上皮細(xì)胞間質(zhì)轉(zhuǎn)型與腫瘤轉(zhuǎn)移

1、第27卷第5期2007年10月國際病理科學(xué)與臨床雜志I nternati onal Journal of Pathol ogy and ClinicalMedicineVol.27No.5Oct.2007綜述上皮細(xì)胞間質(zhì)轉(zhuǎn)型與腫瘤轉(zhuǎn)移徐江鋒1,羅庚求2(1.中南大學(xué)湘雅醫(yī)學(xué)院2003級七年制,長沙410078;2.中南大學(xué)基礎(chǔ)醫(yī)學(xué)院病理學(xué)系,長沙410078摘要上皮細(xì)胞間質(zhì)轉(zhuǎn)型(ep ithelial2mesenchy mal transiti ons,E MT是具有極性的上皮細(xì)胞轉(zhuǎn)換成為具有活動能力的間質(zhì)細(xì)胞并獲得侵襲和遷移能力的過程,它存在于人體多個生理和病理過程中。E MT的發(fā)生涉及到多

2、個信號轉(zhuǎn)導(dǎo)通路和復(fù)雜的分子機(jī)制,與鈣連接素、生長因子、轉(zhuǎn)錄因子、微環(huán)境等有關(guān)。E MT與腫瘤細(xì)胞的侵襲和轉(zhuǎn)移關(guān)系密切。關(guān)鍵詞上皮細(xì)胞間質(zhì)轉(zhuǎn)型(E M T;發(fā)生機(jī)制;腫瘤轉(zhuǎn)移中圖分類號R730.26文獻(xiàn)標(biāo)識碼A文章編號167322588(20070520393204 Ep itheli a l2m esenchyma l tran siti on s and tu m or m et a st a sisXU J iang2feng1,LUO Geng2qiu2(1.C linical M edicine,X iangya School of M edicine,Central South U

3、niversity,Changsha410078;2.D epart m ent of Pathology,X iangya School of M edicine,Central South U niversity,Changsha410078,ChinaAbstractEp ithelial2mesenchy mal transiti ons(E MTis a p r ocess that ep ithelial cell layers l ose polarity and acquire exp ressi on of mesenchy mal components and manife

4、st a m igrat ory phenotype.It exists in many physi ol ogical and pathol ogical p r ocesses in hu man body.The p r ogress of E MT involves a number of signal transducti on path ways and co mp lex molecular mechanis m s,and is related t o calcium catenin, gr owth fact ors,transcri p ti on fact ors,m i

5、cr o2envir onment,and s o on.E MT p lay an i m portant r ole in tu mor metastasis.Key wordsep ithelial2mesenchy mal transiti ons;mechanis m s;tu mor metastasisI nt J Pathol Clin Med,2007,27(5:0393204上皮細(xì)胞間質(zhì)轉(zhuǎn)型(ep ithelial2mesenchy mal tran2 siti ons,E MT是一種基本的生理病理現(xiàn)象,參與胚胎發(fā)育、組織重建和腫瘤轉(zhuǎn)移,上皮細(xì)胞表型的缺失及間質(zhì)特性的獲得是

6、其主要特征。E MT最早發(fā)現(xiàn)于發(fā)育生物學(xué),Garry Greenburg與Elisabeth Hay經(jīng)細(xì)胞實驗證明上皮細(xì)胞會暫時喪失他們的細(xì)胞極性,并且表現(xiàn)出具有移行能力的間質(zhì)細(xì)胞特征,正式提出E MT的概念1。以后的研究證實223,E MT在胚胎發(fā)育、組織發(fā)生中起重要作用。此外,E MT也存在于多種病理過程中,如上皮組織的傷口愈合過程,腎臟纖維化,假上皮瘤樣增生和腫瘤轉(zhuǎn)移。E MT在腫瘤細(xì)胞的侵襲和遠(yuǎn)處轉(zhuǎn)移中起著重要作用,因而成為腫瘤研究中的一個熱點(diǎn)。1E M T的概念E MT是具有極性的上皮細(xì)胞轉(zhuǎn)換成具有活動能力、能夠在細(xì)胞基質(zhì)間自由移動的間質(zhì)細(xì)胞的過程。它以上皮細(xì)胞極性的喪失及間質(zhì)特性的

