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        一種潛在的骨肉瘤治療靶向—TWEAK/Fn14 信號通路

        2013-08-15 00:54:32綜述俞光榮審校
        外科研究與新技術(shù) 2013年1期
        關(guān)鍵詞:基因治療靶向細(xì)胞因子

        于 濤(綜述),俞光榮(審校)

        同濟(jì)大學(xué)附屬同濟(jì)醫(yī)院骨科,上海 200065

        骨肉瘤是骨骼系統(tǒng)最常見的原發(fā)性惡性腫瘤,好發(fā)于中、青年,在中國的發(fā)病率占到原發(fā)惡性骨腫瘤的44%[1],近三分之一的患者會發(fā)生肺轉(zhuǎn)移[2]。隨著各種新輔助化療方法的廣泛實(shí)施,術(shù)前術(shù)后化療的綜合治療已使骨肉瘤患者的5年生存率從單純截肢的15%~20%提高到60%~70%[3],但仍有30%~40%的患者最終仍因各種原因死亡。故骨肉瘤惡性程度高,預(yù)后差,目前針對本病尚無有效、徹底的治療方法。給患者及家屬帶來極大的痛苦,給社會造成一定的經(jīng)濟(jì)負(fù)擔(dān)。

        1 骨肉瘤的分子生物學(xué)治療現(xiàn)狀

        隨著分子生物學(xué)技術(shù)的廣泛開展和應(yīng)用,發(fā)現(xiàn)很多致病因子參與骨肉瘤的發(fā)生,也為對該病的治療提供了一條新的有可行性的治療策略。參與骨肉瘤發(fā)生的細(xì)胞因子很多,其中包括CD44、選擇素、鈣粘附素、轉(zhuǎn)化生長因子、骨形態(tài)發(fā)生蛋白(BMP)、血小板衍生生長因子(PDGF)、基質(zhì)金屬蛋白(MMP)等[4]。參與骨肉瘤發(fā)生相關(guān)的基因有MDM2、p53、p16、CDK4、PTEN、HER2 等[5]。

        基因治療是將人正?;蚧蛴兄委熥饔玫幕?靶基因)通過載體導(dǎo)入人體靶細(xì)胞,以糾正基因缺陷或發(fā)揮治療作用。達(dá)到治療疾病目的的一種生物醫(yī)學(xué)高科技療法。骨肉瘤基因治療的載體包括病毒載體和非病毒載體兩大類。目前針對骨肉瘤開展了抗腫瘤血管生成、促進(jìn)腫瘤細(xì)胞凋亡及免疫基因治療等多種研究。骨肉瘤的基因治療研究已取得一定進(jìn)展,但很多基因治療缺乏特異性靶向。如何開發(fā)更多對骨肉瘤治療有效的基因,更好地實(shí)現(xiàn)基因調(diào)控,提高載體靶向性和轉(zhuǎn)染效率、實(shí)現(xiàn)基因聯(lián)合治療等還有待進(jìn)一步深入研究。

        2 TWEAK/Fn14 信號通路與骨肉瘤的關(guān)系

        隨著信號通路研究的開展和深入,各種信號通路在骨肉瘤發(fā)生發(fā)展中的作用也越來越受到關(guān)注。其在骨肉瘤的發(fā)病和治療方面都有重要意義。

        Wnt[6-11]、Notch[12-14]、Hedgehog[15-16]、PI3/AKT[17-19]、RAS[20-22]、NF-kappa B[18,23-24]等信號轉(zhuǎn)導(dǎo)通路均被證實(shí)在骨肉瘤的發(fā)病過程中發(fā)揮著一定作用。近年來,TWEAK/Fn14 通路在腫瘤發(fā)生發(fā)展中的作用逐漸受到關(guān)注,即與成纖維細(xì)胞因子誘導(dǎo)14(Fn14)綁定的大鼠腫瘤壞死因子樣細(xì)胞凋亡弱誘導(dǎo)因子(TWEAK)通路。

        2.1 TWEAK/Fn14 信號通路簡介

        TWEAK 是一種分泌性蛋白質(zhì),是腫瘤壞死因子超家族(TNFSF)的新成員,最早于1997年由Chicheportiche 報(bào)道[25]。其結(jié)構(gòu)高度保守,在人和鼠TWEAK 的受體結(jié)合區(qū)有93%的氨基酸同源性[26]。人類TWEAK 基因位于染色體17p13.1 上,編碼產(chǎn)物為Ⅱ型跨膜蛋白,由249個氨基酸組成,其N 端包含疏水鍵,允許其N 端插入細(xì)胞膜,C 端胞外區(qū)域包含其受體結(jié)合位點(diǎn)。TWEAK 合成初是一種膜結(jié)合蛋白,很快被轉(zhuǎn)變具有生物學(xué)特性的小的可溶性片段。成纖維細(xì)胞因子誘導(dǎo)14 (fibroblast growth factor-inducible14,F(xiàn)n14)為TWEAK 的受體。人類Fn14 基因位于染色體16p13.3 上,編碼產(chǎn)物為129個氨基酸組成的Ⅰ型跨膜蛋白。人和鼠的Fn14 的全部序列有90%的同源性,并且人的TWEAK 能和鼠的Fn14 結(jié)合,鼠的TWEAK 也可與人的Fn14 結(jié)合[27]。Fn14 本身不具有蛋白激酶活性,是通過接頭分子(adaptor molecules)將其與下游信號傳導(dǎo)分子聯(lián)系起來。有實(shí)驗(yàn)證實(shí),TNFR 相關(guān)因子家族(TRAF)是聯(lián)系Fnl4和下游信號傳導(dǎo)通路的一組重要接頭分子。當(dāng)可溶性TWEAK 作用于Fnl4 陽性細(xì)胞株后,可通過TRAF 活化核轉(zhuǎn)錄因子(NF-KB)、胞外信號調(diào)節(jié)激酶(ERK)、p38 絲裂原活化蛋白激酶(p38MAPK)和c-Jun 氨基末端激酶(JNK)信號傳導(dǎo)通路[28]。

