匡夢 黃艷姣 鄭蘭榮
皖南醫(yī)學院病理學教研室(安徽蕪湖421002)
神經(jīng)膠質(zhì)瘤發(fā)生于神經(jīng)外胚層,根據(jù)膠質(zhì)瘤細胞的分化情況分為:星形細胞瘤、少突膠質(zhì)瘤、室管膜瘤、髓母細胞瘤、多形性膠質(zhì)母細胞瘤等。越來越多的證據(jù)[1-2]表明神經(jīng)膠質(zhì)瘤與Ras相關的C3肉毒素底物1(RAC1)的異常有關。RAC1是小鳥苷酸三磷酸酶的成員,可以通過細胞前端的肌動蛋白聚合來促進遷移,并誘導膜皺褶和鱗片狀偽足的形成[3]。通過調(diào)節(jié)細胞骨架重排,RAC1在腫瘤細胞黏附、遷移和侵襲起到了重要作用[4-5]。RAC1及其下游效應物的異常與乳腺、肺、卵巢癌和神經(jīng)膠質(zhì)瘤等腫瘤細胞遷移,侵襲和轉(zhuǎn)移相關[6-9]。
酪氨酸激酶按其結(jié)構(gòu)可以分為兩大類:受體酪氨酸激酶和非受體酪氨酸激酶。受體型的酪氨酸激酶通常具有胞外配體結(jié)合結(jié)構(gòu)域、一個跨膜區(qū)以及胞內(nèi)激酶域。胞外結(jié)構(gòu)域與配體結(jié)合并引起構(gòu)象變化,激活具有自磷酸化位點的胞內(nèi)段的酪氨酸激酶。具體成員及作用如下。
1.1 表皮生長因子受體(epithelial growth factor receptor,EGFR)家族EGFR家族共有4個成員,即EGFR、HER2、HER3和 HER4。SOOMAN 等[10]發(fā) 現(xiàn) 喜 樹 堿 和 EGFR 或RAC1協(xié)同作用,阻止膠質(zhì)瘤的發(fā)展。FENG等[11]證實EGFRvlll通過類固醇受體輔助活化因子(steroid receptor coactivator,Src)家族蛋白酪氨酸激酶、Src誘導抑制胞質(zhì)分裂作用因子 180Y722(dedicator of cytokinesis ,DOCK180Y722)位點的磷酸化,而DOCK180可以刺激RAC1的活化,從而導致膠質(zhì)瘤細胞的遷移。表明靶向EGFRvIII/Dock180/RAC1信號軸可成為惡性膠質(zhì)瘤發(fā)展?jié)撛诘闹委煱悬c。KARPEL-MASSLER 等[12-13]發(fā)現(xiàn) NSC23766的運用可以增強了HER1/EGFR靶向藥物厄洛替尼抗腫瘤作用。
1.2 血小板衍化生長因子受體(platelet derived growth factor receptor,PDGFR)家族PDGFR-α與PDGF結(jié)合,使其發(fā)生自磷酸化[14],繼而激活下游因子,刺激血管增生和細胞增殖導致腫瘤的形成。含有SH2結(jié)構(gòu)域的酪氨酸磷酸酶的異常,將會抑制PDGFR刺激的RAC1、細胞分裂周期蛋白42(cell division cycle 42,CDC42)、絲氨酸蘇氨酸蛋白激酶(serine threonine kinase,AKT)等的磷酸化,從而阻礙了PDGFR/RAC1影響的膠質(zhì)瘤細胞的生長和侵襲[15]。此外,PDGFR-α的刺激導致DOCK180S1250的磷酸化,激活RAC1、AKT,同時在體外促進細胞遷移[16]。通過LY294002抑制磷脂酰肌醇3激酶(phosphoinositide 3-kinase,PI3K),從而抑制誘導的AKT,消除PDGF刺激的細胞生長和膠質(zhì)瘤細胞的存活[17]。同時,F(xiàn)ENG等[18]發(fā)現(xiàn)膠質(zhì)母細胞瘤中的PDGFR-α信號傳導刺激DOCK180Y1811的Src依賴性磷酸化,促進RAC1的激活和隨后影響細胞生長和侵襲。
1.3 成纖維細胞生長因子受體家族成纖維細胞生長因子受體家族包括成纖維細胞生長因子受體-1,-2,-3,-4這4位成員。FUKAI等[19]發(fā)現(xiàn)在膠質(zhì)瘤中酪氨酸激酶受體A4 mMRA是正常組織的4倍,酪氨酸激酶受體A4與成纖維細胞生長因子受體形成異源受體復合物,該復合物增強了RAC1、CDC42信號通路,促進膠質(zhì)瘤的遷移。FORTIN等[20]證實,CDC42在成纖維細胞生長因子誘導分子14介導活化RAC1中起至關重要的作用。消耗上皮細胞轉(zhuǎn)化序列2癌基因,廢除腫瘤壞死因子樣凋亡微弱誘導劑/成纖維細胞生長因子誘導分子14引起的CDC42和RAC1的活化,影響膠質(zhì)瘤細胞遷移、侵襲。
