Platelet-activating factor inactivation by local expression of platelet-activating factor acetyl-hydrolase modifies tumor vascularization and growth.
OBJECTIVE
Platelet-activating factor (PAF), a phospholipid mediator of inflammation, has been recently detected on tumor cells but its effect in tumor development is largely undefined.


METHODS
To address its potential role in tumor biology, we inhibited intratumor PAF activity by engineering tumor cell lines to express plasma PAF-acetylhydrolase (PAF-AH), the major PAF-inactivating enzyme, and studied their behavior in vitro and in vivo.


RESULTS
When transfected with PAF-AH, KS-Imm human Kaposi's sarcoma cells implanted in SCID mice and B16F10 mouse melanoma cells implanted in syngenic C57Bl/6J mice showed significantly reduced vascularization and growth allowing longer survival compared with control tumors. The amounts of bioactive PAF extracted from PAF-AH-transfected tumors were significantly reduced. In vitro, expression of PAF-AH did not influence cell proliferation, whereas it inhibited PAF-dependent cell motility in Kaposi's sarcoma cells that express PAF-receptor but not in melanoma cells that did not express it. On the other hand, PAF-induced endothelial tubulogenesis in Matrigel was inhibited by incubation with supernatant from PAF-AH-transfected melanoma cells, indicating that PAF-AH inhibits in vitro neoangiogenesis.


CONCLUSIONS
We demonstrated that in situ PAF inactivation affects tumor vascularization and growth through inhibition of neoangiogenesis and, in the case of cells expressing PAF receptor, also tumor cell motility.
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D017931:DNA Primers; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase