艾軍華(綜述)，時(shí) 軍(審校)

(1.南昌大學(xué)第一附屬醫(yī)院普外科,南昌 330006; 2.武警8710部隊(duì)醫(yī)院外科,福建 莆田 351133)

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腫瘤干細(xì)胞和上皮-間質(zhì)轉(zhuǎn)化之間的關(guān)系及其在腫瘤侵襲轉(zhuǎn)移中的作用

艾軍華1,2(綜述)，時(shí) 軍1※(審校)

(1.南昌大學(xué)第一附屬醫(yī)院普外科,南昌 330006; 2.武警8710部隊(duì)醫(yī)院外科,福建 莆田 351133)

腫瘤干細(xì)胞(CSCs)是腫瘤中能通過(guò)分化成異源的癌細(xì)胞系而具有自我更新并保持腫瘤啟動(dòng)能力的細(xì)胞。近年來(lái)研究表明，CSCs是腫瘤治療后復(fù)發(fā)轉(zhuǎn)移的起源細(xì)胞。上皮-間質(zhì)轉(zhuǎn)化(EMT)可產(chǎn)生與CSCs分子特征相同的細(xì)胞，而且EMT與腫瘤侵襲轉(zhuǎn)移有關(guān)，是開(kāi)啟早期腫瘤進(jìn)入侵襲性惡性表型的關(guān)鍵過(guò)程。因此，開(kāi)發(fā)阻止腫瘤細(xì)胞發(fā)生EMT的治療策略，將不僅可從源頭上消滅腫瘤復(fù)發(fā)的“種子”，還可抑制早期腫瘤進(jìn)展為侵襲性表型的過(guò)程，從而達(dá)到有效防治惡性腫瘤術(shù)后復(fù)發(fā)的目的。

上皮-間質(zhì)轉(zhuǎn)化；腫瘤干細(xì)胞樣細(xì)胞；腫瘤啟動(dòng)細(xì)胞；藥物抗性

上皮-間質(zhì)轉(zhuǎn)化(epithelial-to-mesenchymal transition, EMT)作為胚胎發(fā)育的特征首先被認(rèn)識(shí)。研究表明，EMT參與早期腫瘤進(jìn)展為侵襲性惡性腫瘤的過(guò)程[1]，而且EMT能使腫瘤細(xì)胞獲得浸潤(rùn)周圍組織的能力，并使腫瘤細(xì)胞轉(zhuǎn)移到遠(yuǎn)處器官[2]。大部分癌癥的進(jìn)展與間葉表型的獲得相關(guān)，并伴有上皮標(biāo)志物表達(dá)的喪失和間葉標(biāo)志物的上調(diào)，從而導(dǎo)致細(xì)胞移動(dòng)和侵襲能力增強(qiáng)[3]。腫瘤的發(fā)生和復(fù)發(fā)被認(rèn)為與腫瘤干細(xì)胞(cancer stem cells, CSCs)或腫瘤啟動(dòng)細(xì)胞的生物學(xué)特性密切相關(guān)[4-5]，而且由不同因子誘導(dǎo)、具有EMT表型的細(xì)胞是腫瘤干細(xì)胞樣細(xì)胞的豐富來(lái)源[6]。腫瘤細(xì)胞中EMT的誘導(dǎo)不僅促進(jìn)腫瘤細(xì)胞侵襲和轉(zhuǎn)移而且有助于藥物抗性[7-9]。因此闡明這些細(xì)胞的分子特征將有助于開(kāi)發(fā)新的、完全消滅腫瘤的新方法?，F(xiàn)對(duì)CSCs和EMT之間的關(guān)系及其在腫瘤侵襲轉(zhuǎn)移中的作用進(jìn)行綜述。

