艾軍華(綜述)，時 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部隊醫(yī)院外科,福建 莆田 351133)

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腫瘤干細胞和上皮-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 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部隊醫(yī)院外科,福建 莆田 351133)

腫瘤干細胞(CSCs)是腫瘤中能通過分化成異源的癌細胞系而具有自我更新并保持腫瘤啟動能力的細胞。近年來研究表明，CSCs是腫瘤治療后復(fù)發(fā)轉(zhuǎn)移的起源細胞。上皮-間質(zhì)轉(zhuǎn)化(EMT)可產(chǎn)生與CSCs分子特征相同的細胞，而且EMT與腫瘤侵襲轉(zhuǎn)移有關(guān)，是開啟早期腫瘤進入侵襲性惡性表型的關(guān)鍵過程。因此，開發(fā)阻止腫瘤細胞發(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展為侵襲性表型的過程，從而達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；腫瘤干細胞樣細胞；腫瘤啟動細胞；藥物抗性

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

1 EMT在腫瘤進展和轉(zhuǎn)移中的作用

EMT是指上皮細胞在特定的情況下向間質(zhì)細胞轉(zhuǎn)分化的現(xiàn)象[10]，EMT過程對癌癥進展和轉(zhuǎn)移是非常重要的。實體腫瘤細胞通過空間和時間上的EMT而進展為更具侵襲性的表型。具有間葉表型的轉(zhuǎn)移瘤細胞經(jīng)過相反的過程，即轉(zhuǎn)移部位的間葉-上皮轉(zhuǎn)化(mesenchymal-to-epithelial transition, MET)后獲得對應(yīng)的原發(fā)瘤病理學(xué)特征，MET過程是關(guān)鍵的一步，通過MET轉(zhuǎn)移瘤細胞在第二部位生長。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]。在腫瘤中心的細胞仍表達上皮性鈣黏蛋白(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，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)系列細胞株篩選轉(zhuǎn)移能力增強的細胞，發(fā)現(xiàn)轉(zhuǎn)移能力更強的細胞亞群具有EMT特征。在前列腺癌，Yates等[13]用DU145)或PC3細胞與肝細胞共培養(yǎng)，發(fā)現(xiàn)在共培養(yǎng)條件下緊密連接處周圍的DU145和PC3細胞的E-cadherin表達上調(diào)，而且這些細胞系顯示出細胞-細胞間黏附連接如E-cadherin分子標志物的表達與上皮樣形態(tài)是相同的。這些結(jié)果表明，細胞中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完整腫瘤所必需的所有異源腫瘤細胞系的細胞。CSCs的存在首先在白血病細胞中分離并被證實[14]。他們發(fā)現(xiàn)僅有一小部分具有CD34+CD38-細胞表面標志物的白血病細胞亞群移植到嚴重聯(lián)合免疫缺陷的小鼠身上，才能導(dǎo)致癌癥擴散和白血病細胞形態(tài)與原發(fā)灶中的癌細胞形態(tài)相似。此后CSCs在實體腫瘤如乳腺癌、結(jié)腸癌、腦腫瘤和前列腺癌中被鑒定出來。Ricci-Vitiani 等[15]發(fā)現(xiàn)，105個CD133-結(jié)腸癌細胞并不能誘導(dǎo)腫瘤形成，而在基質(zhì)膠中注入106個結(jié)腸癌細胞懸液5周后可產(chǎn)生肉眼可見的腫瘤，而注入3000個CD133+結(jié)腸癌細胞4周后即可誘導(dǎo)生成肉眼可見的腫瘤。O′Brien等[16]也發(fā)現(xiàn)，262個CD133+結(jié)腸癌細胞能誘導(dǎo)嚴重聯(lián)合免疫缺陷小鼠腫瘤形成。這些結(jié)果表明，結(jié)腸癌啟動細胞是CD133+結(jié)腸癌細胞。用中樞干細胞表面標志物CD133分離到了大腦腫瘤干細胞，從侵襲性很強的髓母細胞瘤的臨床標本中分離的細胞亞群具有增強的自我更新能力[17-18]。這些CD133+細胞在培養(yǎng)基中能分化成形態(tài)類似于癌癥患者中的腫瘤細胞。他們還發(fā)現(xiàn)在非肥胖糖尿病、嚴重聯(lián)合免疫缺陷小鼠大腦中注入100個 CD133+細胞可誘導(dǎo)腫瘤發(fā)生。在人前列腺癌中，Patrawala等[19]從用CD44表面標志物建立的異種移植物中鑒定出了腫瘤啟動細胞，并用CD44+α2β1+篩選充實了這些細胞。研究表明，多潛能標志物如Oct4、Sox2、Nanog、lin28、Klf4和c-myc 的共表達能重新編程體細胞成為多潛能的胚胎干細胞樣細胞，說明干細胞相關(guān)的因子和癌基因的聯(lián)合表達也可誘導(dǎo)這些細胞呈未分化狀態(tài)[20]。Jeter等[21]發(fā)現(xiàn)，來源于人、具有上皮表型的前列腺細胞可被人端粒酶逆轉(zhuǎn)錄酶永生化并且表達胚胎干細胞標志物如Oct4、Nanog和Sox2，這與分化差的腫瘤中Oct4、Sox2、Nanog和c-myc過表達的結(jié)果是一致的，而Nanog、Sox2和Oct4在癌癥進展中發(fā)揮重要作用[22-24]。

