骨髓間質(zhì)干細(xì)胞在結(jié)直腸腫瘤微環(huán)境中的作用

王少川(綜述),宋　武(審校)

(中山大學(xué)附屬第一醫(yī)院胃腸胰外科,廣州 510080)

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骨髓間質(zhì)干細(xì)胞在結(jié)直腸腫瘤微環(huán)境中的作用

王少川△(綜述),宋武※(審校)

(中山大學(xué)附屬第一醫(yī)院胃腸胰外科,廣州 510080)

摘要：骨髓間質(zhì)干細(xì)胞(MSCs)是由中胚層發(fā)育而來(lái)的一類成體干細(xì)胞，存在于全身結(jié)締組織和器官間質(zhì)中，屬于骨髓非造血干細(xì)胞，具有干細(xì)胞的一般特性，即自我更新以及多向分化能力。MSCs能夠促進(jìn)結(jié)直腸腫瘤的生長(zhǎng)。在腫瘤條件下，骨髓中的MSCs隨血運(yùn)遷至腫瘤微環(huán)境，參與腫瘤的構(gòu)建過(guò)程。MSCs促進(jìn)腫瘤侵襲的機(jī)制是復(fù)雜的，包括MSCs轉(zhuǎn)化為腫瘤相關(guān)纖維母細(xì)胞參與腫瘤間質(zhì)的形成以及MSCs對(duì)微環(huán)境的調(diào)節(jié)作用。MSCs在結(jié)直腸癌靶向治療策略中的應(yīng)用前景是廣闊的，通過(guò)不斷的研究，將為MSCs在臨床中的安全應(yīng)用提供新的理論依據(jù)。

關(guān)鍵詞：結(jié)直腸腫瘤；骨髓間質(zhì)干細(xì)胞；腫瘤相關(guān)纖維母細(xì)胞

早在1889年，Paget[1]即提出腫瘤生長(zhǎng)的“種子-土壤學(xué)說(shuō)”，器官微環(huán)境(“土壤”)可影響特定腫瘤細(xì)胞(“種子”)的種植、侵襲、存活、生長(zhǎng)?；仡櫧陙?lái)腫瘤學(xué)研究進(jìn)展不難發(fā)現(xiàn)，腫瘤的發(fā)生及轉(zhuǎn)移并不僅和腫瘤細(xì)胞自身有關(guān)，腫瘤細(xì)胞的周邊環(huán)境對(duì)腫瘤的生長(zhǎng)也發(fā)揮重要作用[2]。腫瘤微環(huán)境包含多種成分，骨髓間質(zhì)干細(xì)胞(mesenchymal stem cells,MSCs)是其中重要的一群，MSCs在腫瘤微環(huán)境中的作用一直是學(xué)者們關(guān)注的焦點(diǎn)。MSCs是由中胚層發(fā)育而來(lái)的一類成體干細(xì)胞，具有干細(xì)胞的一般特性，即自我更新及多向分化的能力，這些特點(diǎn)尤其體現(xiàn)在間質(zhì)干細(xì)胞對(duì)損傷組織的歸巢與修復(fù)作用上[3]。隨著干細(xì)胞工程技術(shù)的進(jìn)步，間質(zhì)干細(xì)胞與腫瘤間的關(guān)系備受矚目。已經(jīng)證實(shí)，間質(zhì)干細(xì)胞對(duì)于腫瘤組織亦能表現(xiàn)出類似于炎性白細(xì)胞的歸巢作用[4]。近年來(lái)，隨著診斷技術(shù)的進(jìn)步，癌前病變檢出率顯著提高，結(jié)直腸癌的病死率大幅降低[5]。美國(guó)癌癥聯(lián)合會(huì)公布的結(jié)果顯示，Ⅰ期結(jié)直腸癌患者5年生存率為93.2%，而Ⅳ期只有8.1%[6]?？梢?jiàn)，晚期結(jié)直腸癌的預(yù)后不容樂(lè)觀，其死因多為腫瘤向肝、肺、腹腔淋巴結(jié)等多器官轉(zhuǎn)移[7]。該文回顧并總結(jié)了MSCs與結(jié)直腸腫瘤微環(huán)境之間關(guān)系的研究方法及結(jié)果，旨在為結(jié)直腸癌早期診斷、預(yù)測(cè)轉(zhuǎn)移風(fēng)險(xiǎn)、評(píng)估預(yù)后、研發(fā)新型靶向治療策略等方面提供新的思路和認(rèn)識(shí)。

