Vascular Permeability Factor: A Tumor-derived Polypeptide that Induces Endothelial Cell and Monocyte Procoagulant Activity, and Promotes Monocyte Migration

Summary Systemicinfusionoflowconcentrations oftumor necrosis factor/cachectin (TNF) intomicethat bearTNF-sensitivetumorsleadstoactivation ofcoagulation, fibrinformation,and occlusive thrombosisexclusively withinthetumor vascularbed.To identifymechanismsunderlyingthe localization ofthisvascularprocoagulantresponse,atumor-derivedpolypeptidehasbeenpurified tohomogeneityfromsupernatants ofmurinemethylcholanthrene A-inducedfibrosarcomas that inducesendothelial tissuefactorsynthesisandexpression(half-maximalresponseat-300 pM), and augmentstheprocoagulantresponsetoTNF ina synergistic fashion.Thistumor-derived polypeptidewas identified asthemurinehomologue ofvascularpermeability factor(VPF)based on similarmobilityon SDS-PAGE, an homologous NH2-terminalamino acidsequence,and recognitionby a monospecificantibodytoguineapigVPF .Inaddition,VPF was shown to inducemonocyteactivation, asevidencedbyexpressionoftissuefactor .Finally, VPF was shown toinducemonocytechemotaxisacrosscollagenmembranesandendothelial cellmonolayers.Taken together,theseresults indicatethatVPF canmodulatethecoagulantproperties ofendothelium andmonocytes,and canpromotemonocyte migrationintothetumor bed.Thissuggestsone mechanism throughwhich tumor-derivedmediatorscanalterpropertiesofthevesselwall. T umor vasculature, derivedfromtheingrowthofnormal vessels, isincontinuouscontactwithhostmediatorsand metabolic/regulatory productsofthetumor.Sincetheendotheliumistheactualinterface between hostand tumor, studiesintotheproperties oftumor vascularendothelium provideinsightsintotheeffects oflocalfactorson vascular function.One strikingexampleofthealteredresponsiveness oftumor vasculature isobservedafterthesystemicinfusion ofa low concentrationoftumor necrosisfactor/cachectin (TNF) intomice thatbearTNF-sensitivetumors,suchas methylcholanthreneA-inducedfibrosarcomas (methA sarcomas)'(1-3).Under theseconditions,intravascular fibrin deposition, progressing toocclusive thrombosisandassociated with afallinbloodflow,isobservedintumor vessels, but not inthenormal vessels .An importantpotentialmecha