乳腺癌干细胞与基因分型

1、综述=文章编号1007-9424(201003-0302-04乳腺癌干细胞与基因分型韩明利*,吴诚义*=摘要目的总结乳腺癌干细胞与基因分型的研究进展,并分析二者之间的相关性。方法分析近年来有关乳腺癌干细胞与基因分型研究的文献报道。结果乳腺癌干细胞与基因分型的相关性研究支持了乳腺癌的肿瘤干细胞起源学说,解释了乳腺癌基因分型的复杂性及其异质性。结论乳腺癌干细胞和基因分型的相关性研究能为从细胞分子水平研究乳腺癌的形成机理和生物学特性找到新的途径,有望为乳腺癌的诊断和治疗提供新的策略与手段。=关键词乳腺癌;异质性;基因分型;肿瘤干细胞=中图分类号R737.9=文献标识码ABr east Cancer

2、Stem Cells a nd Genotyping H AN M i ng2li*,WU C heng2y i*.*Depa rtment of E ndocr ine Sur ger y, The F irst Af f ilia ted H ospita l of Chongqing Medica l Univer sity,Chong qing400016,China=AbstractObjectiv e To summar ize t he advancement of br east cancer stem cells and genotyping and analyze the

3、correlation between the two.Methods R elevant liter at ur es about br east cancer stem cells and genot yping, which wer e published recently were collected and r eviewed.Results Cancer stem cell origin t heory was supported by researches of corr elation between br east cancer stem cells and genotypi

4、ng,which also explained the complexity of intrinsic subtypes and heterogeneity of breast cancer.Conclusions A new way can be detected to study the forma2 tion mechanism and biological character istics of breast cancer at the cellular and molecular level by r esear ches of cor2 r elation between br e

5、ast cancer stem cells and genotyping,which are expected to provide new str ategies and tools for diagnosis and tr eatment of br east cancer.=Key wor dsBreast cancer;H eterogeneity;Genotyping;Cancer stem cell乳腺癌是一类高度异质性的肿瘤,除了在病理组织形态、分化级别以及激素受体表达方面可分为不同亚型之外,根据基因表达差异也可分为不同基因亚型;此外,肿瘤干细胞理论认为,单个肿瘤内也存在不同特性

6、细胞的亚群,这就使得乳腺癌的个体化治疗更加复杂化1,2。现就乳腺癌干细胞与基因分型的研究进展作一综述。1乳腺癌干细胞1.1乳腺癌干细胞理论的形成与内涵目前,众多研究支持了实体肿瘤的肿瘤干细胞学说:一小部分具有自我更新能力、能产生多种祖细胞的干细胞最终分化为肿瘤内所有的细胞类型3。2003年Al2H ajj等4最先在乳腺癌中证实了乳腺癌干细胞的存在,并且表明乳腺癌干细胞具有自我更新、无限增殖和多向分化的特性;他们在8例癌性胸水和1例原发病灶中分离出了Lin-ESA+ CD44+CD24-/low表型乳腺癌细胞,此表型细胞只需200个=作者单位*重庆医科大学附属第一医院内分泌外科(重庆400016

7、1.2乳腺癌干细胞的临床意义2乳腺癌的基因分型2.1基因分型理论的形成和内涵2000年Perou等14对65例乳腺癌标本和17株乳腺癌细胞株进行了含有8012个人类基因的cDNA微阵列分析,发现同一乳腺癌的基因表达相对稳定,不同乳腺癌之间基因表达则存在着较大差别;化疗前、后及肿瘤原发灶和转移灶之间的基因表达则无明显差异。基于此现象,他们根据基因表达的聚类分析将乳腺癌分为ER+及ER-2组:ER+组又被称为luminal型,并被进一步分为luminal A型和luminal B型;ER-组被分为3型:H ER2过表达型、basal2like型和nor mal breast2like型。5种基因亚

8、型分别具有各自特征7,14 (表1。luminal型具有正常乳腺腔上皮细胞基因表型,lu2 minal A型免疫表型为ER+和(或PR+、H ER2-,ER高表达,低分级,低增殖,预后好;luminal B型免疫表型为ER+和(或P R+、H ER2+,ER中低水平表达,预后较好;HER2过表达型免疫表型为ER-、P R-、H ER2+,基底上皮细胞基因高表达,腔上皮细胞基因低表达,预后较差;basal2like型免疫表型为ER-、PR-、H ER2-,增殖基因高表达,预后最表1乳腺癌基因分型和各基因亚型的特征及其与乳腺癌干细胞的关系Table1Characteristic of br eas

9、t can cer genotyping and each subtype and its relationship with breast cancer s tem cells项目Item lum inal A型lum inal A typeluminal B型luminal B typebasal2like型basal2like typeH ER2过表达型HER2overexpression typen orm al br east2like型n orm al br east2like type分子标记M olecule marker 高表达ERH igh ER ex pres sion中

10、低表达E RLow to moderate ER CK5/6H ER2+脂肪细胞基因标记物Adip os e gene m ark erPR+PR+EGFR+H ER3+脂蛋白脂酶Lip op rotein lipaseGAT A3HER2+肌钙蛋白21T roponin21Grb7整联蛋白A7Integrin A7XB P1Ki67+Grol基因Grol gen ep53突变71%p53m utation71%p53突变33%p53mutation33%FOXA1p53突变40%p53mu tation40%细胞因子家族Cytokine familyp53突变13%p53mutation13

