張思磊,王雄偉
(三峽大學(xué)神經(jīng)病研究所三峽大學(xué)第一臨床醫(yī)學(xué)院神經(jīng)外科,湖北 宜昌443003)
小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞與膠質(zhì)瘤研究進(jìn)展
張思磊,王雄偉
(三峽大學(xué)神經(jīng)病研究所三峽大學(xué)第一臨床醫(yī)學(xué)院神經(jīng)外科,湖北 宜昌443003)
膠質(zhì)瘤是腦腫瘤中最常見(jiàn)的類(lèi)型,其強(qiáng)大的侵襲力是一個(gè)非常棘手的臨床問(wèn)題,惡性腫瘤侵襲轉(zhuǎn)移機(jī)制是腫瘤學(xué)研究的熱點(diǎn)。小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞在膠質(zhì)瘤的發(fā)展及侵襲過(guò)程中具有兩方面作用,可以在膠質(zhì)瘤微生態(tài)環(huán)境中通過(guò)膠質(zhì)瘤分泌釋放細(xì)胞因子調(diào)控促進(jìn)膠質(zhì)瘤的增生擴(kuò)張,也能在人為作用影響下發(fā)揮腫瘤免疫作用。小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞透過(guò)血腦屏障改變腫瘤微生態(tài)環(huán)境使其表現(xiàn)為抑制膠質(zhì)瘤侵襲擴(kuò)張,將可能為膠質(zhì)瘤的研究及治療提供新思路和方法。
膠質(zhì)瘤;侵襲;小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞
膠質(zhì)瘤是最多見(jiàn)的中樞神經(jīng)系統(tǒng)腫瘤,在國(guó)內(nèi)占顱內(nèi)腫瘤的35.26%~60.96%,平均44.69%[1],盡管各種治療方法已取得一些進(jìn)展,但是治療效果卻未能獲得明顯改善,死亡率極高,成為神經(jīng)外科領(lǐng)域的一個(gè)難題[2]。腫瘤細(xì)胞增殖快、侵襲性高、腫瘤微環(huán)境血管生成等是惡性膠質(zhì)瘤的基本病理特征,腫瘤細(xì)胞高度侵襲是惡性膠質(zhì)瘤高死亡率的主要原因之一[3]。膠質(zhì)瘤中有大量的小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞浸潤(rùn),其不僅出現(xiàn)在未受損的瘤組織中而且出現(xiàn)在腫瘤壞死區(qū)域,他們的浸潤(rùn)程度也與膠質(zhì)瘤的級(jí)別和侵襲性緊密相關(guān)。有研究表明[4],小膠質(zhì)細(xì)胞參與營(yíng)造有利于膠質(zhì)瘤生長(zhǎng)演進(jìn)的微環(huán)境,尤其是為膠質(zhì)瘤的侵襲和免疫抑制微環(huán)境提供便利條件。越來(lái)越多的研究顯示腫瘤相關(guān)巨噬細(xì)胞在膠質(zhì)瘤的發(fā)生、演進(jìn)、侵襲擴(kuò)張過(guò)程中起重要作用,現(xiàn)就近年來(lái)小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞與膠質(zhì)瘤的作用關(guān)系的研究做一綜述。
巨噬細(xì)胞在發(fā)育早期進(jìn)入腦中并分化成大腦固有細(xì)胞,即小膠質(zhì)細(xì)胞[5]。正常生理情況下小膠質(zhì)細(xì)胞的周轉(zhuǎn)率非常低,所以被稱(chēng)為是腦固有細(xì)胞、永久細(xì)胞[6],其在免疫監(jiān)視、突觸完整性的維持、神經(jīng)病性疼痛及神經(jīng)退行性疾病的發(fā)展過(guò)程中起重要作用[7-8]。