and specific, high affinity binding site for PAF were present in KS cells. Nanomolar concentration of PAF stimulated the chemotaxis and chemokinesis of KS cells, endothelial cells, and vascular smooth muscle cells. The migration response to PAF was inhibited by WEB 2170, a hetrazepinoic PAF receptor antagonist. Because neoangiogenesis is essential for the growth and progression of KS and since PAF can activate vascular endothelial cells, we examined the potential role of PAF as an instrumental mediator of angiogenesis associated with KS. Conditioned medium (CM) from KS cells (KS-CM) or KS cells themselves induced angiogenesis and macrophage recruitment in a murine model in which Matrigel was injected subcutaneously. These effects were inhibited by treating mice with WEB 2170. Synthetic PAF or natural PAF extracted from plasma of patients with classical KS also induced angiogenesis, which in turn was inhibited by WEB 2170. The action of PAF was amplified by expression of other angiogenic factors and chemokines: these included basic and acidic fibroblast growth factor, placental growth factor, vascular endothelial growth factor and its specific receptor flk-1, hepatocyte growth factor, KC, and macrophage inflammatory protein-2. Treatment with WEB 2170 abolished the expression of the transcripts of these molecules within Matrigel containing KS-CM. These results indicate that PAF may cooperate with other angiogenic molecules and chemokines in inducing vascular development in KS.
Bussolino
F
F
Dipartimento di Genetica, Biologia e Chimica Medica, University of Torino, Italy.
Arese
M
M
Montrucchio
G
G
Barra
L
L
Primo
L
L
Benelli
R
R
Sanavio
F
F
Aglietta
M
M
Ghigo
D
D
Rola-Pleszczynski
M R
MR
D000368:Aged; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D002822:Choriocarcinoma / Q000473:pathology; D003094:Collagen; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004285:Dogs; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007797:Laminin; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000503:physiopathology*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000473:pathology; D013917:Thrombin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins; D014594:Uterine Neoplasms / Q000473:pathology
D001381:Azepines; D017077:Culture Media, Conditioned; D016207:Cytokines; D004338:Drug Combinations; D006133:Growth Substances; D007375:Interleukin-1; D007797:Laminin; D009363:Neoplasm Proteins; C029271:O-deacetyl platelet activating factor; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; C059485:matrigel; D003094:Collagen; C063964:bepafant; D013917:Thrombin