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        磷脂酰肌醇3 激酶相關(guān)放射抵抗機(jī)制在口腔鱗狀細(xì)胞癌中的研究進(jìn)展

        2025-03-18 00:00:00盧妍蓓李正娟雷蕾羅晶晶
        國際口腔醫(yī)學(xué)雜志 2025年2期
        關(guān)鍵詞:放射療法激酶

        [摘要] 口腔鱗狀細(xì)胞癌(OSCC) 是口腔頜面部最常見的惡性腫瘤,惡性程度較高。放射治療是OSCC綜合序列治療的重要手段,對原位腫瘤治療效果良好,但術(shù)后腫瘤復(fù)發(fā)和轉(zhuǎn)移較常見,致死率高;其主要原因在于部分腫瘤具有顯著的放射抵抗,存活的癌細(xì)胞可表現(xiàn)出增殖、侵襲和遷移增強(qiáng),發(fā)生上皮-間充質(zhì)轉(zhuǎn)化,甚至獲得癌干細(xì)胞表型。磷脂酰肌醇3 激酶/蛋白激酶B (PI3K/PKB,通常稱PI3K/Akt) 信號通路及其信號組分廣泛參與OSCC發(fā)生發(fā)展和治療預(yù)后的調(diào)控,已被證明與OSCC放射抵抗呈正相關(guān);但其具體調(diào)控機(jī)制仍待進(jìn)一步探索。本綜述聚焦PI3K信號通路與OSCC的放射抵抗,從癌細(xì)胞、癌干細(xì)胞和腫瘤微環(huán)境三方面總結(jié)當(dāng)前的研究進(jìn)展,討論P(yáng)I3K介導(dǎo)的放射抵抗分子機(jī)制,以期為提高OSCC放療敏感性和改善患者預(yù)后提供有效的潛在分子靶標(biāo)。

        [關(guān)鍵詞] 口腔鱗狀細(xì)胞癌; 放射療法; 輻射耐受性; 磷脂酰肌醇3 激酶

        [中圖分類號] R739.8 [文獻(xiàn)標(biāo)志碼] A [doi] 10.7518/gjkq.2025028

        口腔鱗狀細(xì)胞癌(oral squamous cell carcinoma,OSCC) 是頭頸部常見的惡性腫瘤之一[1],可發(fā)生在舌、唇、牙齦、頰黏膜、口底、硬腭等部位[2]。2022年全球口腔癌(包含唇癌) 的死亡人數(shù)估計(jì)76萬例,呈逐年上升趨勢,每年新增病例超過30萬,而患者的5年生存率不超過60%[3-4]。目前,OSCC的常規(guī)治療手段包括手術(shù)、放射治療(簡稱放療)、化學(xué)治療(簡稱化療)、生物/分子治療等。根據(jù)美國國立綜合癌癥網(wǎng)絡(luò)治療指南[5]建議,OSCC的治療方案應(yīng)密切結(jié)合其臨床分期、預(yù)后風(fēng)險(xiǎn)等多因素進(jìn)行綜合評估。其中,放療作為重要治療手段之一,治療原則嚴(yán)格,須對患者進(jìn)行個體化放療方式,如計(jì)劃靶區(qū)、短程放療、調(diào)強(qiáng)放療或三維適形放療等,近距離放療可被視為治療早期小原發(fā)性腫瘤的唯一方法[2]。

        放療一般對原發(fā)腫瘤具有較好療效,可以誘導(dǎo)直接或間接的DNA損傷,殺死近一半的腫瘤細(xì)胞[6-7],但部分癌細(xì)胞在放療后獲得了放射抵抗性,甚至進(jìn)一步發(fā)生上皮-間充質(zhì)轉(zhuǎn)化(epithelial-mesenchymaltransition,EMT),獲得癌干細(xì)胞(cancerstem cell,CSC) 表型,同時促進(jìn)腫瘤微環(huán)境(tumor microenvironment,TME) 的重塑以促進(jìn)其侵襲、轉(zhuǎn)移和放射抵抗的增強(qiáng)[8]。

        腫瘤細(xì)胞的放射抵抗不僅受到自身多因素影響,也可受到TME的多細(xì)胞、多環(huán)節(jié)、多信號通路的復(fù)雜調(diào)控。磷脂酰肌醇3激酶(phosphoinositide3-kinase,PI3K) 信號通路是包括OSCC在內(nèi)的腫瘤發(fā)生發(fā)展中的重要參與者,被證實(shí)對癌細(xì)胞和TME均具有顯著的調(diào)控作用[9]。近年來多數(shù)研究發(fā)現(xiàn):抑制PI3K信號激活可增強(qiáng)OSCC的放射敏感,但PI3K介導(dǎo)OSCC放射抵抗的分子調(diào)控機(jī)制仍有待進(jìn)一步闡明。