11、%p53突变82%p53mutation82%5年生存率SAT B1ex pres sion-+-B CSC表型B CSC p henotype 无/侧群细胞?No/Side p opu lation?极少CD44+CD24-Few CD44+CD24-CD44+CD24-ALDH1ALDH1无No治疗Therapy 内分泌治疗Endocrine therapy内分泌治疗Endocrin e th erapy化疗Ch emotherapy赫赛汀H erceptin?化疗Chem oth erapy拉帕替尼Lapatinib赫赛汀Herceptin化疗Chemotherapy差;nor ma l

12、 breast2like型与正常乳腺组织的免疫表型和基因表达相似,预后较好。值得一提的是,Kreike等15对97例乳腺癌标本的7770个基因进行了基因谱分析,认为basal2like型乳腺癌仍具有异质性,可以进一步分为、及5种亚型,说明上述目前公认的基因分型可能并不完善。2.2基因分型的临床意义3乳腺癌干细胞与基因分型具有不同分子标记和不同病理表现的乳腺癌基因亚型的存在意味着可能存在不同类型的乳腺癌干细胞,乳腺癌干细胞的类型不同反过来又可以解释不同基因亚型乳腺癌对相同治疗反应不同的原因。研究表明,ER+乳腺癌的MCF27、T472D等细胞系中CD44+CD24-表型乳腺癌干细胞的比例为0,而

13、ER-细胞系如MDA2MB2231其比例高达85%,SUM1315则高达97%5;而且并不是所有的乳腺癌组织标本体外培养都可形成微球体(mammosphere8。这就意味着不同基因亚型乳腺癌的乳腺癌干细胞群体可能不一样,从而造成了不同基因亚型乳腺癌的基因表达、侵袭、转移、治疗和预后差异(表1。具体来讲,CD44+/CD24-表型乳腺癌干细胞与basal2like型乳腺癌密切相关7,22。basal2 like型乳腺癌可进一步分为basal2like A型和basal2like B 型,basal2like B型更多表达间叶细胞样标志物23。研究表明,CD44+/CD24-表型乳腺癌干细胞和ba

14、sal2like B型相关,经过上皮2间充质细胞转化(EMT显示癌细胞表型6,诱导EMT的基因能使非CD44+/CD24-乳腺癌上皮细胞表达CD44+/CD24-表型24,但只有特定的基因才能诱导EMT 获得CD44+/CD24-表型,basal2like型细胞基因能获得这种表型,而luminal型细胞基因则不能7;并且basal2like型和CD44+/CD24-表型乳腺癌患者预后都很差20,25。因此, CD44+/CD24-表型乳腺癌干细胞可能只和basal2like型乳腺癌相关。而ALDH1+表型乳腺癌干细胞与basal2like型以及H ER2过表达型乳腺癌均相关7,8。H ER2过

15、表达能增加ALDH1+表型乳腺癌干细胞的百分比,但这种表型乳腺癌干细胞比例增加与ER表达无关26。luminal A型和luminal B型与乳腺癌干细胞的关系尚未见报道,但有研究表明,具有侧群细胞表型乳腺癌干细胞可以从luminal A型的M CF27细胞系中分离出来27;在剔除了p53基因的小鼠实验中,Lin-/CD24high/CD29high亚型的癌细胞可以产生ER+的乳腺癌28,但在人乳腺癌中尚无同样报道。可见ER-乳腺癌是最可能直接来源于乳腺癌干细胞的亚型,其中的basal2like型可能来源于最原始的乳腺癌干细胞。以上是关于乳腺癌干细胞与基因亚型关系的主要观点,另外还存在多种假说

16、。如区域癌化(field cancerization假说认为干细胞经多次突变可产生表型正常而遗传变异的子细胞区域,如果该区域再经一次必需的突变即可发生转化,表现为该区域内任何一个获得自我更新能力的细胞均可形成肿瘤29。此外,Dontu等30认为,正常乳腺干细胞为ER-的细胞群,正常情况下产生ER+的祖细胞,继续生长分化为正常的乳腺上皮细胞;癌变时则可形成3种不同的乳腺癌细胞群:由ER-干细胞转化而来,ER+细胞少于10%,分化低,内分泌治疗不敏感,预后最差;由突变的ER-干细胞转化而来,部分癌细胞可分化成ER+细胞,内分泌治疗可抑制ER+细胞的增殖,起初有效,但随着ER-干细胞继续增殖或有新的

17、突变下调ER+的表达,内分泌治疗逐渐失效;由ER+祖细胞转化而来,分化好,对激素敏感,内分泌治疗敏感,预后最好。此假说在一定程度上可以解释ER-乳腺癌患者的疗效往往不如ER+患者的原因。4结语总之,乳腺癌干细胞是乳腺癌发生、发展、复发和转移的原因;乳腺癌基因分型可为乳腺癌的诊断、治疗和预后提供重要依据;乳腺癌干细胞和基因分型的相关研究理念以及近年在该领域所取得的成就解释了乳腺癌基因分型的复杂性,也更好地解释了乳腺癌的异质性,跳出了单一方向研究乳腺癌的模式,为从细胞分子水平研究乳腺癌的形成机理和生物学特性找到新的途径,有望为乳腺癌的预防、临床诊断、预后判断以及个体化治疗提供新的策略与手段。5参考

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