高小妹　張凱莉 (綜述)　郁新新　欽倫秀1,2,△ (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?！?00040; 3復(fù)旦大學(xué)生物醫(yī)學(xué)研究院　上?！?00032)

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干細(xì)胞在實(shí)體腫瘤轉(zhuǎn)移中的作用與地位

高小妹3張凱莉3(綜述)郁新新3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】腫瘤干細(xì)胞 (cancer stem cell,CSC)被認(rèn)為是治療失敗、藥物耐受和轉(zhuǎn)移復(fù)發(fā)的原因所在。CSC具有自我更新 (self-renewal)和高侵襲潛能的特性,并最終組成腫瘤的異質(zhì)性 (heterogeneity)。無(wú)論是在原發(fā)瘤、循環(huán)腫瘤細(xì)胞 (circulating tumor cell),還是在轉(zhuǎn)移灶的形成中,CSC都發(fā)揮著重要作用,且與患者預(yù)后密切相關(guān)。因此,更好地認(rèn)識(shí)CSC在轉(zhuǎn)移過(guò)程中的重要作用,研發(fā)有效的靶向CSC及其微環(huán)境 (microenvironment)的治療藥物,將有望使之成為抗轉(zhuǎn)移的理想途徑。

【關(guān)鍵詞】腫瘤干細(xì)胞;腫瘤轉(zhuǎn)移;腫瘤治療

癌癥作為眾病之王,每年占全球15%的死因,因而學(xué)者對(duì)它的研究從未停止過(guò)。對(duì)于實(shí)體腫瘤,絕大部分的腫瘤患者都是死于轉(zhuǎn)移。腫瘤轉(zhuǎn)移過(guò)程主要分為兩個(gè)部分,第一步是腫瘤細(xì)胞從原發(fā)瘤脫離后侵入血管,進(jìn)入到遠(yuǎn)處器官的微環(huán)境中;第二步是幸存的腫瘤細(xì)胞在新的環(huán)境中定居,增殖生長(zhǎng)形成轉(zhuǎn)移灶[1]。現(xiàn)有的常用腫瘤治療手段包括手術(shù)切除、放療和藥物治療 (包括化療和靶向藥物治療等),手術(shù)切除可斬?cái)嗄[瘤轉(zhuǎn)移的來(lái)源,但并不適合所有腫瘤和所有患者;放療和藥物治療多為晚期患者的無(wú)奈之選,患者很快就會(huì)復(fù)發(fā)且病程進(jìn)展加快。腫瘤干細(xì)胞(cancer stem cell,CSC)學(xué)說(shuō)可部分解釋這些現(xiàn)象背后的機(jī)制。

外界的刺激會(huì)打破原發(fā)瘤中的CSC的休眠,使其從G0期進(jìn)入細(xì)胞分裂周期[2],或是激活相關(guān)信號(hào)通路PI3K/AKT[3],IL6/STAT3[4],Wnt/β-catenin[5]等產(chǎn)生抗藥性。CSC或非CSC進(jìn)行上皮細(xì)胞間質(zhì)化 (epithelial-mesenchymal transition,EMT)[6]后進(jìn)入血液循環(huán)成為循環(huán)腫瘤細(xì)胞 (circulating tumor cell,CTC) 的組分后,激活胞內(nèi)抗凋亡途徑[7]。到達(dá)遠(yuǎn)端器官后,又可能表現(xiàn)出與原發(fā)瘤不一樣的生物學(xué)特性,如蛋白質(zhì)修飾的改變,LRP6的磷酸化,會(huì)激活下游Wnt信號(hào)通路。