        本文將聚焦以PI3K信號通路為核心的OSCC放射抵抗機(jī)制,從癌細(xì)胞、癌干細(xì)胞和腫瘤微環(huán)境三方面總結(jié)當(dāng)前研究進(jìn)展并進(jìn)行綜述,討論P(yáng)I3K介導(dǎo)的放射抵抗分子機(jī)制。

        1 OSCC 的放射抵抗

        放射抵抗是惡性腫瘤應(yīng)對放療的一種常見反應(yīng)特征,表現(xiàn)為腫瘤的放射敏感性降低,放療效果不佳。研究[6,10]表明:放射抵抗會造成癌細(xì)胞遺傳不穩(wěn)定、增殖和侵襲以及血管生成等,導(dǎo)致OSCC患者放療失敗、腫瘤復(fù)發(fā)/轉(zhuǎn)移和預(yù)后不良,甚至發(fā)展出第二原發(fā)癌。臨床Ⅲ和Ⅳ期OSCC患者放療6~7周后未被消除的瘤組織被證實(shí)具有明顯的放射抵抗[11]。一項(xiàng)單中心回顧性的研究[12]顯示:在1990—2013年中國華南地區(qū)癌癥中心收治的1 915例OSCC患者中,接受放療的患者5年疾病特異性生存率未超過60%。

        從生物學(xué)過程來看,癌細(xì)胞的放射抵抗機(jī)制復(fù)雜,涉及癌細(xì)胞DNA損傷反應(yīng)(DNA damageresponse,DDR)、細(xì)胞周期再分布、細(xì)胞增殖和凋亡能力改變、細(xì)胞缺氧后再氧合等[13]。此外,CSC自身生態(tài)位和TME調(diào)控在放射抵抗、腫瘤復(fù)發(fā)和遠(yuǎn)處轉(zhuǎn)移中也發(fā)揮著顯著作用。放療后的OSCC細(xì)胞可以發(fā)生EMT、誘導(dǎo)CSC表型,并伴有基質(zhì)金屬蛋白酶過表達(dá)[14]。與已分化的癌上皮細(xì)胞相比,CSC具有更強(qiáng)的內(nèi)在放射抵抗,而電離輻射可進(jìn)一步降低其放射敏感性,增強(qiáng)癌細(xì)胞增殖能力并促進(jìn)CSC轉(zhuǎn)化,進(jìn)而增加殘留原發(fā)腫瘤組織中的CSC比例[15]。本課題組前期提出放射可“喚醒”口腔CSC導(dǎo)致口腔癌復(fù)發(fā)和轉(zhuǎn)移的科學(xué)假說[7],也證實(shí)了耐放射的OSCC細(xì)胞株顯著增強(qiáng)了自我更新特性和EMT表型[16]。

        2 PI3K 信號通路

        2.1 PI3K信號通路的概述

        PI3K信號通路作用于細(xì)胞表面,是各種癌癥中重要的胞內(nèi)信號通路,直接參與腫瘤的發(fā)生發(fā)展,包括癌細(xì)胞的增殖、存活、侵襲性、凋亡、血管內(nèi)皮生長、炎癥以及細(xì)胞骨架重組等多種生物學(xué)功能的調(diào)控過程[17]。

        磷脂酰肌醇3- 激酶/蛋白激酶B (phosphatidylinositol3-kinase/protein kinase B, PI3K/PKB)信號通路的經(jīng)典信號轉(zhuǎn)導(dǎo)關(guān)鍵分子包括PI3K和PKB (又稱Akt,下文統(tǒng)稱Akt)。PI3K作為胞內(nèi)磷脂酰肌醇激酶,兼有磷脂酰肌醇激酶和絲氨酸/蘇氨酸(Ser/Thr) 激酶的活性[18]。Akt主要由IA型PI3K 催化生成的磷脂酰肌醇-3, 4, 5- 三磷酸(phosphatidylinositol-3,4,5-trisphosphate,PIP3) 激活,是三類PI3K共同的底物,也是中心調(diào)節(jié)效應(yīng)分子,通過作用一系列下游靶蛋白[雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、半胱氨酸天冬氨酸蛋白酶9 (cysteinyl aspartatespecific proteinase 9,Caspase9) 等] 抑制癌細(xì)胞的凋亡,調(diào)節(jié)細(xì)胞的增殖生長及糖原代謝等[19]。該信號通路上游包括Toll樣受體(Toll-like receptors,TLR),Janus激酶信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)錄激活因子途徑(JAK-STAT signaling pathway,JAK/STAT),B細(xì)胞受體(B-cell receptor,BCR) 在內(nèi)的信號傳導(dǎo)途徑都可通過激活PI3K/Akt來促進(jìn)癌癥的發(fā)生發(fā)展[18]。

