王超群　孫豪庭(綜述)　欽倫秀,3△(審校)

(1復(fù)旦大學(xué)附屬華山醫(yī)院普外科　上?！?00040; 2復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所　上?！?00040; 3復(fù)旦大學(xué)生物醫(yī)學(xué)研究院　上?！?00032)

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外泌體與腫瘤侵襲轉(zhuǎn)移相關(guān)研究進(jìn)展

王超群1,2孫豪庭1,2(綜述)欽倫秀1,2,3△(審校)

(1復(fù)旦大學(xué)附屬華山醫(yī)院普外科上海200040;2復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所上海200040;3復(fù)旦大學(xué)生物醫(yī)學(xué)研究院上海200032)

【摘要】外泌體(又稱外泌小體,exosomes)是一種能由絕大多數(shù)細(xì)胞釋放的、具有脂質(zhì)雙分子層和豐富內(nèi)容物的微囊泡結(jié)構(gòu),直徑約30～100 nm。1981年科學(xué)家首次發(fā)現(xiàn)腫瘤源性外泌體,近10年來發(fā)現(xiàn)外泌體中不僅包含功能性蛋白,還有功能性核酸物質(zhì),這些蛋白質(zhì)、核酸等對(duì)腫瘤侵襲轉(zhuǎn)移具有促進(jìn)作用,成為腫瘤相關(guān)研究的熱點(diǎn)。外泌體以其獨(dú)特的方式包裹蛋白質(zhì)和核酸物質(zhì),穩(wěn)定有效地進(jìn)行細(xì)胞間信號(hào)的傳遞和交換。更好地了解外泌體促進(jìn)腫瘤侵襲轉(zhuǎn)移的機(jī)制,將有助于明確腫瘤侵襲轉(zhuǎn)移的關(guān)鍵環(huán)節(jié),進(jìn)而有針對(duì)性地研發(fā)有效的防治策略,改善腫瘤患者預(yù)后。

【關(guān)鍵詞】腫瘤;轉(zhuǎn)移;外泌體

腫瘤源性外泌體 (exosomes)的研究始于1981年,Trams等[1]首次發(fā)現(xiàn)腫瘤源性外泌體包含具有生物活性的核苷酸酶,根據(jù)其大小可以分為直徑500～1 000 nm和40 nm左右兩類。1987年,Johnstone等[2]在對(duì)網(wǎng)織紅細(xì)胞成熟的研究過程中同樣發(fā)現(xiàn)了外泌體的釋放,重新定義了外泌體的直徑為30～100 nm[2],這一定義也為之后的多數(shù)科學(xué)家所認(rèn)可。此后的25年間,外泌體研究相對(duì)比較緩慢。一直到最近10年,尤其是近5年來,外泌體與腫瘤的相關(guān)研究迅速增加,掀起了外泌體的研究熱潮,主要原因在于腫瘤相關(guān)的外泌體無論是在腫瘤轉(zhuǎn)移機(jī)制、腫瘤診斷與監(jiān)測(cè)以及腫瘤治療等方面都表現(xiàn)出了相對(duì)強(qiáng)大的優(yōu)勢(shì)。

外泌體是由細(xì)胞膜內(nèi)陷后通過一系列復(fù)雜的機(jī)制形成多囊泡小體(multivesicular bodies,MVBs),然后MVBs與細(xì)胞膜融合,釋放外泌體至細(xì)胞外。這些外泌體的大小為30～100 nm,內(nèi)含蛋白質(zhì)、核酸以及脂類物質(zhì),外泌體可以作為這些物質(zhì)的運(yùn)輸及存儲(chǔ)工具,存在于很多體液中,包括血液、尿液、唾液及腹水等,被靶細(xì)胞內(nèi)呑后其內(nèi)容物通過多種機(jī)制發(fā)揮功能[3]。本文主要總結(jié)國內(nèi)外有關(guān)外泌體與腫瘤侵襲轉(zhuǎn)移的相關(guān)研究進(jìn)展,為研究腫瘤外泌體相關(guān)轉(zhuǎn)移機(jī)制提供新的線索。