1MSCs的細(xì)胞學(xué)特性

MSCs存在于全身結(jié)締組織和器官間質(zhì)中，屬于骨髓非造血干細(xì)胞，具有干細(xì)胞的一般特性；在適當(dāng)?shù)臈l件下，MSCs可分化為軟骨細(xì)胞、脂肪細(xì)胞、肌細(xì)胞等多種細(xì)胞[8]。在細(xì)胞培養(yǎng)中，MSCs具有貼壁生長(zhǎng)的特點(diǎn)，表達(dá)細(xì)胞表面標(biāo)志(CD105、CD90、CD73等)，不表達(dá)典型的造血細(xì)胞標(biāo)志(如CD14、CD34、CD19、CD45等)[9]。基于這些特性，在組織發(fā)生損傷時(shí)，MSCs能夠被募集到損傷組織參與組織修復(fù)，遂被廣泛應(yīng)用于再生醫(yī)學(xué)等領(lǐng)域。研究人員通過(guò)比較腫瘤與組織損傷過(guò)程，發(fā)現(xiàn)其相似之處，即腫瘤同樣可以釋放細(xì)胞因子、趨化因子以及生長(zhǎng)因子等炎性介質(zhì)[10]。試驗(yàn)表明，在神經(jīng)膠質(zhì)瘤[11]、乳腺[12-14]、結(jié)腸[15]、卵巢[16]、肺及其他轉(zhuǎn)移性腫瘤[17-18]的微環(huán)境中，這種定向遷移的機(jī)制同樣存在；骨髓中的MSCs隨血運(yùn)遷移至腫瘤部位，參與腫瘤的構(gòu)建過(guò)程[14]。Chamberlain等[8]推測(cè)，整合蛋白和黏附分子參與調(diào)控MSCs的遷移。研究者們通過(guò)構(gòu)建其他類型的腫瘤模型，發(fā)現(xiàn)了一系列參與這一過(guò)程的調(diào)節(jié)因子(如內(nèi)皮生長(zhǎng)因子、趨化因子)[4]。但目前針對(duì)結(jié)直腸腫瘤構(gòu)建模型的研究尚不多見(jiàn)，有待進(jìn)行更深入的研究去探索MSCs在結(jié)直腸腫瘤微環(huán)境下的作用和機(jī)制。