正常生理?xiàng)l件下,血腦屏障的存在使血液巨噬細(xì)胞幾乎不進(jìn)入腦實(shí)質(zhì);當(dāng)腦實(shí)質(zhì)內(nèi)產(chǎn)生膠質(zhì)瘤細(xì)胞后血腦屏障受損,小膠質(zhì)細(xì)胞受到膠質(zhì)瘤細(xì)胞分泌的單核細(xì)胞趨化蛋白3的趨化作用而聚集在瘤周?chē)?,血液巨噬?xì)胞也通過(guò)受損血腦屏障進(jìn)入腦實(shí)質(zhì)到達(dá)膠質(zhì)瘤位置[9],小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞在腫瘤微生態(tài)環(huán)境作用下成為腫瘤相關(guān)巨噬細(xì)胞。通過(guò)碳酸銀染色Wilder博士在1925年首先發(fā)現(xiàn)小膠質(zhì)細(xì)胞在腦腫瘤中浸潤(rùn);Badie和Schartner博士用嚙齒動(dòng)物模型標(biāo)記細(xì)胞CD45,巨噬細(xì)胞主要在腫瘤中檢測(cè)到,小膠質(zhì)細(xì)胞在整個(gè)腦組織都可以檢測(cè)到;Ginhoux等[10]的研究發(fā)現(xiàn)成年大鼠腦中的小膠質(zhì)細(xì)胞主來(lái)源于胚胎8 d以前原始卵黃囊的髓系前體細(xì)胞,而出生后的血液循環(huán)中造血前體細(xì)胞,如單核細(xì)胞并不是小膠質(zhì)細(xì)胞來(lái)源;也有研究者認(rèn)為骨髓來(lái)源的巨噬細(xì)胞至少是膠質(zhì)瘤中小膠質(zhì)細(xì)胞的重要組成部分之一[11]。因此,據(jù)上所述膠質(zhì)瘤中浸潤(rùn)的小膠質(zhì)細(xì)胞至少有兩個(gè)來(lái)源:大腦中固有小膠質(zhì)細(xì)胞和骨髓來(lái)源單核細(xì)胞,所以腫瘤中小膠質(zhì)細(xì)胞的確切起源仍然有待確定。膠質(zhì)瘤手術(shù)切除的瘤組織中不僅包含瘤細(xì)胞,而且還含有相當(dāng)量的未癌變細(xì)胞,這些未癌變細(xì)胞中大部分是腫瘤相關(guān)的巨噬細(xì)胞[12]。而巨噬細(xì)胞有極強(qiáng)的可塑性,在不同微環(huán)境中可極化為不同亞群活化,活化的巨噬細(xì)胞至少有M1型巨噬細(xì)胞和M2型巨噬細(xì)胞兩種亞型;M1和M2起截然相反作用,M1型起抗腫瘤作用,而M2型具有免疫抑制作用,可以促進(jìn)膠質(zhì)瘤的生長(zhǎng)和侵襲擴(kuò)張,也能刺激腫瘤相關(guān)血管形成和瘤轉(zhuǎn)移。據(jù)此有學(xué)者認(rèn)為[13]將膠質(zhì)瘤組織中小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞表型檢測(cè)作為臨床判斷膠質(zhì)瘤惡性程度及預(yù)后的參考指標(biāo)。
小膠質(zhì)細(xì)胞是腦的固有免疫細(xì)胞,當(dāng)受到炎癥或其他病理刺激時(shí)激活,從而在中樞神經(jīng)系統(tǒng)的先天和適應(yīng)性免疫應(yīng)答中起重要作用。小膠質(zhì)細(xì)胞可分泌基質(zhì)金屬蛋白酶,基質(zhì)金屬蛋白酶通過(guò)膜結(jié)合來(lái)調(diào)停降解細(xì)胞外基質(zhì)從而促進(jìn)腫瘤的侵襲。膠質(zhì)瘤中小膠質(zhì)細(xì)胞的密度與腫瘤的良惡性、侵襲性以及分級(jí)呈正相關(guān)[14-15],有研究顯示在腫瘤組織中有高達(dá)30%的小膠質(zhì)細(xì)胞招募聚集于其周?chē)鶾16],可能與膠質(zhì)瘤細(xì)胞分泌大量的趨化因子和生長(zhǎng)因子有關(guān)。小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞在腫瘤微環(huán)境影響下不僅不釋放抗腫瘤的促炎細(xì)胞因子,反而上調(diào)MMP-2促進(jìn)腫瘤侵襲和分泌MMP-9、血管內(nèi)皮生長(zhǎng)因子、表皮生長(zhǎng)因子促進(jìn)瘤細(xì)胞增殖。MMP-2通過(guò)降解Ⅳ、Ⅴ型膠原實(shí)現(xiàn)對(duì)ECM的重塑促進(jìn)腫瘤新生血管形成有助于腫瘤侵襲擴(kuò)張[17]。