目前關(guān)于外泌體抑制腫瘤的相關(guān)報(bào)道較少,2013年,Bruno等[4]通過研究發(fā)現(xiàn)間充質(zhì)干細(xì)胞源性的外泌體可以抑制肝癌 (HepG2)、Kaposi肉瘤、卵巢癌 (Skov-3)細(xì)胞體內(nèi)體外的增殖以及生長。但是,間充質(zhì)干細(xì)胞究竟對(duì)腫瘤進(jìn)展發(fā)揮了促進(jìn)還是抑制作用,仍然有待進(jìn)一步研究加以證實(shí)[5]。相對(duì)而言,近些年外泌體促進(jìn)腫瘤轉(zhuǎn)移方面的研究報(bào)道則越來越多,主要集中在以下4個(gè)方面: (1)腫瘤細(xì)胞通過分泌外泌體直接為腫瘤侵襲轉(zhuǎn)移開辟道路[7-8]; (2)高轉(zhuǎn)移潛能的腫瘤細(xì)胞可以通過外泌體促進(jìn)腫瘤細(xì)胞自身或者其他相對(duì)低轉(zhuǎn)移潛能腫瘤細(xì)胞的侵襲轉(zhuǎn)移能力[9-10]; (3)腫瘤微環(huán)境中間質(zhì)細(xì)胞與腫瘤細(xì)胞通過外泌體進(jìn)行相互對(duì)話,促進(jìn)腫瘤轉(zhuǎn)移[11]; (4)腫瘤源性外泌體通過對(duì)遠(yuǎn)處轉(zhuǎn)移灶微環(huán)境中的間質(zhì)細(xì)胞進(jìn)行改造,進(jìn)而促進(jìn)循環(huán)腫瘤細(xì)胞的遠(yuǎn)處定植和增殖[12,14]。另外,還存在一些其他腫瘤中外泌體促進(jìn)腫瘤侵襲轉(zhuǎn)移的機(jī)制研究有待探討。

腫瘤細(xì)胞源性外泌體開辟腫瘤侵襲轉(zhuǎn)移之路腫瘤細(xì)胞源性外泌體可以富含多種基質(zhì)金屬蛋白酶 (matrix metalloproteinases,MMPs),比如MMP1、MMP2、MMP13等,以及ADAMs,如ADAM-10和ADAMTS1等[7-8,15],而MMPs以及ADAMs可通過降解細(xì)胞外基質(zhì) (extracellular matrix,ECM)以及剪切細(xì)胞間黏附分子,從而促進(jìn)腫瘤細(xì)胞侵襲轉(zhuǎn)移[16]。

腫瘤細(xì)胞源性外泌體促進(jìn)腫瘤細(xì)胞的轉(zhuǎn)移能力2008年,Al-NedawiK等[9]首次發(fā)現(xiàn)EGFR突變 (EGFRvⅢ)的膠質(zhì)瘤細(xì)胞可以通過釋放富含突變受體蛋白EGFRvⅢ的外泌體賦予野生型膠質(zhì)瘤細(xì)胞更強(qiáng)的侵襲能力。富含EGFRvⅢ的外泌體進(jìn)入野生型膠質(zhì)瘤細(xì)胞后,可以激活EGFRvⅢ調(diào)節(jié)的下游通路,如VEGF、BCL-XL、p27,從而增強(qiáng)受體細(xì)胞侵襲能力。2013年,Demory Beckler等[17]研究發(fā)現(xiàn)K-RAS突變的結(jié)腸癌細(xì)胞株可將突變的K-RAS蛋白、EGFR、SRC激酶、整合素等惡性相關(guān)蛋白質(zhì)傳遞給K-RAS野生型細(xì)胞株,從而增強(qiáng)后者的惡性表型[17]。從首次發(fā)現(xiàn)腫瘤源性的外泌體以來,科學(xué)家們就知道了外泌體可包含功能性的蛋白質(zhì)[1]。但是,直到2007年,Valadi等[18]首次系統(tǒng)闡述了人肥大細(xì)胞源性外泌體中包含功能的mRNA和microRNA,可由供體細(xì)胞傳遞給受體細(xì)胞?；谶@一發(fā)現(xiàn),Le等[19]研究發(fā)現(xiàn),高轉(zhuǎn)移乳腺癌細(xì)胞通過外泌體可以將miRNA-200傳遞給低轉(zhuǎn)移潛能的乳腺癌細(xì)胞,從而增強(qiáng)后者的侵襲轉(zhuǎn)移能力。Kogure等[10]也發(fā)現(xiàn)含有miRNAs的腫瘤細(xì)胞源性外泌體可調(diào)控靶細(xì)胞TAK1表達(dá),進(jìn)一步促進(jìn)侵襲轉(zhuǎn)移,而這一靶細(xì)胞甚至可以是腫瘤細(xì)胞系本身。這就說明了腫瘤細(xì)胞源性的外泌體不僅對(duì)相對(duì)低轉(zhuǎn)移侵襲能力的腫瘤細(xì)胞具有促轉(zhuǎn)移作用,其對(duì)腫瘤細(xì)胞自身的轉(zhuǎn)移侵襲能力的維持也具有至關(guān)重要的作用。

