CellulardeterminantsandmicroenvironmentalregulationofprostatecancermetastasisKieraRycaja,HangwenLia,b,JianjunZhoub,XinChena,andDeanG.Tanga,baDepartmentofPharmacology&Therapeutics,RoswellParkCancerInstitute,Buffalo,NY14263,USAbCancerStemCellInstitute,ResearchCenterforTranslationalMedicine,EastHospital,TongjiUniversitySchoolofMedicine,Shanghai200120,ChinaAbstractMetastasiscausesmorethan90%ofcancer-relateddeathsandmostprostatecancer(PCa)patientsalsodiefrommetastasis.The‘metastaticcascade’isacomplexbiologicalprocessthatencompassestumorcelldissociation(fromtheprimarytumor),localinvasion,intravasation,transportincirculation,extravasation,colonization,andovertgrowthinendorgans.Ithasbecomeclearthatsuccessfulmetastasisnotonlyinvolvesmanytumorcell-intrinsicpropertiesbutalsodependsonproductiveinteractionsbetweencancercellsandthetumormicroenvironment.InthisReview,webeginwithageneralsummaryoncancermetastasisandaspecificdiscussiononPCametastasis.WethendiscussrecentadvancesinourknowledgeofthecellulardeterminantsofPCametastasisandtheimportanceoftumormicroenvironment,especiallyanimmunosuppressivetumormicroenvironment,inshapingmetastaticpropensities.WeconcludewithapresentationofcurrentandfuturetherapeuticoptionsforpatientswithPCametastasis,emphasizingthedevelopmentofnovel,mechanism-basedcombinatorialstrategiesfortreatingmetastaticandcastration-resistantPCa.Keywordsmetastasis;prostatecancer;cancerstemcells;microenvironmentIntroductionDespitetheoverwhelmingprevalenceofmetastases-associateddeathsincancerpatients,manybiologicalprogramsunderlyingthiscomplexprocessremainunknown.ResearchhasbeenhinderedinpartbythecomplexitiessurroundingthemetastaticprocessandtheCorrespondence:KieraRycaj,Tel:716-845-5644;Fax:716-845-8857;Kiera.Rycaj@Roswellpark.org;DeanTang,Tel:716-845-1245;Fax:716-845-8857;Dean.Tang@Roswellpark.org.Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaservicetoourcustomersweareprovidingthisearlyversionofthemanuscript.Themanuscrip...