Ye等[18]在膠質(zhì)瘤樣本中發(fā)現(xiàn)小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞的數(shù)量與表達(dá)CD133膠質(zhì)瘤干細(xì)胞樣細(xì)胞相關(guān),且進(jìn)一步證實(shí)小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞分泌的TGF-β1上調(diào)CD133膠質(zhì)瘤干細(xì)胞樣細(xì)胞中MMP-9的表達(dá)促進(jìn)膠質(zhì)瘤的侵襲。有研究顯示[19],敲除toll樣受體配體蛋白 MyD88或抑制 p38可以阻止MT1-MMP表達(dá)和活化;在MT1-MMP缺乏的腦組織和小膠質(zhì)細(xì)胞敲除模型中,顯示小膠質(zhì)細(xì)胞MT1-MMP反過(guò)來(lái)激活膠質(zhì)瘤衍生的pro-MMP-2,大量活性MMP-2被分泌釋放入膠質(zhì)瘤微環(huán)境中,最終促進(jìn)膠質(zhì)瘤侵襲和遷移;在MyD88缺乏和小膠質(zhì)細(xì)胞敲除的兩個(gè)獨(dú)立模型中膠質(zhì)瘤侵襲擴(kuò)張大幅衰減。膠質(zhì)瘤釋放的可溶性因子,導(dǎo)致小膠質(zhì)細(xì)胞的toll樣受體(Toll-like receptors,TLRs)激活,通過(guò)下游信號(hào)分子MyD88和p38MAPK途徑使MT1-MMP表達(dá)上調(diào)。反過(guò)來(lái),小膠質(zhì)細(xì)胞MT1-MMP的表達(dá)和活化又促進(jìn)膠質(zhì)瘤細(xì)胞的侵襲與腫瘤擴(kuò)張。另外研究顯示,TLR2在調(diào)節(jié)小膠質(zhì)細(xì)胞原致癌作用對(duì)膠質(zhì)瘤的增生擴(kuò)張的影響中的一種關(guān)鍵的TLRs之一[20-22],他們用膠質(zhì)瘤實(shí)驗(yàn)小鼠模型證明小膠質(zhì)細(xì)胞TLR2誘導(dǎo)MT1-MMP基因和蛋白的表達(dá),從而促進(jìn)膠質(zhì)瘤的增生擴(kuò)張進(jìn)展。其實(shí)驗(yàn)結(jié)果顯示鼠GL261膠質(zhì)瘤細(xì)胞植入TLR2敲除小鼠體內(nèi)瘤體積明顯減??;而對(duì)照組中,膠質(zhì)瘤衍生的可溶性因子和TLR2特異性配體誘導(dǎo)MT1-MMP的表達(dá),TLR2敲除組中沒(méi)有MT1-MMP基因的表達(dá);還發(fā)現(xiàn)TLR2的同源二聚體TLR1和TLR6對(duì)MT1-MMP表達(dá)也有調(diào)節(jié)作用。他們著重闡釋小膠質(zhì)細(xì)胞TLR2通過(guò)MT1-MMP對(duì)膠質(zhì)瘤的擴(kuò)張侵襲影響的原致癌作用的分子機(jī)制。因此,如果能夠抑制膠質(zhì)瘤TLR受體的表達(dá)及MT1-MMP表達(dá),則有可能提高膠質(zhì)瘤患者的生存率。也有研究發(fā)現(xiàn)[23]膠質(zhì)瘤來(lái)源的CC趨化因子配體2作用于小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞相應(yīng)受體增加IL-6表達(dá)促進(jìn)膠質(zhì)瘤生長(zhǎng);另有研究[24]顯示,瘤細(xì)胞產(chǎn)生的細(xì)胞外基質(zhì)可上調(diào)小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞IL-18表達(dá)增強(qiáng)膠質(zhì)瘤的浸潤(rùn)。
膠質(zhì)瘤是人類(lèi)原發(fā)性腦腫瘤中最具有侵襲性的腫瘤。小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞積聚在腫瘤內(nèi)部和周?chē)c腫瘤的良惡性以及不良的臨床預(yù)后有密切關(guān)系。通過(guò)調(diào)節(jié)小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞之間與膠質(zhì)瘤瘤細(xì)胞的雙向信息傳遞及作用,減少小膠質(zhì)細(xì)胞向腫瘤中浸潤(rùn),降低腫瘤的侵襲擴(kuò)張,以期望成為將來(lái)膠質(zhì)瘤臨床治療的極其重要策略和方法。