2MSCs與腫瘤相關(guān)纖維母細(xì)胞

MSCs類似白細(xì)胞可定向遷移至腫瘤部位。MSCs在腫瘤微環(huán)境中的間接作用基于一種假設(shè)，即MSCs是腫瘤相關(guān)纖維母細(xì)胞(tumor associated fibroblast,TAF)的前體[19]。TAF是腫瘤微環(huán)境中的重要細(xì)胞群，在腫瘤微環(huán)境中參與血管構(gòu)建，促進(jìn)腫瘤細(xì)胞浸潤(rùn)、轉(zhuǎn)移[20]。研究者通過(guò)免疫組織化學(xué)方法證實(shí),TAF能夠表達(dá)α平滑肌蛋白、大量膠原以及其他基質(zhì)成分，是膠原積聚和組織結(jié)構(gòu)改變的重要原因[21]。此外，TAF分泌可溶性因子(如轉(zhuǎn)化生長(zhǎng)因子、血小板衍生生長(zhǎng)因子等)促進(jìn)腫瘤細(xì)胞的生長(zhǎng)和侵襲，且兩者共同反饋，構(gòu)成腫瘤生長(zhǎng)、浸潤(rùn)和轉(zhuǎn)移的微環(huán)境[22]。在腫瘤微環(huán)境中，兩者均可利用腫瘤細(xì)胞代謝出的乳酸鹽作為能量來(lái)源，參與腫瘤的構(gòu)建[23]?？梢?jiàn)，MSCs和TAF的關(guān)系是十分密切的。據(jù)Shinagawa等[24]的研究報(bào)道，MSCs在結(jié)直腸癌微環(huán)境中表達(dá)α平滑肌蛋白；而Nakagawa等[25]通過(guò)免疫熒光檢測(cè)出轉(zhuǎn)移性結(jié)直腸癌TAF中亦表達(dá)此蛋白；不僅如此，他還通過(guò)聚合酶鏈?zhǔn)椒磻?yīng)檢測(cè)到結(jié)直腸TAF中波形蛋白的表達(dá)。波形蛋白是存在于MSCs中的一種中間絲蛋白,能夠調(diào)節(jié)細(xì)胞骨架蛋白、細(xì)胞黏附分子等蛋白間的相互作用,參與腫瘤細(xì)胞和腫瘤相關(guān)內(nèi)皮細(xì)胞、巨噬細(xì)胞的黏附、遷移、侵襲和細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)等[26]?？梢?jiàn)，波形蛋白與腫瘤發(fā)生、轉(zhuǎn)移密切相關(guān)，是MSCs的重要標(biāo)志。這些MSCs與TAF的共性表達(dá)，均支持“MSCs是TAF的前體”這一假說(shuō)。