1 EMT在腫瘤進(jìn)展和轉(zhuǎn)移中的作用

EMT是指上皮細(xì)胞在特定的情況下向間質(zhì)細(xì)胞轉(zhuǎn)分化的現(xiàn)象[10]，EMT過(guò)程對(duì)癌癥進(jìn)展和轉(zhuǎn)移是非常重要的。實(shí)體腫瘤細(xì)胞通過(guò)空間和時(shí)間上的EMT而進(jìn)展為更具侵襲性的表型。具有間葉表型的轉(zhuǎn)移瘤細(xì)胞經(jīng)過(guò)相反的過(guò)程，即轉(zhuǎn)移部位的間葉-上皮轉(zhuǎn)化(mesenchymal-to-epithelial transition, MET)后獲得對(duì)應(yīng)的原發(fā)瘤病理學(xué)特征，MET過(guò)程是關(guān)鍵的一步，通過(guò)MET轉(zhuǎn)移瘤細(xì)胞在第二部位生長(zhǎng)。研究表明，原發(fā)性結(jié)腸癌及其轉(zhuǎn)移癌顯示出一種混合的上皮-間葉表型[11]。在腫瘤中心的細(xì)胞仍表達(dá)上皮性鈣黏蛋白(E-cadherin)和胞質(zhì)β-聯(lián)蛋白(β-catenin)，而在周圍的腫瘤細(xì)胞顯示出表面E-cadherin喪失和波形蛋白(Vimentin)上調(diào)及核β-catenin 表達(dá)，即典型的EMT表型特征。Chaffer等[12]用膀胱癌非雄激素依賴型前列腺癌(TSU-prl, T24)系列細(xì)胞株篩選轉(zhuǎn)移能力增強(qiáng)的細(xì)胞，發(fā)現(xiàn)轉(zhuǎn)移能力更強(qiáng)的細(xì)胞亞群具有EMT特征。在前列腺癌，Yates等[13]用DU145)或PC3細(xì)胞與肝細(xì)胞共培養(yǎng)，發(fā)現(xiàn)在共培養(yǎng)條件下緊密連接處周圍的DU145和PC3細(xì)胞的E-cadherin表達(dá)上調(diào)，而且這些細(xì)胞系顯示出細(xì)胞-細(xì)胞間黏附連接如E-cadherin分子標(biāo)志物的表達(dá)與上皮樣形態(tài)是相同的。這些結(jié)果表明，細(xì)胞中EMT表型改變有助于腫瘤侵襲。

2 CSCs的發(fā)現(xiàn)

CSCs是腫瘤中具有自我更新并分化成一個(gè)完整腫瘤所必需的所有異源腫瘤細(xì)胞系的細(xì)胞。CSCs的存在首先在白血病細(xì)胞中分離并被證實(shí)[14]。他們發(fā)現(xiàn)僅有一小部分具有CD34+CD38-細(xì)胞表面標(biāo)志物的白血病細(xì)胞亞群移植到嚴(yán)重聯(lián)合免疫缺陷的小鼠身上，才能導(dǎo)致癌癥擴(kuò)散和白血病細(xì)胞形態(tài)與原發(fā)灶中的癌細(xì)胞形態(tài)相似。此后CSCs在實(shí)體腫瘤如乳腺癌、結(jié)腸癌、腦腫瘤和前列腺癌中被鑒定出來(lái)。Ricci-Vitiani 等[15]發(fā)現(xiàn)，105個(gè)CD133-結(jié)腸癌細(xì)胞并不能誘導(dǎo)腫瘤形成，而在基質(zhì)膠中注入106個(gè)結(jié)腸癌細(xì)胞懸液5周后可產(chǎn)生肉眼可見(jiàn)的腫瘤，而注入3000個(gè)CD133+結(jié)腸癌細(xì)胞4周后即可誘導(dǎo)生成肉眼可見(jiàn)的腫瘤。O′Brien等[16]也發(fā)現(xiàn)，262個(gè)CD133+結(jié)腸癌細(xì)胞能誘導(dǎo)嚴(yán)重聯(lián)合免疫缺陷小鼠腫瘤形成。這些結(jié)果表明，結(jié)腸癌啟動(dòng)細(xì)胞是CD133+結(jié)腸癌細(xì)胞。用中樞干細(xì)胞表面標(biāo)志物CD133分離到了大腦腫瘤干細(xì)胞，從侵襲性很強(qiáng)的髓母細(xì)胞瘤的臨床標(biāo)本中分離的細(xì)胞亞群具有增強(qiáng)的自我更新能力[17-18]。這些CD133+細(xì)胞在培養(yǎng)基中能分化成形態(tài)類似于癌癥患者中的腫瘤細(xì)胞。他們還發(fā)現(xiàn)在非肥胖糖尿病、嚴(yán)重聯(lián)合免疫缺陷小鼠大腦中注入100個(gè) CD133+細(xì)胞可誘導(dǎo)腫瘤發(fā)生。在人前列腺癌中，Patrawala等[19]從用CD44表面標(biāo)志物建立的異種移植物中鑒定出了腫瘤啟動(dòng)細(xì)胞，并用CD44+α2β1+篩選充實(shí)了這些細(xì)胞。研究表明，多潛能標(biāo)志物如Oct4、Sox2、Nanog、lin28、Klf4和c-myc 的共表達(dá)能重新編程體細(xì)胞成為多潛能的胚胎干細(xì)胞樣細(xì)胞，說(shuō)明干細(xì)胞相關(guān)的因子和癌基因的聯(lián)合表達(dá)也可誘導(dǎo)這些細(xì)胞呈未分化狀態(tài)[20]。Jeter等[21]發(fā)現(xiàn)，來(lái)源于人、具有上皮表型的前列腺細(xì)胞可被人端粒酶逆轉(zhuǎn)錄酶永生化并且表達(dá)胚胎干細(xì)胞標(biāo)志物如Oct4、Nanog和Sox2，這與分化差的腫瘤中Oct4、Sox2、Nanog和c-myc過(guò)表達(dá)的結(jié)果是一致的，而Nanog、Sox2和Oct4在癌癥進(jìn)展中發(fā)揮重要作用[22-24]。

