Oncological Pharmacology 干细胞与癌干细胞

StemCellandCancerStemCell干细胞与癌干细胞2011-4-28ThePatternofStem-Branch-Terminal/atlas/phystutorial/phystutorial6.shtmlThePatternofStem-Branch-Terminal/images/download_lo_res.html?id=805800125StemCellRealityDefiningfeatures:Self-renew;differentiation.Existinembryo,fetal,andadult.Differentpotency:Totipotency.Pluripotenty.Multipotency.Oligopotency.Unipotency.StemcellswithdifferentpotencyTotipotentstemcell:e.g.Spore/Zygote.Pluripotentstemcell:e.g.EmbryonicStemCells,candifferentiateintoanyofthethreegermlayers:endoderm,mesoderm,orectoderm.Multipotentstemcell:e.g.HematopoieticStemcells,giverisetomultiple,butalimitednumberoflineages.Oligopotentstemcell(Progenitor):e.g.MyloidStemCells,canonlydifferentiateintoafewcelltypes.Unipotent(Precursor)Cell:e.g.Hepatocytes,non-stemcell.StemCellAsymmetricDivision/index.php?P=AMSER--ResourceFrame&resourceId=5613HematopoieticDifferentiationStemcellandCancerBothcancerandstemcellsarecapableof(unlimited)self-renewal(telomerase+).Stemcellsresideinthebodythroughoutthelife,givingprolongedexposuretocarcinogen.Balancebetweenself-renewalandasymmetricdivisionneedstobetightlyregulated,i.e.aneasytargetoftransformation.StemcellandCancer/info/2006report/2006chapter9.htmCancerStemCell-EvidenceUnlimitedself-renewal-ahallmarkofcancer.Genesinvolvedinstemcellmaintenanceareusuallyoncogenes.Cancercellheterogeneity:Tumorcellshavedifferentpotency-onlyasmallfractionofcancercellsarecapableofmaintainthecancerousstate.Cancercaninitiateeitherinastemcellwithunregulatedself-renewal,orinadifferentiatedcellthatregaintheself-renewalcapability.CancerStemCell-EvidenceThesmallportionofcancercellsexpressingstemcellmarkers(CD133,CD44,CD34,etc.),canreconstitutethecancerinimmune-compromisedXenograftmodels.Deletionofthe“stem”typecancercellsleadstothetotalremissionofcancerinanimalmodels.CancerStemCell-TheoryCancersareorganizedbyahierarchylineagesofmalignantcells(heterogeneity).CancerStemCells(CSCs)isararesubpopulationpossessthecapacitytoself-renewandtogeneratetheheterogeneouscancerlineages.TumorgrowthandmetastasisaredrivenbyCSCs.EradicationofCSCswillleadtoacureofcancer.Cancerstemcellmigration/MetastasisNatureReviewsCancer5,744-749PathwaysAssociatewithself-renewalTheWntsignalingpathway.TheHedgehogsignalingpathway.TheNotchsignalingpathway.TheregulationofdifferentiationThePolycombGroupProteins(PcGs).Transforminggrowthfactorbeta(TGFβ)signalingpathway.TheWntSignalingPathwayWnt=Wingless+Int.