現(xiàn)在被認(rèn)為是腫瘤發(fā)生根源的腫瘤干細(xì)胞,人們研究它的歷史最早可以追溯到十八世紀(jì)的畸胎瘤實(shí)驗(yàn),然而目前在實(shí)體腫瘤的治療中,靶向CSC來(lái)攻克腫瘤似乎也差強(qiáng)人意,警示著CSC是個(gè)復(fù)雜的群體,它的來(lái)源、在腫瘤轉(zhuǎn)移中的作用以及最終的分化都亟待更多的揭示。現(xiàn)在對(duì)于CSC的研究已經(jīng)由最初的生物標(biāo)記物的尋找與篩選過(guò)渡到分子調(diào)控機(jī)制以及臨床轉(zhuǎn)化的探索。本綜述將討論CSC的概念,其在實(shí)體腫瘤轉(zhuǎn)移中扮演的角色以及可能的臨床治療策略。

CSC學(xué)說(shuō)的提出與發(fā)展CSC學(xué)說(shuō)由Bergsagel[8]于1967年首次提出,是對(duì)經(jīng)典的達(dá)爾文進(jìn)化演變學(xué)說(shuō),即“克隆選擇學(xué)說(shuō)”的挑戰(zhàn)[9]?！翱寺∵x擇學(xué)說(shuō)”認(rèn)為腫瘤是起源于群體中單個(gè)具有優(yōu)勢(shì)細(xì)胞,且這個(gè)細(xì)胞由于累積的基因突變而發(fā)生惡性轉(zhuǎn)化。但有研究報(bào)道,當(dāng)某一亞克隆群體細(xì)胞瀕臨清除時(shí),總有小于5%的細(xì)胞會(huì)幸存,且獲得更加惡性的生物學(xué)表型——成瘤與轉(zhuǎn)移能力、自我更新能力和抗藥能力。這一很小比例的細(xì)胞被命名為CSC。1997年,Bonnet等[10]首次在急性髓系白血病 (acute myeloid leukemia,AML)中運(yùn)用標(biāo)志物CD34+/CD38-篩選到了CSC。在實(shí)體腫瘤中,2003年Al-Hajj等[11]利用CD44+/CD24-這兩個(gè)標(biāo)志物也成功分選到了乳腺癌干細(xì)胞。隨后,在腦癌、肝癌等多數(shù)腫瘤中都相繼找到了CSC。更令人振奮的是到2012年,臨床上已經(jīng)有針對(duì)AML中CSC的藥物[12]。而在其他腫瘤中,相關(guān)CSC的藥物研發(fā)也在進(jìn)行中。

CSC的三大特性CSC似乎是干細(xì)胞的一種,它可以通過(guò)非對(duì)稱分裂的方式產(chǎn)生子代的CSC和非CSC,并且具有自我更新能力[13],此外它也共用著在成體干細(xì)胞 (adult stem cell)中經(jīng)典的三大信號(hào)通路——Wnt、Shh和Notch。但是CSC無(wú)法像干細(xì)胞那樣產(chǎn)生類器官,這也是它迄今為止仍被質(zhì)疑的根本原因,導(dǎo)致了有學(xué)者將這群細(xì)胞稱之為干細(xì)胞樣腫瘤細(xì)胞 (cancer stem-like cell)或是腫瘤起始細(xì)胞 (tumor initiating cell)。然而除此之外,CSC的生物學(xué)特性基本同干細(xì)胞一致,所以現(xiàn)今研究CSC的主要方法基本是沿襲于干細(xì)胞。歸納現(xiàn)有針對(duì)CSC的研究成果,可以總結(jié)出它的三大特點(diǎn): (1)CSC具有特定的生物學(xué)標(biāo)志物。如,在腦膠質(zhì)瘤中,CD133是個(gè)較為明確的標(biāo)記分子[14];Lgr5+在結(jié)腸癌中也較權(quán)威地代表了這群細(xì)胞。但是在某些腫瘤中,標(biāo)志物并不唯一,如在肝癌中,有報(bào)道稱CD133[15]、CD24[16]、CD90[17]或CD47[18]等都是肝癌干細(xì)胞的標(biāo)記分子。這就意味著沒(méi)有一種分子可以代表所有腫瘤中的這群細(xì)胞,即使是在同一種腫瘤中,標(biāo)志物也有幾種,所以我們不能僅僅依靠表面分子來(lái)識(shí)別CSC。 (2)CSC具有自我更新和分化的能力。 (3)CSC具有較強(qiáng)的致瘤能力、轉(zhuǎn)移能力和抗藥能力。

