PNAS：结肠癌和直肠癌中发现肿瘤干细胞

来源生物谷2007-6-159:05:38PNAS：结肠癌和直肠癌中发现肿瘤干细胞生物谷生物谷：斯坦福大学医学院MichaelClarke率领的研究小组最近从结肠癌和直肠癌中鉴别出肿瘤干细胞，为治疗这些致命的癌症带来新的希望。研究结果发表在6月12日出版的PNAS杂志上。

早在2003年Clarke于密歇根大学工作时，就在乳腺癌中首次发现肿瘤干细胞。2005年转到斯坦福后，他又在头颈、胰腺和结肠直肠肿瘤中发现肿瘤干细胞。这些干细胞会不断地分裂产生新肿瘤细胞。尽管其他肿瘤细胞能够分裂，通过体积膨胀而引起损伤，但生命周期很短，不能维持肿瘤生长。肿瘤干细胞似乎还与肿瘤转移有关。

鉴别新的肿瘤干细胞是斯坦福干细胞生物学和再生医学中心的主要研究项目之一。该研究中心的主任IrvingWeissman博士希望获得可以专一地杀死这些肿瘤干细胞的疗法，彻底攻克癌症。目前的疗法虽然可以杀死大部分肿瘤细胞，但如果有幸存的肿瘤干细胞，肿瘤就会死灰复燃。

结肠直肠癌干细胞的发现，强调了CD44蛋白的重要性，因为之前有研究证实乳腺癌、头颈癌干细胞的表面也存在CD44蛋白，文章第一作者PieroDalerba博士推测这些肿瘤起源相似，意味着这三种类型的肿瘤干细胞可利用相同的方法治疗。Dalerba在结肠直肠癌干细胞上还发现一种新蛋白－－CD166，将可能成为鉴别、治疗结肠直肠癌的特定靶点。

结肠直肠癌是美国第二大常见的致死性癌症，每年导致5万多人死亡，通常到了后期才会被发现。传统的治疗方法包括化疗、放疗和外科手术。

结肠直肠癌外科副教授AndrewShelton博士说，很难肯定哪些患者适合哪种治疗方法。Clarke等已经在治疗效果不佳的患者群中发现一组开启/关闭方式特异的基因，希望在结肠直肠癌干细胞中进行相似工作，以区分出那些需要更多治疗的患者。（引自生命经纬）

PublishedonlinebeforeprintJune4,2007,10.1073/pnas.0703478104PNAS|June12,2007|vol.104|no.24|10158-10163BIOLOGICALSCIENCES/MEDICALSCIENCES

Phenotypiccharacterizationofhumancolorectalcancerstemcells

PieroDalerba*,

*DepartmentofInternalMedicine,UniversityofMichigan,AnnArbor,MI48109;

CommunicatedbyIrvingL.Weissman,StanfordUniversitySchoolofMedicine,Stanford,CA,April24,2007（receivedforreviewNovember30,2006）

Recentobservationsindicatethat,inseveraltypesofhumancancer,onlyaphenotypicsubsetofcancercellswithineachtumoriscapableofinitiatingtumorgrowth.Thisfunctionalsubsetofcancercellsisoperationallydefinedasthe"cancerstemcell"（CSC）subset.HerewedevelopedaCSCmodelforthestudyofhumancolorectalcancer（CRC）.SolidCRCtissues,eitherprimarytissuescollectedfromsurgicalspecimensorxenograftsestablishedinnonobesediabetic/severecombinedimmunodeficient（NOD/SCID）mice,weredisaggregatedintosingle-cellsuspensionsandanalyzedbyflowcytometry.Surfacemarkersthatdisplayedintratumorheterogeneousexpressionamongepithelialcancercellswereselectedforcellsortingandtumorigenicityexperiments.Individualphenotypiccancercellsubsetswerepurified,andtheirtumor-initiatingpropertieswereinvestigatedbyinjectioninNOD/SCIDmice.Ourobservationsindicatethat,insixofsixhumanCRCtested,theabilitytoengraftinvivoinimmunodeficientmicewasrestrictedtoaminoritysubpopulationofepithelialcelladhesionmolecule（EpCAM）high/CD44+epithelialcells.TumorsoriginatedfromEpCAMhigh/CD44+cellsmaintainedadifferentiatedphenotypeandreproducedthefullmorphologicandphenotypicheterogeneityoftheirparentallesions.AnalysisofthesurfacemoleculerepertoireofEpCAMhigh/CD44+cellsledtotheidentificationofCD166asanadditionaldifferentiallyexpressedmarker,usefulforCSCisolationinthreeofthreeCRCtested.TheseresultsvalidatethestemcellworkingmodelinhumanCRCandprovideahighlyrobustsurfacemarkerprofileforCRCstemcellisolation.

CD44|CD166/ALCAM|tumordifferentiation|tumorheterogeneityAgrowingbodyofevidenceisincreasinglylendingsupporttotheideathathumancancercanbeconsideredasastemcelldisease（1C3）.Accordingtothe"cancerstemcell"（CSC）theory,tumorsarenottobeviewedassimplemonoclonalexpansionsoftransformedcells,butratherascomplextissueswhereabnormalgrowthisdrivenbyaminority,pathologicalCSCpoolthat,ontheonehand,hasacquiredtumor-relatedfeaturessuchasuncontrolledgrowthandtheabilitytoformmetastasesand,ontheotherhand,maintainsitsinherentcapacitytoself-renewanddifferentiateintoaphenotypicallyheterogeneous,althoughaberrant,progeny.Thishypothesisissupportedbythreekeyexperimentalobservationsinitiallyperformedonhumanacutemyeloidleukemia（4）andsubsequentlyextendedtohumansolidtumors（5,6）:（i）Onlyaminorityofcancercellswithineachtumorisendowedwithtumorigenicpotentialwhentransplantedintoimmunodeficientmice,（ii）tumorigeniccancercellsarecharacterizedbyadistinctiveprofileofsurfacemarkersandcanbedifferentiallyandreproduciblyisolatedfromnontumorigeniconesbyflowcytometry,and（iii）tumorsgrownfromtumorigeniccellscontainmixedpopulationsofbothtumorigenicandnontumorigeniccancercells,thusre-creatingthefullphenotypicheterogeneityoftheparenttumor.Currently,cancercellsubpopulationsselectivelyendowedwithtumorigenicpotentialareoperationallydefinedasCSCsandhavebeenprospectivelyidentifiedfromselectedtypesofhumansolidcancer,suchasbreast（5）,brain（6,7）,colon（8,9）,headandneck（10）,andpancreaticcancer（11）.However,theCSCworkingmodelisstillbeingsubjectedtointensedebate（12）,anddatapublishedoncolorectalcancer（CRC）indicatethatasubgroupofprimaryCRCislikelytobenegativeforthemarkercurrentlyusedforisolationofcolorectalCSCs（Co-CSCs）（9）.Inthepresentstudy,wedevelopedanalternative,veryrobustprotocolfortheisolationofhumanCo-CSCs.全文链接：http://www.pnas.org/cgi/content/full/104/24/10158?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=Michael++Clarke&andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT相关报道:韩伟：肿瘤干细胞为癌症治疗带来新曙光癌症的靶向治疗瞄准肿瘤干细胞NatureGenetics：肿瘤的干细胞来源学说获得新支持干细胞可治疗脑肿瘤肿瘤中是否存在癌症干细胞Nature：研究称癌症也有类似干细胞疑似肿瘤细胞源泉研究人员从肿瘤中发现出的新的前癌干细胞用干细胞追踪肿瘤、传递药物

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