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

Cellular Therapy and Transplantation

Joseph P. Ritchie¹  Yang Yang¹  Anurag Purushothaman¹  Ralph D. Sanderson¹  Vishnu C. Ramani¹ 

关键词: myeloma;    tumor microenvironment;    heparan sulfate;    therapy;    angiogenesis;   

DOI  :  10.3205/ctt-2010-No9-abstract78

学科分类：肿瘤学

来源: Universitaetsklinikum Hamburg - Eppendorf / University Medical Center Hamburg - Eppendorf

【 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.

【 授权许可】

Unknown