外泌體在間質(zhì)細(xì)胞與腫瘤細(xì)胞相互對(duì)話過程中的作用間質(zhì)細(xì)胞促進(jìn)腫瘤細(xì)胞發(fā)生發(fā)展的研究早在100多年前就已有報(bào)道[20]。而近10年來科學(xué)界開始著眼于間質(zhì)細(xì)胞與腫瘤細(xì)胞間通過外泌體進(jìn)行相互對(duì)話的研究[21]。富含TGFβ1蛋白的腫瘤源性外泌體可以將靜息狀態(tài)的成纖維細(xì)胞活化形成肌成纖維細(xì)胞,從而促進(jìn)腫瘤血管新生以及腫瘤的生長,而單純的可溶性TGFβ1雖然可以激活成纖維細(xì)胞,但卻沒有促進(jìn)血管新生和腫瘤生長的作用[22-23]。腫瘤細(xì)胞源性外泌體還可以誘導(dǎo)單核細(xì)胞向M2型巨噬細(xì)胞的分化,進(jìn)而促進(jìn)腫瘤血管新生及腫瘤生長、侵襲轉(zhuǎn)移[24-25]。除了間接促進(jìn)腫瘤血管新生,腫瘤細(xì)胞源性外泌體還可以通過傳遞miRNA-210、組織因子等直接調(diào)控血管內(nèi)皮細(xì)胞的靶基因或信號(hào)通路,從而促進(jìn)血管新生[26-29],為腫瘤轉(zhuǎn)移創(chuàng)造條件。富含癌蛋白KIT的腫瘤源性外泌體可促進(jìn)腫瘤微環(huán)境平滑肌細(xì)胞分泌MMP1,進(jìn)而為腫瘤細(xì)胞的侵襲轉(zhuǎn)移鋪平道路[30]。反之,間質(zhì)細(xì)胞源性外泌體亦可促進(jìn)腫瘤細(xì)胞的侵襲轉(zhuǎn)移。2012年,Luga等[11]通過嚴(yán)密的實(shí)驗(yàn)結(jié)果證明,小鼠成纖維細(xì)胞釋放的外泌體攜帶CD81進(jìn)入受體乳腺癌細(xì)胞,從而裝載WNT11蛋白,激活WNT-PCP自分泌的信號(hào)通路,進(jìn)一步促進(jìn)乳腺癌細(xì)胞的運(yùn)動(dòng)遷移能力。而Shimoda等[31]的研究發(fā)現(xiàn)活化后的成纖維細(xì)胞釋放的外泌體中富含的ADAM10可以激活腫瘤細(xì)胞NOTCH及RhoA通路并促進(jìn)腫瘤細(xì)胞的運(yùn)動(dòng)能力。巨噬細(xì)胞源性的富含Wnt5a蛋白的外泌體亦可促進(jìn)腫瘤細(xì)胞侵襲轉(zhuǎn)移。除了腫瘤細(xì)胞與間質(zhì)細(xì)胞之間,間質(zhì)細(xì)胞與間質(zhì)細(xì)胞之間也可通過外泌體進(jìn)行相互對(duì)話。2014年,Burke等[33]研究發(fā)現(xiàn)骨髓源性抑制細(xì)胞 (myeloid-derived suppressor cells,MDSC)源性外泌體可以誘導(dǎo)巨噬細(xì)胞向M2促癌型分化。