1.4 血管內(nèi)皮細胞生長因子受體(vascular endothelial growth factor receptor,VEGFR)家族VEGF也稱血管通透因子或血管調(diào)節(jié)因子。當VEGFR被異常激活,就會導致內(nèi)皮細胞增殖、遷移,并誘導抗凋亡基因表達,以及腫瘤血管形成,推測可通過抑制VEGF信號通路以達到治療腫瘤目的[21]。MALLA等[22]通過破壞VEGF表達,RAC1、細胞周期蛋白D1的表達被下調(diào),膠質(zhì)瘤的血管生成被抑制,膠質(zhì)瘤的增殖和遷移也受到影響。
1.5 肝細胞生長因子受體家族肝細胞生長因子受體主要為間質(zhì)表皮轉(zhuǎn)化因子(cellular-mesenchymal to epithelial transition factor,C-MET),其信號通路活化主要是由于CMET基因的擴增、突變,或過度表達導致癌癥形成[23]。FAN等[24]研究發(fā)現(xiàn)MET的內(nèi)吞和再循環(huán)有利于RAC1信號傳導,以最佳的膜起皺和細胞遷移和侵襲。細胞MET的回收降低,肝細胞生長因子誘導的絲裂原細胞外信號調(diào)節(jié)激酶和AKT的磷酸化降低,PI3K、RAC1、CDC42的活化下調(diào),導致細胞極性的喪失和降低了細胞的遷移能力。DOCK7能顯著阻止依賴肝細胞生長因子的RAC1的活性以及膠質(zhì)瘤的侵襲[25]。
非受體酪氨酸激酶又稱胞漿型酪氨酸激酶,存在于胞漿或胞膜內(nèi)側(cè)藕聯(lián)結(jié)合跨膜受體。非受體酪氨酸激酶能夠介導G蛋白偶聯(lián)受體、外界受體酪氨酸激酶和整聯(lián)蛋白的信號,調(diào)控細胞生長、細胞遷移、細胞生存等多種功能。主要成員及功能如下。
2.1 Src家族蛋白酪氨酸激酶Src家族酪氨酸激酶主要由 Src、Fyn、Yrk、Lyn 等 11個成員組成。Src/黏著斑激酶(focal adhesion kinase,F(xiàn)AK)信號通路參與膠質(zhì)瘤的增殖、遷移、侵襲以及血管新生等多個病理過程[26-28]。許多小分子Src抑制劑已被開發(fā)用于治療不同的腫瘤。早先有相關報道Musashi1通過RAC1和Src等作用靶點促進膠質(zhì)瘤的生長,并且通過基因芯片發(fā)現(xiàn)RAC1與Musashi1相關聯(lián),與膠質(zhì)瘤的增殖、生長、存活、凋亡等多個進程相關[29]。THIYAGARAJAN等[30]發(fā)現(xiàn)安卓奎諾爾阻止FAK/Src復合物的形成,膠質(zhì)瘤細胞系的RAC1、CDC42、Src、FAK蛋白水平降低,將腫瘤細胞抑制在G1期。研究[31-32]發(fā)現(xiàn)Lyn、Src同源性3結(jié)構(gòu)域的鳥嘌呤核苷酸交換因子的激活刺激腫瘤壞死因子樣凋亡微弱誘導劑/成纖維細胞生長因子誘導分子14誘導的RAC1激活,促進片狀偽足的形成,膠質(zhì)瘤的侵襲增加。
2.2 FAK家族局部黏著斑激酶目前,F(xiàn)AK家族發(fā)現(xiàn)兩個成員,即FAK和富含脯氨酸的酪氨酸激酶2。在高級別的神經(jīng)膠質(zhì)瘤,TROY(TNFRSF expressed on the mouse embryo)通過富含脯氨酸的酪氨酸激酶2/RAC1信號通路促進膠質(zhì)瘤細胞的侵襲,通過AKT/核因κB通路促進膠質(zhì)瘤細胞的生存[33-34]。安卓奎諾爾作用于FAK的Y397位點,RAC1、CDC42、Src、FAK蛋白水平降低,膠質(zhì)瘤細胞在細胞周期G1期出現(xiàn)活力抑制[30]。
近10年,神經(jīng)膠質(zhì)瘤常用的治療手段為手術(shù)切除,輔以放化療,DTI示蹤皮質(zhì)脊髓束的運用,減低了皮質(zhì)脊髓束輻射劑量[35],針對膠質(zhì)瘤的臨床藥物研發(fā)取得了一定的成就,但仍然存在許多問題,例如:膠質(zhì)瘤的侵襲和遷移并沒有得到有效的阻滯;已投入臨床使用的一些藥物已經(jīng)出現(xiàn)了藥物的靈敏性下降以及出現(xiàn)耐藥性等問題,導致總體療效不讓人滿意。針對酪氨酸激酶/RAC1信號通路的靶向藥物給臨床膠質(zhì)瘤的治療提供新的方向,為腫瘤的防治、預后等方面開辟新的思路。
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