        2.2 PI3K信號通路在OSCC中的作用

        大量證據(jù)表明PI3K/Akt通路或其組分的激活與OSCC的發(fā)生發(fā)展密切相關(guān),該通路的相關(guān)標(biāo)志物廣泛存在于各類OSCC組織中。與異常增生和非異常增生的口腔上皮組織相比,OSCC上皮細(xì)胞表達(dá)出更高的p-Akt和p-mTOR水平[20]。腫瘤晚期和無術(shù)后轉(zhuǎn)移的OSCC組織高表達(dá)p-Akt,侵襲性晚期OSCC組織高表達(dá)p-mTOR[21]。此外,Akt及其下游mTOR的激活表現(xiàn)出與某些口腔致癌危險(xiǎn)因素,如煙草、酒精和人乳頭瘤病毒(human papillomavirus,HPV) 等,也具有相關(guān)性[22-23]。

        PI3K/Akt能參與調(diào)節(jié)OSCC細(xì)胞的多項(xiàng)特征,如增殖、存活、侵襲、轉(zhuǎn)移和血管生成等。由癌細(xì)胞分泌的血管內(nèi)皮生長因子(vascular endothelialgrowth factor,VEGF)、堿性成纖維細(xì)胞生長因子(basic fibroblast growth factor,b-FGF) 等生長因子可激活PI3K/Akt通路轉(zhuǎn)導(dǎo)[24]。該通路作為一種細(xì)胞存活信號途徑,抑制凋亡蛋白的表達(dá)[25],同時增加細(xì)胞周期進(jìn)程上游因子骨髓細(xì)胞瘤癌基因(myelocytomatosis oncogene,c-Myc)、細(xì)胞周期蛋白D1 (Cyclin D1) 等的表達(dá)[26]。PI3K信號激活可上調(diào)缺氧誘導(dǎo)因子-1α (hypoxia-inducible"factor1, alpha subunit,HIF-1α),通過增強(qiáng)糖酵解[27]以及參與膠原蛋白ⅩⅧ 之間的表型轉(zhuǎn)換、纖連蛋白(fibronectin,F(xiàn)N) 轉(zhuǎn)錄和替代剪接等,促進(jìn)腫瘤生長和遠(yuǎn)處轉(zhuǎn)移[28-29]。PI3K通路也參與了TME對腫瘤發(fā)生發(fā)展的調(diào)控。PI3Kγ抑制劑可有效減少小鼠口腔異常增生組織的多形核髓源性抑制細(xì)胞募集,逆轉(zhuǎn)微環(huán)境免疫抑制,進(jìn)而抑制OSCC發(fā)生[30]。腫瘤相關(guān)巨噬細(xì)胞的表面標(biāo)志物CD44與透明質(zhì)酸結(jié)合,能夠上調(diào)磷脂酰肌醇3激酶/真核生物翻譯起始因子4E結(jié)合蛋白1/SRY箱蛋白2信號通路[phosphatidylinositol 3-kinase/eukaryotic translationinitiation factor 4E-binding protein 1/SRY (sexdetermining region Y) -box 2 signaling pathway,PI3K/4EBP1/SOX2]可增加CSC比例、促進(jìn)頭頸部鱗狀細(xì)胞癌(squamous cell carcinoma of head andneck,HNSCC) 的腫瘤生長和侵襲性[31]。

        2.3 放療與PI3K信號通路的關(guān)系

        在多種腫瘤中,抑制PI3K/Akt通路可起到放療增敏的作用。在乳腺癌細(xì)胞中,抑制PI3K/Akt/mTOR能夠減少集落形成、促進(jìn)細(xì)胞周期停滯和細(xì)胞凋亡,增強(qiáng)放射敏感性[32];在肺癌A549細(xì)胞中抑制PI3K/Akt介導(dǎo)的自噬調(diào)控,可增強(qiáng)其放射敏感性[33];在小細(xì)胞肺癌動物模型中,PI3K/mTOR抑制劑也可通過促進(jìn)葡萄糖-6-磷酸脫氫酶(glucose-6-phosphate dehydrogenase, G6PD) 自噬降解、加劇氧化應(yīng)激損傷,從而使放射增敏[34];在鼻咽癌中,靶向抑制LZTS2/PI3K/Akt在體內(nèi)外實(shí)驗(yàn)中證實(shí)可有效提高腫瘤放療敏感性[35]。