CSC的來(lái)源腫瘤的產(chǎn)生源于正常細(xì)胞的惡性轉(zhuǎn)化,但CSC的產(chǎn)生卻不僅限于正常細(xì)胞。迄今為止,有三種學(xué)說(shuō)[19]。一是來(lái)自于正常組織成體干細(xì)胞[20]或是前體細(xì)胞 (progenitor cell)由于基因或是表觀水平的改變,又或是已經(jīng)分化的腫瘤細(xì)胞可以通過(guò)EMT途徑惡化成CSC[21]。二是分化的細(xì)胞與組織干細(xì)胞發(fā)生融合,形成異倍體細(xì)胞 (aneuploidy)。這個(gè)融合細(xì)胞的基因組不穩(wěn)定,較容易產(chǎn)生突變導(dǎo)致CSC的出現(xiàn)。三是吸收外源DNA片段的細(xì)胞。腫瘤中有很多凋亡的細(xì)胞會(huì)釋放出游離的DNA片段,如果這些DNA被鄰近的細(xì)胞捕捉,隨機(jī)整合到基因組,很可能導(dǎo)致某些基因的異位表達(dá)或是抑制,從而使得該細(xì)胞發(fā)生惡性轉(zhuǎn)化,成為一個(gè)CSC的候選者?，F(xiàn)在多數(shù)的研究集中在第一種假說(shuō)上。肝癌中,有報(bào)道將肝祖細(xì)胞中異檸檬酸脫氫酶2(IDH2)突變阻止了該細(xì)胞向肝細(xì)胞分化的可能,若再有二次打擊,如K-Ras突變可導(dǎo)致腫瘤的產(chǎn)生,這提示了膽管癌的CSC可能來(lái)自于肝祖細(xì)胞[22]?；|(zhì)樣乳腺癌中,K14陽(yáng)性的細(xì)胞高表達(dá)ΔNp63可導(dǎo)致該細(xì)胞的惡性轉(zhuǎn)化[23],這樣的研究在腸癌、前列腺癌和肺癌[24]等都有進(jìn)行,即在某種特定標(biāo)志物的祖細(xì)胞中,將其原癌基因激活表達(dá)或是抑癌基因失活,利用轉(zhuǎn)基因老鼠中種系追蹤 (lineage-tracing)的實(shí)驗(yàn)方法,準(zhǔn)確確定最后發(fā)生轉(zhuǎn)變的細(xì)胞種類。

