Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target

Medulloblastomasarethemostcommonmalignantbraintumorsinchildren.�Theyexpresshighlevelsof� COX-2�andproducePGE2,�whichstimulatestumorcellproliferation.�Humancytomegalovirus�(HCMV)�is� prevalentinthehumanpopulationandencodesproteinsthatprovideimmuneevasionstrategiesandpro- moteoncogenictransformationandoncomodulation.�Inparticular,�HCMVinducesCOX-2�expression;�STAT3� phosphorylation;�productionofPGE2,�vascularendothelialgrowthfactor,�andIL-6;�andtumorformationin� vivo.�Here,�weshowthatalargeproportionofprimarymedulloblastomasandmedulloblastomacelllinesare� infectedwithHCMVandthatCOX-2�expression,�alongwithPGE2�levels,�intumorsisdirectlymodulatedby� thevirus.�OuranalysisindicatedthatbothHCMVimmediate-earlyproteinsandlateproteinsareexpressed� inthemajorityofprimarymedulloblastomas.�Remarkably,�allofthehumanmedulloblastomacelllinesthat� weanalyzedcontainedHCMVDNAandRNAandexpressedHCMVproteinsatvariouslevelsinvitro.�When� engraftedintoimmunocompromisedmice,�humanmedulloblastomacellsinducedexpressionofHCMVpro- teins.�HCMVandCOX-2�expressioncorrelatedinprimarytumors,�celllines,�andmedulloblastomaxenografts.� TheantiviraldrugvalganciclovirandthespecificCOX-2�inhibitorcelecoxibpreventedHCMVreplication�� invitroandinhibitedPGE2�productionandreducedmedulloblastomatumorcellgrowthbothinvitroand�� invivo.�GanciclovirdidnotaffectthegrowthofHCMV-negativetumorcelllines.�Thesefindingsimplyanimpor- tantroleforHCMVinmedulloblastomaandsuggestHCMVasanoveltherapeutictargetforthistumor.