Cellular Therapy and Transplantation | |
Heparanase promotes the aggressive phenotype of myeloma tumors and is a novel target for myeloma therapy | |
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
【 预 览 】
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