3MSCs與結(jié)直腸腫瘤的形成和轉(zhuǎn)移

體外實(shí)驗(yàn)證實(shí)，MSCs能夠同時(shí)抑制腫瘤細(xì)胞增殖和凋亡；然而體內(nèi)試驗(yàn)發(fā)現(xiàn)，MSCs通過(guò)免疫抑制作用，能夠降低淋巴細(xì)胞活性，重構(gòu)腫瘤微環(huán)境，使其更利于腫瘤的生長(zhǎng)[27]。Tsai等[28]將MSCs與結(jié)直腸癌細(xì)胞混合后進(jìn)行體外培養(yǎng)，發(fā)現(xiàn)MSCs能夠通過(guò)旁分泌作用直接促進(jìn)腫瘤生長(zhǎng)。Shinagawa等[24]將人類骨源性MSCs按不同比例與癌細(xì)胞混合后接種于小鼠體內(nèi)，并與單獨(dú)接種癌細(xì)胞的小鼠進(jìn)行對(duì)照，結(jié)果發(fā)現(xiàn)較高比例的MSCs明顯促進(jìn)了結(jié)直腸癌的生長(zhǎng)和轉(zhuǎn)移，而較低比例的MSCs不能催生結(jié)直腸癌的轉(zhuǎn)移。另?yè)?jù)Liu等[29]的研究，較之未經(jīng)處理過(guò)的MSCs,干擾素γ和腫瘤壞死因子α預(yù)刺激過(guò)的MSCs通過(guò)活化低氧誘導(dǎo)因子1α信號(hào)通路，表達(dá)更高水平的血管內(nèi)皮細(xì)胞生長(zhǎng)因子,從而更好地促進(jìn)腫瘤血管構(gòu)建；對(duì)照組數(shù)據(jù)提示，即便混合培養(yǎng)的MSCs比例較低，但在某些炎性因子刺激下，MSCs亦能夠發(fā)揮更大的促腫瘤作用。上述研究均構(gòu)建于小鼠模型之中，其人為設(shè)定的MSCs與癌細(xì)胞比例，不能充分反映MCSs在人體腫瘤微環(huán)境中的作用，未來(lái)應(yīng)通過(guò)模擬更趨近于人體結(jié)直腸腫瘤微環(huán)境中的MSCs比例，來(lái)證實(shí)這一觀點(diǎn)。轉(zhuǎn)化生長(zhǎng)因子β是另一類重要的慢性炎性因子，傳統(tǒng)觀點(diǎn)認(rèn)為轉(zhuǎn)化生長(zhǎng)因子β的表達(dá)可以抑制腫瘤細(xì)胞的繁殖。據(jù)Shangguan等[30]報(bào)道，抑制轉(zhuǎn)化生長(zhǎng)因子β/Smad信號(hào)通路可以有效阻止MSCs向TAF轉(zhuǎn)化，繼而達(dá)到抗腫瘤的目的。Calon等[31]的研究卻提示，轉(zhuǎn)化生長(zhǎng)因子β在微環(huán)境中的表達(dá)能夠促進(jìn)結(jié)直腸腫瘤的轉(zhuǎn)移。MSCs與轉(zhuǎn)化生長(zhǎng)因子β信號(hào)通路間的復(fù)雜關(guān)系值得進(jìn)一步探索。MSCs具有免疫調(diào)節(jié)功能，在某些因子的作用下，可以對(duì)淋巴細(xì)胞產(chǎn)生抑制作用，繼而促進(jìn)腫瘤逃避免疫監(jiān)視[32]。另有學(xué)者研究發(fā)現(xiàn)，MSCs可以增強(qiáng)B細(xì)胞的活力，但抑制B細(xì)胞的增殖[33-34]。而Corcione等[35]認(rèn)為，B細(xì)胞分泌細(xì)胞因子的活動(dòng)并不受MSCs的影響。Schioppa等[36]發(fā)現(xiàn)一種調(diào)節(jié)性B細(xì)胞(tumor-evoked Bregs，tBreg)，在腫瘤微環(huán)境中抑制了抗腫瘤免疫，使腫瘤壞死因子α促進(jìn)腫瘤生長(zhǎng)。腫瘤微環(huán)境中產(chǎn)生的腫瘤壞死因子α通過(guò)誘導(dǎo)核因子κB抗凋亡分子的表達(dá)而促進(jìn)腫瘤細(xì)胞存活、促進(jìn)腫瘤血管新生，抑制T細(xì)胞反應(yīng)逃避免疫監(jiān)視[37]。Olkhanud等[38]通過(guò)小鼠模型發(fā)現(xiàn)，tBreg借助生長(zhǎng)因子β，使靜止的CD4+T細(xì)胞向叉頭狀轉(zhuǎn)錄因子3+調(diào)節(jié)性T細(xì)胞轉(zhuǎn)化，進(jìn)而促進(jìn)腫瘤的轉(zhuǎn)移。這進(jìn)一步說(shuō)明tBreg可以促進(jìn)腫瘤生長(zhǎng)。然而，腫瘤微環(huán)境中的MSCs是否能夠促進(jìn)或抑制tBreg產(chǎn)生，兩者之間有何聯(lián)系，具體發(fā)揮何種作用，這些問(wèn)題仍不明確。盡管上述研究是基于人乳腺癌細(xì)胞株小鼠構(gòu)建的模型，但已有文獻(xiàn)報(bào)道叉頭狀轉(zhuǎn)錄因子3+調(diào)節(jié)性T細(xì)胞與結(jié)腸癌細(xì)胞之間的緊密聯(lián)系[39]。因此，tBreg與MSCs的關(guān)系及作用機(jī)制更加值得關(guān)注。