3 EMT表型細胞是CSCs的起源細胞

大部分腫瘤向惡性進展與上皮分化的喪失和以增強的細胞移動和侵襲為特征的間葉表型的獲得相關(guān)，并促進腫瘤轉(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干細胞樣細胞特征能通過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)信號通路從一種非腫瘤性乳腺上皮細胞CD44lowCD24+細胞產(chǎn)生。他們還發(fā)現(xiàn)CD44+CD24-/low細胞顯示出E-cadherin表達喪失和Vimentin表達獲得為特征的EMT表型，因而假設(shè)EMT的誘導(dǎo)可能與CD44lowCD24+細胞轉(zhuǎn)化為CD44+CD24-/low干細胞樣細胞有關(guān)。用轉(zhuǎn)化生長因子β處理CD24+細胞，處理后8 d出現(xiàn)CD24-細胞，伴隨以E-cadherin喪失和Vimentin表達為特征的間葉表型細胞增多。Mani等[33]進一步研究表明，由twist或snail誘導(dǎo)非腫瘤、永生化的人乳腺上皮細胞成EMT表型將導(dǎo)致上皮表型喪失并獲得間葉表型，同時獲得CD44high/CD24low表達模式并增加微球體形成能力和腫瘤啟動能力。但是，從正常和惡性人乳腺細胞分離出來的CD44high/CD24low干細胞樣細胞顯示出間葉形態(tài)并表達間葉標志物如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)腫瘤過度生長。而且間葉性腫瘤細胞有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。乳腺癌細胞發(fā)生EMT后CD44high/CD24low細胞數(shù)量增加，并且與它們的上皮表型細胞相比這些細胞顯示出了增強100倍的微球體形成能力。這些報道均提示EMT能誘導(dǎo)產(chǎn)生干細胞樣細胞，但調(diào)控該過程的分子機制還不完全清楚。