腫瘤源性外泌體改造腫瘤轉(zhuǎn)移微環(huán)境2012年,Peinado等[12]研究發(fā)現(xiàn),高轉(zhuǎn)移潛能黑色素瘤細(xì)胞B16-F10源性外泌體可以促進(jìn)小鼠原位瘤模型的體內(nèi)轉(zhuǎn)移,其理論基礎(chǔ)涉及到這些富含met蛋白的外泌體對(duì)骨髓源性細(xì)胞 (bone marrow derived cells,BMDCs)的改造,改造后的BMDCs浸潤小鼠肺臟后,會(huì)改變肺臟微環(huán)境,包括血管通透性增強(qiáng)、血管新生等,從而為腫瘤細(xì)胞的肺臟定植與生長提供幫助。類似的,2014年,Zhou等[14]的研究證明,高轉(zhuǎn)移潛能乳腺癌細(xì)胞源性外泌體富含miRNA-105,這些外泌體被肺臟微血管內(nèi)皮細(xì)胞攝取后,內(nèi)皮細(xì)胞的緊密連接蛋白ZO-1的表達(dá)顯著下調(diào),導(dǎo)致血管通透性增加,有助于腫瘤細(xì)胞向肺臟的定植[14]。2015年,Costa-Silva等[13]闡述了腫瘤源性外泌體可以通過更為復(fù)雜精細(xì)的機(jī)制的對(duì)預(yù)轉(zhuǎn)移灶進(jìn)行改造。首先,胰腺癌細(xì)胞可釋放富含巨噬細(xì)胞遷移抑制因子 (macrophage migration inhibitory factor,MIF)的外泌體,這些外泌體循環(huán)至肝臟后促進(jìn)肝臟固有的庫普弗細(xì)胞分泌細(xì)胞因子TGFβ,TGFβ又進(jìn)一步作用于成纖維細(xì)胞,促進(jìn)纖連蛋白 (fibronectin)的分泌,最終促進(jìn)腫瘤細(xì)胞在肝臟的定植,從而增加了轉(zhuǎn)移形成的可能性。

外泌體促進(jìn)腫瘤侵襲轉(zhuǎn)移的其他機(jī)制2014年,Ostenfeld等[34]研究發(fā)現(xiàn)了一個(gè)有趣的現(xiàn)象,高轉(zhuǎn)移潛能膀胱癌細(xì)胞源性的外泌體中抑癌基因miRNA-23b的含量顯著高于非轉(zhuǎn)移細(xì)胞系源性的外泌體,作者通過一系列實(shí)驗(yàn)結(jié)果提出全新理論——腫瘤細(xì)胞通過外泌體釋放舍棄抑癌基因miRNA-23b從而獲得轉(zhuǎn)移潛能。雖然作者的這一理論還沒有得到公認(rèn),但高轉(zhuǎn)移潛能腫瘤細(xì)胞源性的外泌體富含腫瘤抑制的miRNA這一有趣現(xiàn)象的出現(xiàn)卻并非偶然。同是2014年,Zhou等[14]在對(duì)高轉(zhuǎn)移潛能的乳腺癌細(xì)胞系MDA-MB-231和正常乳腺上皮細(xì)胞系MCF10A及其源性的外泌體進(jìn)行了miRNAs的表達(dá)譜檢測(cè),在發(fā)現(xiàn)了促癌基因miRNA-105的同時(shí),作者還列出了許多抑癌基因,包括miRNA-127-3p[35]、miRNA-493[36]、miRNA-451[37]、miRNA-122[38]、miRNA-143[39]等,相對(duì)于MCF10A細(xì)胞,這些抑癌基因在MDA-MB-231細(xì)胞中低表達(dá),但在MDA-MB-231細(xì)胞源性的外泌體卻是高表達(dá)的。如果腫瘤細(xì)胞通過外泌體舍棄抑癌基因的理論真實(shí)存在,那么其內(nèi)在的作用機(jī)制又是如何的呢？目前雖沒有文獻(xiàn)報(bào)道能夠給出明確答案,但可能已經(jīng)有了一點(diǎn)提示。2009年,Jones等[40]研究發(fā)現(xiàn)ZCCHC11蛋白可以選擇性介導(dǎo)miRNA-26a的尿苷化從而使得miRNA-26a失去功能[40]。2014年,Melo等[41]研究發(fā)現(xiàn),在腫瘤源性的外泌體中存在著細(xì)胞非依賴性的將前體miRNA剪切成熟的必要手段,這些剪切成熟的miRNA甚至可以促進(jìn)乳腺正常上皮細(xì)胞的惡性轉(zhuǎn)化。因此,外泌體能否通過某些未知的內(nèi)在機(jī)制從而使得腫瘤細(xì)胞具有舍棄抑癌基因,同時(shí)又保留癌基因的能力,有待進(jìn)一步探索發(fā)現(xiàn)。