        放療在殺死癌細(xì)胞的同時也會擾動TME,引發(fā)炎性反應(yīng)、循環(huán)缺氧、代謝重編程、免疫逃逸、血管重建等一連串細(xì)胞及分子反應(yīng),誘導(dǎo)產(chǎn)生放射抵抗細(xì)胞[36],PI3K/Akt是其中重要的調(diào)控者。轉(zhuǎn)錄組學(xué)和生物信息學(xué)分析表明,在HNSCC的放射抗性細(xì)胞亞系中,PI3K/Akt信號通路為4個被上調(diào)的核心功能通路之一[37];阻斷PI3K/Akt信號通路可抑制腫瘤壞死因子-α (tumor necrosis factor-α,TNF-α) 誘導(dǎo)的EMT及癌細(xì)胞侵襲轉(zhuǎn)移[38]。PI3K信號通路激活也參與CSC抗氧化和誘導(dǎo)自噬等環(huán)節(jié),從而促進(jìn)細(xì)胞增殖、存活[10],密切影響放療抵抗。

        2.4 PI3K參與OSCC放療抵抗的臨床證據(jù)

        PI3K/Akt信號通路是與OSCC患者生存最密切相關(guān)的分子機(jī)制之一,也是 HNSCC中突變最多的通路[39]。PI3K與OSCC預(yù)后生存的關(guān)聯(lián)提示了該通路作為生物診斷標(biāo)志物的可能性。對HNSCC患者預(yù)后分析發(fā)現(xiàn):低水平和高水平的PI3K蛋白都和不良生存結(jié)局呈正比,低表達(dá)者的PI3K/Akt途徑可能以獨(dú)立機(jī)制促進(jìn)了腫瘤侵襲的生長因子受體信號的傳遞[40]。牙齦、硬腭、牙槽嵴組織中的Akt磷酸化水平增加,被認(rèn)為是早期檢測OSCC的潛在診斷標(biāo)志物[41]。PI3K/Akt 信號通路相關(guān)因子pmTOR、p-ERK的高表達(dá)和接受放、化療的HPV陰性HNSCC患者的不良預(yù)后相關(guān)[42-43]。相比治療前,根治性鉑基放化療后磷脂酰肌醇3激酶/上皮間質(zhì)轉(zhuǎn)化/干細(xì)胞信號通路(phosphatidylinositol 3-kinase/epithelial-mesenchymal transition/stemness signalingpathway,PI3K/EMT/Stem) 相對其他相關(guān)通路顯著升高,提示其在持續(xù)性HPV陽性口咽鱗狀細(xì)胞癌(oropharyngeal squamous cell carcinoma,OPSCC) 腫瘤復(fù)發(fā)中的作用[44]。基因集富集分析也顯示:TP53突變HNSCC患者相對共突變患者PI3K/mTOR通路表達(dá)被上調(diào)[45]。在伴淋巴結(jié)轉(zhuǎn)移的OSCC組織中,PI3K陽性表達(dá)率明顯比無淋巴結(jié)轉(zhuǎn)移者高;轉(zhuǎn)移性O(shè)SCC組織中的PI3K/Akt與CXC趨化因子配體-12 (C-X-C motif chemokine ligand12,CXCL12) /CXC趨化因子受體-4 (C-XCmotif chemokine receptor type 4,CXCR4) 蛋白表達(dá)上調(diào)且呈正相關(guān),提示兩者促OSCC淋巴結(jié)轉(zhuǎn)移的相互協(xié)同和共同調(diào)控作用[46]。

        此外,研究證實(shí)靶向下調(diào)PI3K通路可顯著抑制OSCC細(xì)胞存活。雙重阻斷OSCC細(xì)胞PI3K和mTOR激酶,可通過抑制Akt/mTOR引起G2/M期細(xì)胞周期停滯,并下調(diào)細(xì)胞周期蛋白D1/周期蛋白依賴性激酶4 (Cyclin D1/cyclin-dependent kinases 4,Cyclin D1/CDK4)、細(xì)胞周期蛋白B1 (CyclinB1)、B淋巴細(xì)胞瘤-2 (B-cell lymphoma-2,Bcl-2)的表達(dá),顯著提高放療療效[47-49]。而alpelisib (一種PI3K的p110α亞基的選擇性抑制劑) 聯(lián)合同步基于順鉑的放化療治療頭頸部局部晚期鱗狀細(xì)胞癌已通過Ⅰ期臨床試驗(yàn)[50]??梢姡琍I3K通路的藥理靶向是OSCC放射增敏的可選策略之一。