CSC與轉(zhuǎn)移CSC因有很強(qiáng)的轉(zhuǎn)移潛能,也有人將其命名為轉(zhuǎn)移型的腫瘤干細(xì)胞 (metastatic stem cell)。究其與轉(zhuǎn)移的關(guān)系現(xiàn)在的熱點(diǎn)集中在:原發(fā)瘤中的CSC通過(guò)與微環(huán)境的相互作用[25],影響干性因子或通路的變化,從而促進(jìn)侵襲和轉(zhuǎn)移特性的獲得;同時(shí)轉(zhuǎn)移前灶形成后,某些因子的升高會(huì)指導(dǎo)CSC“歸巢”到特異的遠(yuǎn)端組織;而在轉(zhuǎn)移灶形成的過(guò)程中,CSC自身的代謝變化與微環(huán)境的共同作用,又調(diào)節(jié)了干細(xì)胞的自我更新和定居。最后找到這些過(guò)程中的驅(qū)動(dòng)因素,進(jìn)行CSC的靶向性治療。肝癌中,有研究稱CD44+的肝癌干細(xì)胞與CD14+的腫瘤相關(guān)巨噬細(xì)胞 (tumor associated macrophage,TAM)共培養(yǎng)后,TAM產(chǎn)生的白介素6 (IL6)會(huì)促進(jìn)這群肝癌干細(xì)胞的擴(kuò)張和成瘤能力[26]。而TAM與CD90high的乳腺癌細(xì)胞相互作用后,腫瘤細(xì)胞表面分子EphA4上調(diào),激活下游信號(hào)分子Src和NF-κB來(lái)調(diào)節(jié)CD90high的乳腺癌細(xì)胞活性[27]。此外,還發(fā)現(xiàn)CD110+的腸癌干細(xì)胞有非常強(qiáng)的靶向肝轉(zhuǎn)移的潛能[28],而且肝臟產(chǎn)生血小板生成素(thrombopoietin,TPO)是CD110的受體吸引了腸癌細(xì)胞遷移到肝,同時(shí)TPO可以激活這群細(xì)胞胞內(nèi)賴氨酸 (lysine)的降解,所產(chǎn)生的乙酰輔酶A (acetyl CoA)可以激活Wnt信號(hào)通路,促進(jìn)CSC的自我更新,產(chǎn)生的谷氨酸可以促進(jìn)CSC的克隆定植和抗藥能力等,從而使得腸癌成功發(fā)生肝轉(zhuǎn)移[29]。此外,在胰腺癌中,原發(fā)瘤中間質(zhì)細(xì)胞分泌的外泌體(exosome)會(huì)提前到達(dá)靶器官,改造靶器官中的微環(huán)境,使得轉(zhuǎn)移型的胰腺癌細(xì)胞到達(dá)靶器官時(shí)更容易適應(yīng)新環(huán)境,從而提高轉(zhuǎn)移細(xì)胞的存活率[30]。

當(dāng)CSC發(fā)生播散進(jìn)入血液循環(huán)時(shí),就有可能成為CTC的組成部分。

Yu等[31]對(duì)11例乳腺癌患者進(jìn)行CTC檢測(cè),發(fā)現(xiàn)間質(zhì)型CTC的比例與患者疾病進(jìn)展期相關(guān),且間質(zhì)細(xì)胞團(tuán)簇中高表達(dá)的TGF-β會(huì)促進(jìn)腫瘤細(xì)胞向間質(zhì)型轉(zhuǎn)變。無(wú)獨(dú)有偶,Baccelli等[32]發(fā)現(xiàn)與乳腺癌患者預(yù)后更具相關(guān)性的是EpCAM+CD44+CD47+MET+CTC,而不是所有的EpCAM+CTC,同時(shí)小鼠模型中也證實(shí)EpCAM+CD44+CD47+MET+CTC具有更強(qiáng)的腫瘤形成能力和遠(yuǎn)端轉(zhuǎn)移能力[31]。這意味著循環(huán)腫瘤細(xì)胞中能成功地產(chǎn)生轉(zhuǎn)移灶的組分,可能是CSC或是已具有CSC特性的細(xì)胞。肝癌中也發(fā)現(xiàn)EpCAM+CTC 具有干細(xì)胞特性,部分EpCAM+CTC有CD133+或者ABCG2+的表達(dá)[33]。而這也暗示著CSC可能是CTC的主要功能細(xì)胞,或是只有具有或獲得CSC特性的細(xì)胞才能在轉(zhuǎn)移的過(guò)程中存活下來(lái)。將CSC與CTC聯(lián)合起來(lái)的研究也就應(yīng)運(yùn)而生。在結(jié)直腸癌中,報(bào)道發(fā)現(xiàn)雙腎上腺皮質(zhì)激素樣激酶1 (DCLK1)和Lgr5在原位瘤的CSC和循環(huán)腫瘤干細(xì)胞中都一致高表達(dá)[34]。