7、獲得為重要特征3,具體包括:細(xì)胞黏附分子(E2鈣黏蛋白表達(dá)減少;角蛋白為主的細(xì)胞骨架轉(zhuǎn)變?yōu)椴ㄐ蔚鞍诪橹鞯募?xì)胞骨架,從而引起細(xì)胞形態(tài)的改變。但收稿日期:2007203226修回日期:2007207204作者簡介:徐江鋒(19842,男,浙江紹興人,主要從事消化道腫瘤研究。通訊作者:羅庚求,E2mail:luogengqiuhot m 基金項目:中南大學(xué)大學(xué)生創(chuàng)新教育項目(LB06136This work was supported by the Pr oject of I nnovated Educati on for University Students of Central South U

8、niversity(LB06136第5期國際病理科學(xué)與臨床雜志第27卷有時E MT僅發(fā)生功能上的改變,形態(tài)上不發(fā)生變化4。這種表型的轉(zhuǎn)換允許腫瘤細(xì)胞擺脫細(xì)胞2細(xì)胞間連接,而表現(xiàn)得更具侵襲性。2E M T的發(fā)生機(jī)制E MT的發(fā)生涉及到多個信號轉(zhuǎn)導(dǎo)通路和復(fù)雜的分子機(jī)制。目前,其具體機(jī)制尚未完全闡明,可能與鈣連接素、生長因子、轉(zhuǎn)錄因子及微環(huán)境有關(guān)。2.1鈣連接素(cadherins鈣連接素是一種跨膜糖蛋白,主要參與細(xì)胞間的連接,分為E2cadher2 ins,P2cadherins和N2cadherins三種,而E2cadherins 是其中影響腫瘤侵襲轉(zhuǎn)移較重要的一種,同時,也是E MT的關(guān)鍵分子

9、。具有侵襲性的腫瘤細(xì)胞重新表達(dá)E2cadherin,可以逆轉(zhuǎn)腫瘤細(xì)胞的侵襲性。維持穩(wěn)定的細(xì)胞連接需要E2cadherin,抗E2cadherin抗體可以破壞細(xì)胞間連接,從而誘發(fā)E MT。E2cadherin可與連環(huán)素(2catenin和連環(huán)素(2catenin結(jié)合,再與連環(huán)素相連,形成E2cadherin2連環(huán)素2連環(huán)素復(fù)合體5,其與肌動蛋白細(xì)胞骨架的正確連接對于細(xì)胞間粘附的穩(wěn)定相當(dāng)重要6。除了E2cadherin表達(dá)的喪失,E MT過程中還可伴有其他鈣連接素的生成,如N鈣連接素(N2cad2 herin。N2cadherin可促進(jìn)腫瘤細(xì)胞遷移和轉(zhuǎn)移,而且其作用超過E2cadherin介導(dǎo)的細(xì)

10、胞間粘附作用7。因此,Cavallar o等5認(rèn)為E MT過程中伴有E2 cadherin的喪失和N2cadherin的表達(dá)。但是也有研究發(fā)現(xiàn)并不是所有的E MT均有E2cadherin的下調(diào)829,還存在其他的機(jī)制參與E MT的發(fā)生。2.2生長因子E MT的發(fā)生受多種生長因子的調(diào)控,如HGF,FGF,EGF,TGF2等,可與上皮細(xì)胞表面的相應(yīng)受體結(jié)合,經(jīng)不同的信號轉(zhuǎn)導(dǎo)通路,影響細(xì)胞黏附分子與細(xì)胞骨架的功能。研究發(fā)現(xiàn)10211,多種生長因子(FGF21,EGF,TGF2刺激小鼠膀胱癌細(xì)胞株NBT2細(xì)胞,可使細(xì)胞變得松散,失去上皮細(xì)胞的特性,進(jìn)而引發(fā)E MT。HGF是c2met原癌基因跨膜酪氨酸

