Self-Renewing Pten--TP53-- Protospheres Produce Metastatic Adenocarcinoma Cell Lines with Multipotent Progenitor Activity 英文参考文献.docVIP

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Self-Renewing Pten--TP53-- Protospheres Produce Metastatic Adenocarcinoma Cell Lines with Multipotent Progenitor Activity 英文参考文献.doc

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Self-Renewing Pten--TP53-- Protospheres Produce Metastatic Adenocarcinoma Cell Lines with Multipotent Progenitor Activity 英文参考文献

Self-RenewingPten-/-TP53-/- ProtospheresProduce MetastaticAdenocarcinomaCellLineswithMultipotent ProgenitorActivity WassimAbou-Kheir1,2,PaulG.Hynes1,PhilipMartin1¤,JuanJuanYin1,Yen-NienLiu1,VictoriaSeng1, RossLake1,JoshuaSpurrier1,KathleenKelly1* 1CellandCancerBiologyBranch,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland,UnitedStatesofAmerica,2DepartmentofAnatomy,Cell BiologyandPhysiologicalSciences,FacultyofMedicine,AmericanUniversityofBeirut,Beirut,Lebanon Abstract Prostatecancersofluminaladenocarcinomahistologydisplayarangeofclinicalbehaviors.Althoughmostprostatecancers areslow-growingandindolent,aproportionisaggressive,developingmetastasisandresistancetoandrogendeprivation treatment. One hypothesis is that a portion of aggressive cancers initiate from stem-like, androgen-independent tumor- propagatingcells.Herewedemonstratetheinvitrocreationofamousecellline,selectedforgrowthasself-renewingstem/ progenitorcells,whichmanifestsmanyinvivopropertiesofaggressiveprostatecancer.Normalmouseprostateepithelium containingfloxedPtenandTP53alleleswassubjectedtoCRE-mediateddeletioninvitrofollowedbyserialpropagationas protospheres.Apolyclonalcelllinewasestablishedfromdissociatedprotospheresandsubsequentlyaclonaldaughterline was derived. Both lines demonstrate a mature luminal phenotype in vitro. The established lines contain a stable minor populationofprogenitorcellswithprotosphere-formingabilityandmulti-lineagedifferentiationcapacity.Bothlinesformed orthotopicadenocarcinomatumorswithmetastaticpotential tolung.Intracardiac inoculationresulted inbrainandlung metastasis,whileintra-tibialinjectioninducedosteoblasticboneformation,recapitulatingthebonemetastaticphenotype of human prostate cancer. The cells showed androgen receptor dependent growth in vitro. Importantly, in vivo, the deprivation of androgens from established orthotopic tumors resulted in tumor regression and eventually castration- resistantgrowth.Thesedatasuggestthattransformedprostateprogen