PTHrPHPSEOPNCCL2VEGFO2HIF-1αVEGFCXCR4ImmuneevasionIRF7α4β1,αVβ3,α5β1CXCR4NKcellTcellCXCR4CXCL12IntegrinsVCAM1FibronectinHSCmobilizationTumorcellOsteoclastprecursorOsteoclastOsteoblastHematopoieticstemcell(HSC)RANKLRANKMetastaticnicheBONEBONEBonehomingTumorseedingHypoxiaRANKLCSF-1MIP-1αIL-6IL-8GM-CSFJag1NotchPTHrPMMPsIL-6OsteolyticmetastasisRANKLRANKBMPsIGF1/2FGFET-1WNT1VEGFPSAOsteoblasticmetastasisDKK1PTHrPTheviciouscycleTGFβIGFCa2+IL-6SPARCPeriostinRANKLTumorderivedfactorsDormancyandrelapseDormantActiveOsteoclastdifferentiationHSCnicheoccupancyTwist1Srcα4β1SurvivalOtherstromalcontributionBMendothelialcellsImmunecellsNeuronsHoming,angiogenesisPlateletsProliferation,adhesionProliferation,colonizationMSCsDifferentiation,growthBonemetastasistherapeuticsandtheirtargetsBisphosphonatesDenosumabSrcInhibitorsLY2157299,FresolimumabOtherTGFβinhibitorsAtrasentan/ZibotentanFarnesylPyrophosphateSynthaseRANKLSrc(KX2–391),SFKs(Dasatinib,others)TGFβligandorreceptorsCathepsinKEndothelin1(ET-1)OdanacatibVCAM-1Seeonlineversionforlegendandreferences.690Cell151,October26,2012©2012ElsevierInc.DOIhttp://dx.doi.org/10.1016/j.cell.2012.10.005SnapShot:BoneMetastasisBrianEllandYibinKangDepartmentofMolecularBiology,PrincetonUniversity,Princeton,NJ08544,USASnapShot:BoneMetastasisBrianEllandYibinKangDepartmentofMolecularBiology,PrincetonUniversity,Princeton,NJ08544,USA690.e1Cell151,October26,2012©2012ElsevierInc.DOIhttp://dx.doi.org/10.1016/j.cell.2012.10.005Bonemetastasisoccursinthemajorityofpatientswithlate-stagebreastandprostatecancersandisoftendiagnosedinlung,thyroid,bladder,andkidneycancers.Bonemetastasisisassociatedwithcharacteristicmodulationofthebonemicroenvironment,resultingintheformationofa“metastaticniche”thatcanformbeforeoruponthearrivalofdisseminatedtumorcellstofacilitateseedingandexpansionoftumorcoloniesinbone.Tumorcellsconditionthemetastaticnichethroughthesecretionofsolublefactors,suchasPTHrP,HPSE,andOPN.CirculatingPTHrPinducesCCL2productionfromosteoblastsando...