盡管目前已經(jīng)取得了不少研究成果,但是也還有很多問(wèn)題尚需研究解決。在膠質(zhì)瘤相關(guān)的小膠質(zhì)細(xì)胞的確切來(lái)源問(wèn)題上,尚不能有效的區(qū)分其表型,而不同來(lái)源的小膠質(zhì)細(xì)胞可能在腫瘤的發(fā)生和演進(jìn)過(guò)程中起不同甚至相反的作用;有必要去區(qū)分小膠質(zhì)細(xì)胞的來(lái)源,以進(jìn)一步了解其在膠質(zhì)瘤病程中發(fā)揮的作用。其次,小膠質(zhì)細(xì)胞/腦巨噬MT1-MMP上調(diào),調(diào)節(jié)細(xì)胞外基質(zhì)的降解促進(jìn)膠質(zhì)瘤的增生擴(kuò)張侵襲單一機(jī)制已基本闡明,但是目前依然有很多疑問(wèn)尚未解決,腫瘤的侵襲機(jī)制是多因素,各種因素之間存在復(fù)雜相互作用關(guān)系,它們可能相互促進(jìn),相互影響,協(xié)同膠質(zhì)瘤對(duì)腦組織的侵襲,這種復(fù)雜作用及其機(jī)制都尚未完全闡明。此外,TLR介導(dǎo)小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞MT1-MMP的表達(dá),促進(jìn)膠質(zhì)瘤的增生擴(kuò)張仍然需要進(jìn)一步研究,以期尋找膠質(zhì)瘤免疫治療的潛在靶點(diǎn)。在腫瘤微生態(tài)環(huán)境中,小膠質(zhì)細(xì)胞/腦巨噬細(xì)胞雖然可以在膠質(zhì)瘤分泌的細(xì)胞因子作用下促進(jìn)其發(fā)生演進(jìn)及侵襲,也可以通過(guò)人為技術(shù)改變腫瘤微生態(tài)環(huán)境使巨噬細(xì)胞極性改變,M2型向M1型轉(zhuǎn)化發(fā)揮腫瘤免疫殺傷作用??傊?,我們相信隨著對(duì)膠質(zhì)瘤的發(fā)生演進(jìn)及侵襲機(jī)制的進(jìn)一步闡明,必將膠質(zhì)瘤的臨床治療提供新思路及新策略。
[1]王忠誠(chéng).神經(jīng)外科學(xué)[M].武漢:湖北科學(xué)技術(shù)出版社,1998:397-450.
[2]Faith GD,Sally F,Tames G,et al.Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type:an analysis based on Surveillance,epidemi-cology,and end results(SEER)data,1973-1991[J].J Neurosurg,1998,88(1):1-10.
[3]王 平,鄭 芳,李煒修,等.宮頸癌發(fā)病年齡及病因變化趨勢(shì)研究[J].現(xiàn)代腫瘤醫(yī)學(xué),2007,15(12):1835-1837.
[4]Zhai H,Heppner FL,Tsirka SE.Microglia/macrophages promote glioma progression[J].Glia,2011,59(3):472-485.
[5]Hanisch UK,Kettenmann H.Microglia:Active sensor and versatile effector cells in the normal and pathologic brain[J].Nat Neurosci,2007,10(11):1387-1394.
[6]Mildner A,Schmidt H,Nitsche M,et al.Microglia in the adult brain arise from Ly-6ChiCCR21monocytes only under defined host conditions[J].Nat Neurosci,2007,10(12):1544-1553.
[7]Graeber MB.Changing face of microglia[J].Science,2010,330(6005):783-788.