        2.2 TWEAK/Fn14 信號通路的生物學(xué)作用

        2.2.1 TWEAK/Fn14 信號通路的正常生物學(xué)作用

        TWEAK和它的受體成纖維細(xì)胞因子誘導(dǎo)14(Fn14)相互作用可調(diào)節(jié)多種細(xì)胞內(nèi)反應(yīng),其在多種不同組織中構(gòu)成性的表達(dá)。這些反應(yīng)包括血管發(fā)生作用的興奮、促炎性反應(yīng)因子的誘導(dǎo)、細(xì)胞遷移、增生和凋亡的調(diào)控等[29-32]。此外,TWEAK 還可以靶向作用于軟骨細(xì)胞、成骨細(xì)胞和滑膜成纖維細(xì)胞。有實(shí)驗(yàn)證明RANTES(激活調(diào)節(jié)正常T 細(xì)胞表達(dá)和分泌因子)產(chǎn)物和RANKL(破骨細(xì)胞分化因子)表達(dá)在MC3T3- E1 細(xì)胞中被TEEAK/Fn14 通路上調(diào)。所以TWEAK 可能是可以調(diào)節(jié)成骨細(xì)胞功能的一種新型細(xì)胞因子[33]。TWEAK/Fn14 通路可激活RAW 細(xì)胞(小鼠單核巨噬細(xì)胞)和人HT-29 結(jié)腸腺癌細(xì)胞中的NF-kappa B,c-Jun N-terminal 酶信號級聯(lián)反應(yīng),表明TWEAK 可介導(dǎo)RAW264.7 單核巨噬細(xì)胞系向多核的功能性破骨細(xì)胞分化[34]。另外,重組的可溶解TWEAK 濃聚物可誘導(dǎo)內(nèi)皮細(xì)胞核主動脈平滑肌細(xì)胞增生,降低培養(yǎng)物對血清和生長因子的需要量,說明TWEAK 在血管形成過程中起到重要作用[35]。另有研究表明,TWEAK 是內(nèi)皮細(xì)胞存活的有效誘導(dǎo)物,并能在Fn14 的協(xié)同下誘導(dǎo)內(nèi)皮細(xì)胞增生和遷移,誘導(dǎo)毛細(xì)血管腔形態(tài)發(fā)生[36]。TWEAK 亦可增強(qiáng)內(nèi)皮細(xì)胞中FGA-2和VEGF-A 的有絲分裂能力[37]。TWEAK 可抑制骨形態(tài)發(fā)生蛋白(BMP)-2 誘導(dǎo)的成骨細(xì)胞分化標(biāo)記表達(dá),如通過促細(xì)胞分裂激活蛋白酶(MAPK)通路調(diào)節(jié)的堿性磷酸酶。此外,在MC3T3 細(xì)胞中,TWEAK 通過MAPK 細(xì)胞外信號調(diào)節(jié)激酶通路正調(diào)節(jié)RANKL(NF- kappaB 受體活化配體)表達(dá)。所有這些作用于小鼠成骨細(xì)胞系MC3T3- E1 細(xì)胞的效應(yīng)可被Fn14-Fc(TWEAK 抑制蛋白)嵌合體抑制。

        2.2.2 TWEAK/Fn14 信號通路在腫瘤中的生物學(xué)作用

        TWEAK 分布于多種人腫瘤細(xì)胞株。在各種腫瘤組織標(biāo)本中可檢測出TWEAK 的表達(dá)。有研究表明,人神經(jīng)膠質(zhì)瘤、肺癌、直腸癌、肝癌、卵巢癌、宮頸癌、前列腺癌、乳腺癌、腎臟腫瘤、腦部腫瘤中均檢測到TWEAK 的mRNA 或蛋白表達(dá)[38-44]。TWEAK 及其受體Fn14 信號通路可誘導(dǎo)腫瘤細(xì)胞凋亡[45],促進(jìn)腫瘤細(xì)胞增殖[40-41],提高腫瘤細(xì)胞侵襲力[46],誘導(dǎo)腫瘤血管的形成[41],促炎性反應(yīng)并藉此通過炎性介質(zhì)的調(diào)控促進(jìn)腫瘤播散和轉(zhuǎn)移[47]。

        3 總結(jié)與展望

        腫瘤內(nèi)新生血管是影響骨肉瘤侵襲及轉(zhuǎn)移的重要因素,TWEAK/Fn14 不僅可以誘導(dǎo)腫瘤血管形成,還可以誘導(dǎo)腫瘤細(xì)胞凋亡、增殖,增強(qiáng)腫瘤侵襲力、播散和轉(zhuǎn)移,其很有可能在骨肉瘤組織中具有特殊甚至是特異的作用和意義,并且在骨肉瘤的發(fā)生發(fā)展中發(fā)揮重要作用,成為一種潛在的腫瘤治療的新型分子靶向[48]。研究TWEAK/Fn14 在骨肉瘤中的表達(dá),可進(jìn)一步明確骨肉瘤發(fā)生的分子生物學(xué)機(jī)制,且有可能為提供一種全新的潛在的有效的分子靶向治療策略提供理論依據(jù)。

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