MODELLING THE MOLECULAR

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1、REVIEWSMODELLINGTHEMOLECULARCIRCUITRYOFCANCERWilliamC.Hahn*‡andRobertA.Weinberg*§Cancerarisesfromastepwiseaccumulationofgeneticchangesthatliberatesneoplasticcellsfromthehomeostaticmechanismsthatgovernnormalcellproliferation.Inhumans,atleastfourtosixmutations

2、arerequiredtoreachthisstate,butfewerseemtoberequiredinmice.Byrationalizingthesharedanduniqueelementsofhumanandmousemodelsofcancer,weshouldbeabletoidentifythemolecularcircuitsthatfunctiondifferentlyinhumansandmice,andusethisknowledgetoimproveexistingmodelsofc

3、ancer.Thecancerphenotypeencompassesabroadcollectiontumoursinmousemodelsofcancerdependsonfewerofcharacteristicsthattogethercreatetheclinicalentitygeneticchangesthanarerequiredincomparabletissueofcancer.Bycomparingcellsandtissuesthataresitesinhumans.Understand

4、ingpreciselyhowhumanderivedfromcancerpatientswiththosefromnormalandmousemodelsofcancerdifferinmoleculartermsindividualsor,insomecases,withhistologicallynor-shouldleadtoaclearerunderstandingofthecomplexmaltissuefromthesameindividuals,itispossibletonatureofneo

5、plastictransformation.Whatisourcur-cataloguetheirmanydifferencesinmolecular,cellularrentunderstandingofthemolecularcircuitrythatpro-andbiologicalproperties.Indeed,therecentapplica-grammesmalignant-celltransformation,andhowcantionoftranscriptionalprofilingtoc

6、ancerhasdocu-wereconcilethedifferencesbetweenhumancellsys-mentedchangesintheexpressionofthousandsoftemsandanimalmodelstodevelopmodelsthattrulygenes,asnormalcellsundergotransformationintoreflectthemolecularcircuitryofhumancancer?theirneoplasticderivatives1–6.

7、Someofthesechangesinexpressionaresharedbyseveraltypesofcancercell,Multiplestepstocancer:transformationwhereasothersseemtobespecifictooneorasmallDespitetheapparentcomplexityofthecancerpheno-*WhiteheadInstituteforsubsetofthecancer-celltypesthatareencounteredin

8、type,earlystudiesindicatedthatcancermightbetheBiomedicalResearch,theoncologyclinic.Observationssuchasthesehaveresultofveryfewchanges—perhapsasfewasone—9CambridgeCenter,ledsometoproposethatcancer