CSC與臨床治療CSC的存在很好地解釋了腫瘤經(jīng)過(guò)化療[35]、放療[36]或靶向治療[37]后,起初腫瘤會(huì)有縮小甚至消失,但很快復(fù)發(fā)、導(dǎo)致患者死亡的原因。就是這一很小比例的腫瘤細(xì)胞可以通過(guò)休眠逃避藥物的殺傷[38],通過(guò)高表達(dá)ABCG2等分子產(chǎn)生抗藥[39],或依靠細(xì)胞體內(nèi)激活的Wnt、Shh和Notch等信號(hào)通路來(lái)達(dá)到耐藥的目的。因此,目前認(rèn)為CSC很可能是腫瘤的“根”,只有“斬草除根”,治愈腫瘤才成為可能[40]?，F(xiàn)在靶向CSC的臨床治療策略從之前針對(duì)單一信號(hào)通路到現(xiàn)在同時(shí)靶向三大信號(hào)通路[41-42],從僅僅針對(duì)CSC到綜合考慮CSC和它生存的微環(huán)境來(lái)研發(fā)藥物[43],從靶向治療走向聯(lián)合治療。這其中對(duì)靶向CSC來(lái)治療腫瘤最有信心的莫過(guò)于著名科學(xué)家Robert A.Weinberg,他進(jìn)行了一場(chǎng)與CSC的賭博——成立Verastem公司,此公司有超過(guò)2萬(wàn)億美元的投資,同時(shí)進(jìn)行超過(guò)60項(xiàng)與CSC相關(guān)的臨床研究[44]。

結(jié)語(yǔ)CSC的研究愈來(lái)愈熱,對(duì)于攻克腫瘤既是福音也是挑戰(zhàn)。但將CSC廣泛運(yùn)用于臨床還存在許多的問(wèn)題。目前對(duì)CSC的判定標(biāo)準(zhǔn)還不夠準(zhǔn)確和清晰,生物學(xué)標(biāo)志物不夠特異。有研究顯示,CSC的來(lái)源很多且富有動(dòng)態(tài)變化,消滅了已有的CSC,不能保證其他非CSC不能轉(zhuǎn)化成CSC[45]。更有甚者,對(duì)于CSC仍持消極態(tài)度,并不認(rèn)為清除了這群細(xì)胞,腫瘤就會(huì)消失。

綜上,CSC的真面貌正慢慢清晰化,在腫瘤轉(zhuǎn)移中承擔(dān)的使命也一步一步地被揭開(kāi),但遏制住了CSC是否就終結(jié)了腫瘤,下結(jié)論還為時(shí)尚早。因?yàn)橐灿袑W(xué)者認(rèn)為,腫瘤是一個(gè)系統(tǒng)疾病,是打破了身體內(nèi)的大平衡所致,所以有人提出荷瘤生存即腫瘤細(xì)胞共生存。因此,想要攻克腫瘤依然還是路漫漫其修遠(yuǎn)兮,吾將上下而求索。

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Cancer stem cells and their roles in solid cancer metastasis

GAO Xiao-mei3,ZHANG Kai-li3, YU Xin-xin3, QIN Lun-xiu1,2,3△

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

【Abstract】The failure and resistant of treatment,and metastatic recurrence of tumor are mainly due to the existing of a very small number of so-called cancer stem cells (CSCs).This group of cells has the characteristics of self-renewal and high invasive potential and eventually formed the heterogeneity of several tumors.Whether it is in the primary tumor,circulating tumor cells,or in the formation of metastases,CSCs always play important roles,and are closely related to the patients′ prognosis.Therefore,from a therapeutic standpoint,a better understanding of CSCs is helpful for developing effective therapeutic strategies targeting CSCs and their microenvironment,which could be ideal ways to combating cancer metastasis.

【Key words】cancer stem cell;metastasis;cancer therapy

【中圖分類號(hào)】R 730

【文獻(xiàn)標(biāo)識(shí)碼】B

doi:10.3969/j.issn.1672-8467.2016.01.015

(收稿日期:2015-11-06;編輯:張秀峰)

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