3 EMT表型細(xì)胞是CSCs的起源細(xì)胞

大部分腫瘤向惡性進(jìn)展與上皮分化的喪失和以增強(qiáng)的細(xì)胞移動(dòng)和侵襲為特征的間葉表型的獲得相關(guān)，并促進(jìn)腫瘤轉(zhuǎn)移和耐藥[9]。研究表明，EMT不僅在腫瘤轉(zhuǎn)移而且在腫瘤復(fù)發(fā)中發(fā)揮重要作用，這與CSCs的生物學(xué)特性密切相關(guān)[25-31]。Morel等[32]發(fā)現(xiàn)，CD44+CD24-/low干細(xì)胞樣細(xì)胞特征能通過(guò)激活膜受體酪氨酸蛋白激酶Ras/絲裂原活化蛋白激酶(Ras/mitogen-activated protein kinase, Ras/MAPK)信號(hào)通路從一種非腫瘤性乳腺上皮細(xì)胞CD44lowCD24+細(xì)胞產(chǎn)生。他們還發(fā)現(xiàn)CD44+CD24-/low細(xì)胞顯示出E-cadherin表達(dá)喪失和Vimentin表達(dá)獲得為特征的EMT表型，因而假設(shè)EMT的誘導(dǎo)可能與CD44lowCD24+細(xì)胞轉(zhuǎn)化為CD44+CD24-/low干細(xì)胞樣細(xì)胞有關(guān)。用轉(zhuǎn)化生長(zhǎng)因子β處理CD24+細(xì)胞，處理后8 d出現(xiàn)CD24-細(xì)胞，伴隨以E-cadherin喪失和Vimentin表達(dá)為特征的間葉表型細(xì)胞增多。Mani等[33]進(jìn)一步研究表明，由twist或snail誘導(dǎo)非腫瘤、永生化的人乳腺上皮細(xì)胞成EMT表型將導(dǎo)致上皮表型喪失并獲得間葉表型，同時(shí)獲得CD44high/CD24low表達(dá)模式并增加微球體形成能力和腫瘤啟動(dòng)能力。但是，從正常和惡性人乳腺細(xì)胞分離出來(lái)的CD44high/CD24low干細(xì)胞樣細(xì)胞顯示出間葉形態(tài)并表達(dá)間葉標(biāo)志物如Vimentin和纖維連接蛋白。Santisteban等[34]觀察到由一種上皮乳腺癌產(chǎn)生的免疫應(yīng)答誘導(dǎo)的EMT可引起體內(nèi)腫瘤過(guò)度生長(zhǎng)。而且間葉性腫瘤細(xì)胞有CD44+CD24-/low表型，該表型能重建上皮腫瘤并增加耐藥性，這些與乳腺CSCs的特征一致。Gupta等[35]也發(fā)現(xiàn)由短發(fā)夾RNA(short hairpin RNA, shRNA)介導(dǎo)的E-cadherin敲除誘導(dǎo)轉(zhuǎn)化的HMLER。乳腺癌細(xì)胞發(fā)生EMT后CD44high/CD24low細(xì)胞數(shù)量增加，并且與它們的上皮表型細(xì)胞相比這些細(xì)胞顯示出了增強(qiáng)100倍的微球體形成能力。這些報(bào)道均提示EMT能誘導(dǎo)產(chǎn)生干細(xì)胞樣細(xì)胞，但調(diào)控該過(guò)程的分子機(jī)制還不完全清楚。