[8]Aguzzi A,Barnnett ML.Microglia:scapegoal,saboteur,or something else?[J].Science,2013,339(6116):156-161.
[9]Yi L,Xiao H,Xu M,et al.Glioma-initiating cells:A predominant role in microglia/macrophages tropism to glioma[J].J Neuroimmunol,2011,232(1-2):75-82.
[10]Ginhoux F,Greter M,Leboeuf M,et al.Fate mapping analysis reveals that adult microglia derive from primitive macrophages[J]. Science,2010,330(6005):841-845.
[11]AlShakweer W,Alwelaie Y,Mankung AM,et al.Bone marrow-d erived microglia in pilocytoma astrocytoma[J].Front Biosci(Elite Ed),2011,3:371-379.
[12]Ghosh Anirban CS.Microglia action in glioma:A boon turns bane [J].Immunol Lett,2010,131:3-9.
[13]Komohara Y,Horlad H,Ohnishi K,et al.Importance of direct macrophage-tumor cell interaction on progression of human glioma[J]. Cancer Sci,2012,103(11):2165-2172.
[14]Watters JJ,Schartner JM,Badie B.Microglia function in brain tumors[J].Neurosci Res,2005,81:447-450.
[15]Hanisch UK,Kettenmann H.Microglia:active sensor and versatile cells in the normal and pathologic brain Antibody-mediated tumor [J].Nat Neurosci,2007,10(11):1387-1394.
[16]Glass R,Synowitz M,Kronenberg G,et al.Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival[J].J Neurosci,2005,25(10):2637-2646.
[17]Fonseca AC,Rom?o L,Amaral RF,et al.Microglial stress inducible proteinⅠpromotes proliferation and migration in human glioblastoma cells[J].Neuroscience,2012,200:130-141.
[18]Ye XZ,Xu SL,Xin YH,et al.Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via tgf-betal signaling pathway[J].J Immunol,2012,189(1):444-453.
[19]Markovic DS,Vinnakota K,Chirasani S,et al.Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion[J]. Proc NatlAcad Sci USA,2009,106(30):30-36.
[20]Vinnakota K,Hu F,Ku MC,et al.Toll-like receptor2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion[J].Oncol,2013,15(11):1457-1468.
[21]Moresco EM,LaVine D,Beutler B.Toll-like receptors[J].Curr Biol,2011,21(13):R488-R493.
[22]Markovic DS,Vinnakota K,van Rooijen N,et al.Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression[J].Brain Behav Immun,2011,25(4):624-628.
[23]Zhang J,Sarkar S,Cua R,et al.A dialog between glioma and microglia that promotes tumor invasiveness through the ccl2/ccr2/interleukin-6 axis[J].Carcinogenesis,2012,33(2):312-319.
[24]Yeh WL,Lu DY,Lion HC,et al.A forward loop between glioma and microglia:glioma-derived extracellular matrix-activated microglia secrete il-18 to enhance the migration of glioma cells[J].J Cell Physiol,2012,227(2):558-568.
Research advance in microglia/brain macrophage and glioma.
ZHANG Si-lei,WANG Xiong-wei.Department of Neurosurgery,the First Clinical Medical College of China Three Gorges University,Institute of Neuroscience of China Three Gorges University,Yichang443003,Hubei,CHINA
Glioma represents the most frequent type of human brain tumor,and its strong invasiveness is a significant clinical problem.Invasion and metastasis mechanism of malignant tumor is still a hot spot of oncological research.Microglia/brain macrophages have double effects on the expansion and invasion of glioma.On one hand,they can promote the expansion,invasion of glioma by release factor under the microenvironment of tumor.On the other hand,they can kill tumor cell in tumor immunity by the influence of human.Microglia/brain macrophages go cross the blood-brain barrier to change the glioma microenvironment and inhibit the expansion,invasion of glioma.The study of microglia/brain macrophages would provide new ideas and methods for research and treatment of gliomas.
Glioma;Invasion;Microglia/brain macrophages
R730.364
A
1003—6350(2015)20—3038—03
2015-01-05)
10.3969/j.issn.1003-6350.2015.20.1104
王雄偉。E-mail:1836509883@qq.com