11、激酶受體的配體,HGF可增加表達(dá)c2 met的卵巢癌細(xì)胞的遷移力,趨化力及有絲分裂的發(fā)生。將HGF加入到卵巢癌SK OV23細(xì)胞的培養(yǎng)體系中,可刺激細(xì)胞發(fā)生E MT,而HGF中和抗體則可消除其作用12213。Martin等14研究發(fā)現(xiàn),TGF2的下游因子S mad2和H2ras能促進(jìn)腫瘤的轉(zhuǎn)移。在一種新的E MT結(jié)腸癌模型中,T NF2加速了由TGF2介導(dǎo)的E MT過程。T NF2和TGF2協(xié)同作用促進(jìn)了結(jié)腸上皮向間葉細(xì)胞形態(tài)的轉(zhuǎn)變15。在多種高表達(dá)TGF2的腫瘤中,TGF2可以自分泌和旁分泌的形式作用于腫瘤細(xì)胞,從而誘導(dǎo)并維持細(xì)胞的E MT狀態(tài)。最近L iu等證實P68的磷酸化介導(dǎo)了P DG

12、F激發(fā)的E MT過程16。2.3轉(zhuǎn)錄因子已發(fā)現(xiàn)Snail,Slug,Si p1,AP21, NF2B,T wist等多種轉(zhuǎn)錄因子可以誘導(dǎo)E MT。Snail 的穩(wěn)定表達(dá)引起上皮細(xì)胞向間質(zhì)細(xì)胞表型的轉(zhuǎn)變,同時伴有E2cadherin的下調(diào),從而引起E MT17218。Slug則不參與E2cadherin的下調(diào),而是通過對間質(zhì)細(xì)胞表型的維持促進(jìn)E MT19。AP21家庭成員C2 Jun可以導(dǎo)致上皮細(xì)胞極性缺失,C2Fos可降低細(xì)胞間的粘連,Jun D活性喪失會引起基質(zhì)金屬蛋白酶(matrix metall op r oteinase,MMP表達(dá)上調(diào),而MMP 表達(dá)上調(diào)與E MT關(guān)系密切20。Hub

13、er等21研究證明在誘導(dǎo)和維持E MT的過程中,IK22/IB/NF2B的通路是必須的。在Ras轉(zhuǎn)染的上皮細(xì)胞中抑制NF2B信號可以阻止E MT的發(fā)生,而激活此通路可以在缺乏TGF2的情況下促使細(xì)胞向間葉細(xì)胞形態(tài)的轉(zhuǎn)變。此外,在間葉細(xì)胞中抑制NF2B的活性可以導(dǎo)致E MT過程的逆轉(zhuǎn)。T wist是一個高度保守的轉(zhuǎn)錄因子,它可以調(diào)節(jié)胚胎發(fā)育中的組織重建,并賦予細(xì)胞遷移的能力。研究發(fā)現(xiàn)22,表達(dá)T wist的細(xì)胞呈細(xì)長形,E2cadher2 in和2catenin等粘附連接蛋白表達(dá)降低,從而引起E MT。T wist在上皮來源的乳腺癌轉(zhuǎn)移中起重要作用。另外,T wist的過度表達(dá)也是彌漫性胃癌發(fā)生

14、E MT的一種重要因素23。T wist引起E2cadherin下調(diào)的機(jī)制目前尚不十分清楚,它可能是通過直接與E2box位點(diǎn)結(jié)合的方式下調(diào)E2cadherin,也可能通過抑制某些調(diào)節(jié)因子的活性下調(diào)E2cadherin。T wist可以直接促進(jìn)snail的表達(dá)24。作為NF2B的靶基因,T wist能夠建立一個抑制NF2B誘導(dǎo)的炎癥因子表達(dá)的負(fù)反饋環(huán)25。2.4微環(huán)境微環(huán)境在E MT的發(fā)生中起著重要的作用。細(xì)胞外機(jī)制通過多種途徑影響E MT。研究發(fā)現(xiàn)26,骨微環(huán)境能通過誘導(dǎo)TGF21表達(dá)使腫瘤細(xì)胞經(jīng)E MT過程而促進(jìn)和維持前列腺癌骨轉(zhuǎn)移。當(dāng)微環(huán)境發(fā)生改變時,E MT細(xì)胞可以恢復(fù)上皮細(xì)胞特征性標(biāo)記