4MSCs與上皮細(xì)胞間質(zhì)轉(zhuǎn)化

上皮細(xì)胞間質(zhì)轉(zhuǎn)化(epithelial to mesenchymal transition,EMT)的概念于20世紀(jì)80年代被提出，后被學(xué)者闡釋出在結(jié)直腸癌原發(fā)性浸潤(rùn)以及繼發(fā)性轉(zhuǎn)移中占舉足輕重的地位[40]。EMT通過(guò)減弱依賴于E2鈣黏蛋白的胞間黏附并且提高癌細(xì)胞機(jī)動(dòng)性,從而增強(qiáng)癌細(xì)胞浸潤(rùn)能力，使上皮細(xì)胞失去原有特性，并獲得間質(zhì)轉(zhuǎn)化[41]。Loboda等[42]通過(guò)調(diào)查326例結(jié)腸癌患者得出結(jié)論，結(jié)腸癌發(fā)生過(guò)程中主要的基因表達(dá)過(guò)程與EMT高度相關(guān)。Varnat等[43]的研究認(rèn)為，人結(jié)直腸癌上皮細(xì)胞激活Hedgehog/Gli1信號(hào)通路，引發(fā)致瘤性EMT的作用。致瘤性EMT通過(guò)活化Wnt/β聯(lián)蛋白信號(hào)通路，賦予癌細(xì)胞一系列干細(xì)胞學(xué)特性和轉(zhuǎn)移侵襲的能力[44]。據(jù)此認(rèn)為，在結(jié)直腸腫瘤微環(huán)境中，癌細(xì)胞通過(guò)EMT作用獲得了遷移性的表型。癌細(xì)胞由EMT作用而獲得干細(xì)胞特性，使得研究人員對(duì)MSCs和EMT之間存在的聯(lián)系產(chǎn)生了興趣，Martin等[45]的體外研究表明，乳腺癌微環(huán)境中的MSCs可以刺激上皮細(xì)胞發(fā)生EMT；Bhattacharya等[46]將MSCs與肝癌細(xì)胞混合培養(yǎng)，發(fā)現(xiàn)MSCs增強(qiáng)了EMT標(biāo)志性波形蛋白的表達(dá)、參與鈣黏素的調(diào)控，同時(shí)癌細(xì)胞轉(zhuǎn)移侵襲機(jī)制的轉(zhuǎn)錄因子Snail和Slug表達(dá)亦見(jiàn)增多。這進(jìn)一步說(shuō)明MSCs在腫瘤微環(huán)境中促生EMT，而MSCs在結(jié)直腸癌微環(huán)境中是否具有類似的作用有待于進(jìn)一步探索。

5小結(jié)

MSCs促進(jìn)腫瘤侵襲的機(jī)制是復(fù)雜的，包括MSCs轉(zhuǎn)化為TAF參與間質(zhì)形成以及MSCs對(duì)微環(huán)境的調(diào)節(jié)。MSCs與結(jié)直腸腫瘤的浸潤(rùn)、轉(zhuǎn)移間的關(guān)系，目前認(rèn)識(shí)仍不夠清晰。MSCs旁分泌因子的作用及相關(guān)調(diào)控機(jī)制，需要進(jìn)一步探明。同時(shí)，在結(jié)直腸癌微環(huán)境中，MSCs與調(diào)節(jié)性免疫細(xì)胞間的潛在聯(lián)系也是值得探索的。未來(lái)應(yīng)更加注重MSCs的體內(nèi)研究，構(gòu)建出更好的生物模型以更加真實(shí)地反映出人體內(nèi)環(huán)境中的MSCs分布，來(lái)闡釋MSCs結(jié)直腸癌環(huán)境下的作用機(jī)制。

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Study on the Role of Mesenchymal Stem Cells in Colorectal Tumor Microenvironment

WANGShao-chuan,SONGWu.

(DepartmentofGastrointestinalPancreaticSurgery,theFirstAffiliatedHospitalofSunyat-senUniversity,Guangzhou510080,China)

Abstract：Mesenchymal stem cells(MSCs) are a type of adult stem cells,which are developed from the mesoderm.They exist in the interstitium of connective tissues and organs in the whole body,and belong to the bone marrow non-hematopoietic stem cells.It has the general characteristics of stem cells,namely the ability of self-renewal and multi-directional differentiation.MSCs could promote the growth of colorectal cancer.Under the condition of tumor,MSCs move along with the blood stream to the tumor microenvironment,and participate in the process of the construction of the tumor.The mechanism of MSCs in promoting tumor invasion is complex,which includes MSCs′ transformation into tumor associated fibroblast (TAF) to participate in the formation of stroma and their regulating effect on tumor microenviroment.The application prospect of MSCs in colorectal cancer targeted therapy strategy is extensive,further study in this area will provide new theoretical basis for its safety applications.

Key words：Colorectal tumor； Mesenchymal stem cells； Tumor associated fibroblast

doi：10.3969/j.issn.1006-2084.2015.03.019

中圖分類號(hào):R735

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)03-0434-04

收稿日期：2014-03-20修回日期：2014-08-08編輯:辛欣