4 miRNAs以干細胞特征聯(lián)系EMT

已知微RNA(microRNAs，miRNAs)參與胚胎發(fā)育和癌癥進展[36]，而癌癥進展與上皮腫瘤細胞EMT有關(guān)。miRNAs是一類小的非編碼RNA分子，通過與靶基因的3′-非翻譯區(qū)(3′untranslated Regions, 3′UTR)序列相互作用下調(diào)基因表達，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的表達進而調(diào)控EMT過程[38]。ZEB1和ZEB2能通過直接結(jié)合miR-200基因中E-盒的結(jié)合位點抑制miR-200家族的表達，從而在EMT過程中建立一個調(diào)控ZEB1、ZEB2和miR-200家族的雙向負反饋環(huán)。miR-200也可通過調(diào)控B細胞特異性白血病病毒插入位點(B-cell-specific moloney leukemia virus insert sitel, Bmil)、Notch1和Lin28B的表達與干細胞樣細胞特征有關(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，并且用表達ZEB1的Panc1細胞原位注射至胰腺內(nèi)導(dǎo)致裸鼠胰腺形成一個大的原發(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的細胞注射引起一個更小的原發(fā)腫瘤，且該原發(fā)瘤沒有局部浸潤、淋巴結(jié)轉(zhuǎn)移和遠處轉(zhuǎn)移。此外ZEB1不僅抑制miR-200c表達而且也通過抑制miR-203和miR-183表達而調(diào)控干細胞性相關(guān)的因子如Bmil、Sox2和Klf4表達。這些報道均表明miR-200 家族與EMT調(diào)控、CSCs和干細胞樣細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個異構(gòu)體通過調(diào)控miR-200家族的表達誘導(dǎo)EMT發(fā)揮相反的作用。同時，在小鼠乳腺腫瘤病毒(mouse mammary tumor virus, MMTV)-cErbB2/Akt1-/-小鼠生長的腫瘤顯示出miR-200下調(diào)和侵襲能力增加。因此，是Akt-1/Akt2比例而不是Akt的總活性能通過調(diào)控miR-200家族的表達而控制EMT的誘導(dǎo)及維持腫瘤細胞的干細胞性。他們還發(fā)現(xiàn)miR-200家族在CSCs誘導(dǎo)過程中也被抑制，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，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)由血小板源性生長因子-D過表達誘導(dǎo)發(fā)生EMT的PC3細胞具有自我更新和腫瘤生成能力等干細胞特征，這與干細胞標志物如Notch-1、Sox2、Nanog、Oct4 和Lin28B表達增強是一致的[38-39,43]。這些EMT表型細胞也顯示miR-200 或let-7家族表達下調(diào)。此外由轉(zhuǎn)染miR-200前體迫使miR-200再表達誘導(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表達下調(diào)有關(guān)。而敲除Lin28B明顯增強let-7表達并減弱自我更新能力。在發(fā)生EMT的ARCaPM細胞中miR-200c表達被抑制，并且miR-200c 再表達逆轉(zhuǎn)EMT表型至與Notch-1表達下調(diào)、ARCaRM細胞自我更新能力相關(guān)的MET表型[39]。這些報道均提示miRNAs尤其是miR-200家族成員把EMT表型與干細胞特性聯(lián)系在一起，見表1。

5 展 望

傳統(tǒng)的癌癥治療主要靶向分化的腫瘤細胞，但是在相當一部分癌癥患者中，在規(guī)范治療后癌細胞獲得耐藥表型，導(dǎo)致無法根治的腫瘤復(fù)發(fā)和遠處轉(zhuǎn)移。腫瘤復(fù)發(fā)被認為與CSCs或癌啟動細胞的生物學(xué)特性密切相關(guān)[4]。越來越多的證據(jù)表明，腫瘤侵襲特性的獲得與腫瘤細胞發(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細胞特異性白血病病毒插入位點；Sox2：Sry相關(guān)高遷移族蛋白盒2；KLF4：Krüppel樣因子4

腫瘤細胞打破組織架構(gòu)強加的結(jié)構(gòu)限制[44]。EMT誘導(dǎo)的干細胞樣細胞或CSCs為癌癥復(fù)發(fā)提供種子，并且已知這些細胞高度耐藥[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展中的分子機制很重要，這強調(diào)了這些因子對開發(fā)新的完全治愈癌癥的靶向治療的重要性。闡明CSCs、腫瘤干細胞樣細胞和EMT表型細胞的分子機制及生物學(xué)特性將有助于篩選出能選擇性殺死這些細胞以消除腫瘤復(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