結(jié)語總體而言,外泌體在腫瘤中具有強(qiáng)大的作用。外泌體是由脂質(zhì)雙分子層結(jié)構(gòu)包裹而成的微囊泡,相對(duì)于游離的RNA而言,血液循環(huán)中存在于外泌體中的mRNA、miRNA等功能性的RNA由于有了外泌體外衣的保護(hù),可避免迅速被降解從而保持穩(wěn)定性,進(jìn)而更為有效地發(fā)揮遠(yuǎn)距離信號(hào)傳遞功能,為腫瘤遠(yuǎn)處轉(zhuǎn)移提供條件[3,42-43]。另一方面,外泌體以其獨(dú)特的母細(xì)胞釋放及靶細(xì)胞進(jìn)入的方式,不但可以包裹及傳遞分泌型的蛋白,如WNT蛋白[44],還可以裝載非分泌型蛋白,如met蛋白[12],增加了腫瘤細(xì)胞的生物學(xué)多樣性以及腫瘤的難治性。因此,進(jìn)一步理解外泌體在腫瘤侵襲轉(zhuǎn)移中發(fā)揮的作用及機(jī)制,有助于對(duì)腫瘤生物學(xué)多樣性的了解,從而為進(jìn)一步研究如何有針對(duì)性地防治腫瘤轉(zhuǎn)移提供理論依據(jù)。

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Recent progresses in association between exosomes and tumor metastases

WANG Chao-qun1,2,SUN Hao-ting1,2,QIN Lun-xiu1,2,3△

(1DepartmentofGeneralSurgery,HuashanHospital,FudanUniversity,Shanghai200040,China;2CancerMetastasisInstitute,FudanUniversity,Shanghai200040,China;3InstituteofBiomedicalSciences,FudanUniversity,Shanghai200032,China)

【Abstract】Exosomes are a kind of microvesicles with diameters of about 30-100 nm,which are released by most living cells,and are made up of membrane structure with lipid bilayer and rich of functional contents.The tumor-derived exosomes were discovered for the first time in 1981.In recent 10 years,exosomes are found to contain functional proteins as well as functional nucleic acids,both of which acted as powerful promoters for tumor metastases.Depending on the unique way of loading and transporting proteins and nuclear acids,exosomes stably and effectively mediated intercellular communication.To better understand the mechanisms how exosomes promote tumor metastases might facilitate to identify the key issues for tumor metastases,which might further contribute to develop novel strategies to combat cancer metastases.

【Key words】tumor;metastases;exosomes

【中圖分類號(hào)】R730.1;R730.7

【文獻(xiàn)標(biāo)識(shí)碼】B

doi:10.3969/j.issn.1672-8467.2016.01.018

(收稿日期:2015-11-06;編輯:張秀峰)

△Corresponding authorE-mail:qinlx@fudan.edu.cn