ThewinglesswasoriginallyidentifiedasarecessivemutationaffectingwingandhalteredevelopmentinDrosophila.Int1(integration1)wasidentifiedduringthestudyofmousemammarytumorvirus(MMTV).Int1isthemammalianhomologueofWingless.Wntfamilyproteinsconsist19highlyconservedglycoproteinsthatserveasligandsfortheFrizzled(Fz)transmembranereceptor.NatureReviewsClinicalOncology8,97-106TheWntSignalingPathwayWithoutWntligation,theaxin/APC/CKI/GSK-3βcomplexpromotesthephosphorylation/degradationoftheβ-cateninincytoplasm.Wntbindsafrizzled(Fz)/lowdensitylipoproteinreceptorrelatedprotein(LRP)complex,activatingthedishevelled(DshinDrosophilaandDvlinvertebrates).Dsh/DvlrecruitAxindisruptionofβ-catenindegradationcomplex.β-cateninenterthenucleousandactasco-activatorofTcf/LEFfamilyTFsactivationoftargetgenes.NatureReviewsClinicalOncology8,97-106TheWntSignalingPathwayDuringembryogenesis,Wntproteinsdirectcellfatedeterminationandregulatethedevelopmentofavarietyoforgansystem(cardiovascular,lung,CNS).Inadults,Wntsignalingplaysakeyroleintheregulationoftissueself-renewal(intestinalcrypts,hairfollicles,andbonegrowthplates).TheWntSignalingPathwayNatureReviewsClinicalOncology8,97-106TheWntSignalingandCancerAbnormalWntsignalinghasbeenidentifiedinseveraltypesofcancers,especiallyincoloncancer,melanomaandleukemia.DeregulatedWntsignalinghasbeenassociatedwithCSCactivity;specifically,cutaneousCSCsrequireβ-cateninsignalingtomaintaintheirtumorigenicphenotype.

ExperimentalWntinhibitorsNatureReviewsClinicalOncology8,97-106TheHedgehogSignalingPathwayFirstIdentifiedinfruitflyasoneofimportantgenesforcreatingthedifferencesbetweentheanteriorandposteriorpartsofbodysegments.Hhcontrolstissuepolarity,patterning,andstem-cellmaintenanceduringembryonicdevelopment.Hhmutationresultsinabnormally-shapedembryosthatareunusuallyshortandstubby.TheHedgehogSignalingPathwayHhproteins(Sonic,Desert,andIndian)arereleasedthroughadedicatedtransmembranetransporter“Dispatched”afteracylationofHhN-terminusbytheenzymeRasplocatedintheER.TransmembraneproteinPatched(Ptch)andSmoothened(Smo)areresponsiblefortransducingHhsignal.NatureReviewsClinicalOncology8,97-106TheHedgehogSignalingPathwayIntheabsentofHh,PtchinhibitsSmoactivation.AlsotheGlifamilyofzinc-fingerTFsGli1/2/3aresequesteredbytheSufu/PKAcomplexinthecytoplasm.UponHhligationtoreceptorPtch,Hh-PtchinternalizeandreleaseSmo.SmodisruptstheGli-sequesteringcomplex,releasingGliTFsnucleousentrytargetgenetranscription.DetailsofHhsignalingarestillneedtobeclarified.NatureReviewsClinicalOncology8,97-106TheHedgehogSignalingPathwayNatureReviewsClinicalOncology8,97-106HhSignalingandCancerPtch-tumorsuppressorgene;Smo-oncogene.PtchmutationisfoundinBasalCellCancer(BCC),medulloblastoma.GLI1andGLI3mutationsarefoundinpancreaticadenocarcinoma,aswellasGLI1amplificationinglioblastoma.Hhpathwayover-activationeitherfrommutationalactivationorautocrinesignalingisassociatedwithlung,skin,ovarycancersandsomeleukemia(MM,CML),etc.IncreasedHhpathwayactivitytargetgenesaffectingproliferation(CyclinD1,CyclinD2,N-Myc,Igf2,Hes1),cellsurvival(Bcl2),angiogenesis(Vegf),andgeneticinstability(p53)DatafrommanyhumantumorssuggestthatHhsignalingregulatescancerstemcells.Hhsignalingalsoplayacriticalroleinepithelialmesenchymaltransition(EMT)andmetastasis.HhSignalingandCancerClinCancerRes2010;16:3130-3140HhSignalingandCancerExperimentalHedgehoginhibitorsNatureReviewsClinicalOncology8,97-106TheNotchSignalingPathwayNatureReviewsClinicalOncology8,97-106Notchsignalinghasacriticalroleinregulatingintercellularcommunicationduringembryogenesis,proliferation,differentiation,andapoptosis.Notchsignalingisalsocriticalfornormalhematopoiesis,breastdevelopment,colorectalepithelialmaturation,immuneregulation,andne