15、。3E M T與腫瘤轉(zhuǎn)移腫瘤轉(zhuǎn)移是指惡性腫瘤脫離原發(fā)腫瘤通過各種轉(zhuǎn)移方式,到達(dá)繼發(fā)組織或器官得以繼續(xù)增殖生長,第5期徐江鋒,等:上皮細(xì)胞間質(zhì)轉(zhuǎn)型與腫瘤轉(zhuǎn)移第27卷形成與原發(fā)腫瘤相同性質(zhì)的繼發(fā)腫瘤的全過程。它包括多個過程,其中腫瘤細(xì)胞侵襲是腫瘤轉(zhuǎn)移的前提,而E MT在腫瘤細(xì)胞侵襲過程中起著重要作用。當(dāng)腫瘤細(xì)胞E2cadherin下調(diào)時,可使非侵襲性腫瘤轉(zhuǎn)變?yōu)楦咔忠u性腫瘤。若將E2cadherin c DNA轉(zhuǎn)染進(jìn)入高侵襲性腫瘤細(xì)胞中,這些細(xì)胞的侵襲性和遷移性受到極大限制。Putz等26研究發(fā)現(xiàn),從前列腺癌、乳腺癌、結(jié)腸癌患者骨轉(zhuǎn)移灶中收集到的腫瘤細(xì)胞均表達(dá)E MT的標(biāo)記物,證實了E MT的發(fā)生。

16、卵巢癌在發(fā)生轉(zhuǎn)移的過程中也存在E MT。Davies 等27發(fā)現(xiàn)在分化好的卵巢癌中存在E2cadherin表達(dá),而分化差的卵巢癌則不表達(dá)E2cadherin。T wist 表達(dá)的上調(diào)也和黑色素瘤的惡性轉(zhuǎn)型以及T細(xì)胞淋巴瘤有密切關(guān)系28。最近,一種可逆的E MT模型被提出來以更好的解釋腫瘤轉(zhuǎn)移的動態(tài)過程29。在此模型中,癌細(xì)胞首先通過E MT而獲得侵襲性,以實現(xiàn)對周圍組織的浸潤和遠(yuǎn)處器官的轉(zhuǎn)移。一旦這一過程完成,這些細(xì)胞就可能通過間質(zhì)細(xì)胞上皮轉(zhuǎn)型(mesenchy mal2 ep ithelial transiti on,MET而重新獲得增殖能力。這一模型很好的解釋了腫瘤轉(zhuǎn)移的動態(tài)過程,但是還存

17、在著一些挑戰(zhàn):首先,只有一小部分腫瘤細(xì)胞通過E MT而獲得侵襲性,這些細(xì)胞的基因表達(dá)的改變可以被大量無侵襲性細(xì)胞所掩蓋,使我們無法觀察到一些細(xì)微變化。如何擺脫這些因素的干擾是一個值得研究的問題。另一個挑戰(zhàn)是如何找出可靠的分子標(biāo)記,以確定那些正在經(jīng)歷E MT的腫瘤細(xì)胞?？傊?E MT是腫瘤轉(zhuǎn)移的重要機(jī)制之一。一些新的始動因子,T wist誘導(dǎo)E MT的機(jī)制是什么?各種轉(zhuǎn)錄因子在誘導(dǎo)E MT的過程中有怎樣的聯(lián)系?這些問題正成為E MT研究中的熱點(diǎn)。而這些研究將為臨床防治腫瘤轉(zhuǎn)移提供新的思路和方法。參考文獻(xiàn)1Robert L.The extracellular matrix in devel opm

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