Mechanismsthatdriveinflammatorytumormicroenvironment,tumorheterogeneity,andmetastaticprogressionLiYanga,*andP.CharlesLinb,**aLaboratoryofCancerBiologyandGenetics,NationalCancerInstitute,NIH,37ConventDrive,Bethesda,MD20892,USAbCancerandInflammationProgram,CenterforCancerResearch,NationalCancerInstitute,NIH,Frederick,MD,21702,USAAbstractTreatmentofcancermetastaseshasbeenlargelyineffective.Itisparamounttounderstandthemechanismsunderlyingthemetastaticprocess,ofwhichthetumormicroenvironmentisanindispensableparticipant.Whatarethecriticalcellularandmolecularplayersattheprimarytumorsitewheremetastaticcascadeinitiates?Howistumor-associatedinflammationregulated?Howdoalteredvasculaturescontributetometastasis?Whatisthedynamicnatureorheterogeneityofprimarytumorsandwhatarethechallengestocatchamovingtarget?Thisreviewsummarizesrecentprogress,mechanisticunderstanding,andoptionsformetastasis-targetedtherapy.KeywordsTumormetastasis;Microenvironment;Tumorsuppressor;Inflammation/Immune;Heterogeneity1.IntroductionTumormetastasisaccountsformostcancer-associateddeathsinpatients.Currently,thereareveryfeweffectivetreatmentoptions[1].Duringmetastasis,tumorcellsmustdisseminate,intravasateintocirculation,travelthroughvascularnetworks,arrestinvascularbedsoftargetorgans,andsubsequentlyextravasateintotheorganparenchyma[2].Inahostiledistantorgan,theymustescapehostimmunesurveillance,adapttosupportiveniches,surviveaslatenttumor-initiatingseeds,andeventuallybreakouttogrow[3].Evidencefromrecentyearsstronglysuggeststhatthetumormicroenvironment(TME)isanindispensableparticipantinthemetastaticprocess[3,4],allowingthetumorcellsnotonlytoescapefromhostimmunesurveillance,butalsoinducetheformationofnewbloodvesselsandinvadethe*Correspondingauthorat:LaboratoryofCancerBiologyandGenetics,NationalCancerInstitute,NIH,37ConventDrive,Bethesda,MD20892,USA.yangl3@mail.nih.gov(L.Yang),Phonenumbers:240-760-6809.**Correspondingauthorat:CancerandInflammationProgram,CenterforCancerResearch,NationalCancerInstitute,NIH,Frede...
