Heparanase promotes the aggressive phenotype of myeloma tumors and is a novel target for myeloma therapy

[摘要] Heparanaseisanendoglucuronidasethatcleavesheparansulfatechains.Heparanaseexpressionisupregulatedinmanytypesofcancer,particularlyinthosetumorsexhibitinganaggressivephenotype.Inmyelomapatients,heparanaseisoftenpresentinhighlevelsinthebonemarrowwhereitisassociatedwithenhancedangiogenesisandpoorpatientprognosis.Usinginvitroandinvivomodelsofmyeloma,wehaveprobedthemechanismofheparanaseactioninmyelomaanddiscoveredthattheenzymeactivelypromotestumorgrowth,angiogenesis,metastasis,andosteolysis.Thisoccursthroughheparanase-mediatedupregulationofexpressionofanumberofproteinsknowntodriveanaggressivetumorphenotypeincludingHGF,MMP-9,VEGF,andRANKL.Inaddition,heparanaseenhancessheddingofsyndecan-1(CD138),aheparansulfateproteoglycanpresentathighlevelsonthemyelomacellsurface.Thisisimportantbecausetheheparansulfatechainspresentontheshedsyndecan-1bindtoeffectorproteinssuchasHGFandVEGFandenhancetheirabilitytopromotesignaling.Thisfurtherstimulatesmyelomagrowthandangiogenesis.Whenmicebearingmyelomatumorsweretreatedwithinhibitorsofheparanaseenzymaticactivity,tumorgrowthandprogressionweresignificantlyattenuated.Togethertheseresultsdemonstratethatheparanaseplaysacriticalroleinenhancingmyelomaprogressionandthattargetingheparanasemaybeaviabletherapeuticstrategyfortreatingmyelomaandothercancers.

[学科分类] 肿瘤学

[关键词] myeloma;tumor microenvironment;heparan sulfate;therapy;angiogenesis