4 miRNAs以干細(xì)胞特征聯(lián)系EMT

已知微RNA(microRNAs，miRNAs)參與胚胎發(fā)育和癌癥進(jìn)展[36]，而癌癥進(jìn)展與上皮腫瘤細(xì)胞EMT有關(guān)。miRNAs是一類小的非編碼RNA分子，通過(guò)與靶基因的3′-非翻譯區(qū)(3′untranslated Regions, 3′UTR)序列相互作用下調(diào)基因表達(dá)，從而導(dǎo)致翻譯抑制或mRNAs降解[37]。研究表明，miR-200 家族成員能通過(guò)結(jié)合鋅指E-盒結(jié)合同源異形盒(zinc-finger E-box binding homeobox 1, ZEB1)、鋅指E-盒結(jié)合同源異形盒(zinc-finger E-box binding homeobox 2, ZEB2) mRNA的3′UTR序列調(diào)控ZEB1和ZEB2的表達(dá)進(jìn)而調(diào)控EMT過(guò)程[38]。ZEB1和ZEB2能通過(guò)直接結(jié)合miR-200基因中E-盒的結(jié)合位點(diǎn)抑制miR-200家族的表達(dá)，從而在EMT過(guò)程中建立一個(gè)調(diào)控ZEB1、ZEB2和miR-200家族的雙向負(fù)反饋環(huán)。miR-200也可通過(guò)調(diào)控B細(xì)胞特異性白血病病毒插入位點(diǎn)(B-cell-specific moloney leukemia virus insert sitel, Bmil)、Notch1和Lin28B的表達(dá)與干細(xì)胞樣細(xì)胞特征有關(guān)[39]。Wellner等[40]發(fā)現(xiàn)EMT活化因子ZEB1在低分化的人胰腺癌中高表達(dá)，并且用表達(dá)ZEB1的Panc1細(xì)胞原位注射至胰腺內(nèi)導(dǎo)致裸鼠胰腺形成一個(gè)大的原發(fā)腫瘤并侵犯胃、脾臟、小腸和大腸，并轉(zhuǎn)移到淋巴結(jié)和肝臟。而用敲除了ZEB1的細(xì)胞注射引起一個(gè)更小的原發(fā)腫瘤，且該原發(fā)瘤沒(méi)有局部浸潤(rùn)、淋巴結(jié)轉(zhuǎn)移和遠(yuǎn)處轉(zhuǎn)移。此外ZEB1不僅抑制miR-200c表達(dá)而且也通過(guò)抑制miR-203和miR-183表達(dá)而調(diào)控干細(xì)胞性相關(guān)的因子如Bmil、Sox2和Klf4表達(dá)。這些報(bào)道均表明miR-200 家族與EMT調(diào)控、CSCs和干細(xì)胞樣細(xì)胞特征的維持有直接關(guān)系。

Iliopoulos等[41]發(fā)現(xiàn)，蛋白激酶(Akt)的3個(gè)異構(gòu)體通過(guò)調(diào)控miR-200家族的表達(dá)誘導(dǎo)EMT發(fā)揮相反的作用。同時(shí)，在小鼠乳腺腫瘤病毒(mouse mammary tumor virus, MMTV)-cErbB2/Akt1-/-小鼠生長(zhǎng)的腫瘤顯示出miR-200下調(diào)和侵襲能力增加。因此，是Akt-1/Akt2比例而不是Akt的總活性能通過(guò)調(diào)控miR-200家族的表達(dá)而控制EMT的誘導(dǎo)及維持腫瘤細(xì)胞的干細(xì)胞性。他們還發(fā)現(xiàn)miR-200家族在CSCs誘導(dǎo)過(guò)程中也被抑制，但在攜帶可誘導(dǎo)的Src致癌基因的MCF-10A 模型中不轉(zhuǎn)化，并且抑制miR-200b顯示CSCs形成能力增強(qiáng)，且miR-200b直接靶向zeste 12抑制因子(suppressor of zeste 12, Suz12)[42]。

研究發(fā)現(xiàn)由血小板源性生長(zhǎng)因子-D過(guò)表達(dá)誘導(dǎo)發(fā)生EMT的PC3細(xì)胞具有自我更新和腫瘤生成能力等干細(xì)胞特征，這與干細(xì)胞標(biāo)志物如Notch-1、Sox2、Nanog、Oct4 和Lin28B表達(dá)增強(qiáng)是一致的[38-39,43]。這些EMT表型細(xì)胞也顯示miR-200 或let-7家族表達(dá)下調(diào)。此外由轉(zhuǎn)染miR-200前體迫使miR-200再表達(dá)誘導(dǎo)的EMT逆轉(zhuǎn)明顯抑制集落和前列腺生成能力，這與Notch-1和Lin28B表達(dá)下調(diào)有關(guān)。而敲除Lin28B明顯增強(qiáng)let-7表達(dá)并減弱自我更新能力。在發(fā)生EMT的ARCaPM細(xì)胞中miR-200c表達(dá)被抑制，并且miR-200c 再表達(dá)逆轉(zhuǎn)EMT表型至與Notch-1表達(dá)下調(diào)、ARCaRM細(xì)胞自我更新能力相關(guān)的MET表型[39]。這些報(bào)道均提示miRNAs尤其是miR-200家族成員把EMT表型與干細(xì)胞特性聯(lián)系在一起，見(jiàn)表1。

5 展 望

傳統(tǒng)的癌癥治療主要靶向分化的腫瘤細(xì)胞，但是在相當(dāng)一部分癌癥患者中，在規(guī)范治療后癌細(xì)胞獲得耐藥表型，導(dǎo)致無(wú)法根治的腫瘤復(fù)發(fā)和遠(yuǎn)處轉(zhuǎn)移。腫瘤復(fù)發(fā)被認(rèn)為與CSCs或癌啟動(dòng)細(xì)胞的生物學(xué)特性密切相關(guān)[4]。越來(lái)越多的證據(jù)表明，腫瘤侵襲特性的獲得與腫瘤細(xì)胞發(fā)生EMT有關(guān)，這允許

EMT:上皮-間質(zhì)轉(zhuǎn)化；CSCs：腫瘤干細(xì)胞；miRNAs：微RNAs；miR-200a：微RNA-200a；Akt-1：蛋白激酶B1；miR-200：微RNA-200；miR-200b：微RNA-200b；Notch1：Notch受體1；Suz12：zeste 12抑制因子；miR-200c：微miRNA-200c；miR-183：微RNA-183；ZEB1：鋅指E-盒結(jié)合同源異形盒；ZEB2：鋅指E-盒結(jié)合同源異形盒；Bmil：B細(xì)胞特異性白血病病毒插入位點(diǎn)；Sox2：Sry相關(guān)高遷移族蛋白盒2；KLF4：Krüppel樣因子4

腫瘤細(xì)胞打破組織架構(gòu)強(qiáng)加的結(jié)構(gòu)限制[44]。EMT誘導(dǎo)的干細(xì)胞樣細(xì)胞或CSCs為癌癥復(fù)發(fā)提供種子，并且已知這些細(xì)胞高度耐藥[36]。因此，鑒定哪些因子可能誘導(dǎo)EMT并闡明這些因子在癌癥進(jìn)展中的分子機(jī)制很重要，這強(qiáng)調(diào)了這些因子對(duì)開(kāi)發(fā)新的完全治愈癌癥的靶向治療的重要性。闡明CSCs、腫瘤干細(xì)胞樣細(xì)胞和EMT表型細(xì)胞的分子機(jī)制及生物學(xué)特性將有助于篩選出能選擇性殺死這些細(xì)胞以消除腫瘤復(fù)發(fā)的潛在藥物。

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Study on the Correlation between Cancer Stem Cells and Epithelial-to-Mesenchymal Transition and Its Effect on the Invasion and Metastasis of Tumors

AIJun-hua1,2,SHIJun1.

(1.DepartmentofGeneralSurgery,TheFirstAffiliatedHospitalofNanchangUniverstiy,Nanchang330006,China; 2.DepartmentofSurgery,No.8710HospitalofChinesePeople′sArmedPoliceForce,Putian351113,China)

Cancer stem cells(CSCs) are cells that possess the capacity of self-renewal and maintain the capacity of tumor-initiating through differentiation into the heterogeneous lineages of cancer cells in the tumor.Recent studies have shown that CSCs are the original cells of tumor recurrence and metastasis after therapy.Epithelial-to-mesenchymal transition(EMT) could produce cells with similar molecular characteristics as CSCs,besides,EMT is correlated with the invasion and metastasis of tumors,and is the critical process that boots early tumors to evolve into the invasive tumors.Therefore,exploiting the therapeautic strategies to stop tumor cells from developing into EMT will not only extinguish the “seeds” of recurrence of tumors in the source but also inhibit the early tumors from evolving into invasive phenotype,so as to prevent and treat the recurrence of malignant tumors effectively.

Epithelial-to-mesenchymal transition; Cancer stem-like cells; Tumor-initiating cells; Drug resistance

R73-37

A

1006-2084(2015)12-2180-04

10.3969/j.issn.1006-2084.2015.12.025

2014-08-25

2014-12-06 編輯：相丹峰