        2.5 PI3K相關(guān)OSCC放射治療抵抗的機(jī)制

        2.5.1 癌細(xì)胞與DNA損傷 放療能誘導(dǎo)不可修復(fù)的DNA損傷,從而觸發(fā)細(xì)胞凋亡、壞死、有絲分裂突變和衰老,或間接刺激抗腫瘤免疫反應(yīng)導(dǎo)致癌細(xì)胞死亡。抑制DNA損傷或DNA損傷修復(fù)增加均可促進(jìn)癌細(xì)胞的放療抵抗和CSC表型的獲得[6,51]。TP53是HPV陰性O(shè)SCC中常見的與低生存率和放射抵抗相關(guān)的突變基因,放射產(chǎn)生的DNA損傷可以激活TP53調(diào)節(jié)DNA修復(fù)及細(xì)胞周期相關(guān)的多種基因的轉(zhuǎn)錄后調(diào)節(jié)[52]。基因集富集分析顯示:Myc基因相關(guān)通路和PI3K/mTOR通路均在TP53突變的HNSCC中富集,且TP53錯義突變的功能活性能夠被PI3K抑制劑alpelisib所抑制[45,53]。負(fù)向調(diào)節(jié)PI3K/Akt/mTOR通路或可抑制HNSCC中Myc依賴性突變體p53功能獲得,以協(xié)同恢復(fù)類似野生型的p53功能[52-53]。

        非同源末端連接在修復(fù)放射誘導(dǎo)的雙鏈斷裂中起著主導(dǎo)作用,而PI3K和PI3K樣激酶家族以DNA依賴性蛋白激酶的形式參與了HNSCC放射后DDR的激活[54]。因此,PI3K激酶抑制劑作為放射增敏劑在OSCC含放療的聯(lián)合治療中顯示出一定的前景。間充質(zhì)上皮轉(zhuǎn)化因子(mesenchymal epithelialtransition factor,MET) 抑制劑tepotinib在對局部晚期HNSCC放射增敏的作用中,也發(fā)現(xiàn)了PI3K活性的相應(yīng)變化[55]。然而,目前用于OSCC放射增敏的PI3K信號通路激酶抑制劑尚未進(jìn)入臨床視野,其特異性靶向治療性和生物安全性等還亟待進(jìn)一步探索和研究[56]。

        2.5.2 癌干細(xì)胞表型 在OSCC中,放療能導(dǎo)致部分癌細(xì)胞發(fā)生EMT,獲得CSC表型。CSC細(xì)胞群本身具有較高的放射抗性,放射可進(jìn)一步誘導(dǎo)增強(qiáng)這種抗性,并促進(jìn)其增殖能力以及增強(qiáng)剩余原發(fā)腫瘤組織中的CSC轉(zhuǎn)化[15]。研究[10]表明:CSC的輻射抵抗可歸功于包括PI3K/Akt/mTOR在內(nèi)的細(xì)胞存活信號通路的激活,以促進(jìn)CSC抗氧化過程和靜止?fàn)顟B(tài)。

        TME與CSC生態(tài)位的相互作用也可調(diào)控OSCC放療反應(yīng)。低pH、低營養(yǎng)物質(zhì)的TME提供了適合CSC生存的環(huán)境條件,使得CSC可以進(jìn)入休眠或靜止?fàn)顟B(tài)并保持在G0階段[57]。當(dāng)OSCC細(xì)胞長久暴露于TNF-α?xí)r,CSC表型和放射抵抗可被增強(qiáng),這種效應(yīng)可以通過阻斷PI3K/Akt 信號通路得到抑制[58]。甾醇 O-?;D(zhuǎn)移酶 1 (sterol O-acyltransferase1,SOAT1) 是脂質(zhì)代謝中的關(guān)鍵酶,在OSCC組織中高表達(dá),其與M2腫瘤相關(guān)巨噬細(xì)胞(tumor-associated macrophages, TAM) 浸潤呈正相關(guān),而PI3K/Akt/mTOR通路在該過程中被激活并參與調(diào)節(jié)[59]。

        2.5.3 腫瘤微環(huán)境 1) 間質(zhì)細(xì)胞。癌相關(guān)成纖維細(xì)胞(cancer-associated fibroblast,CAF) 和癌相關(guān)內(nèi)皮細(xì)胞(tumor-associated endothelial cell,TEC)等構(gòu)成TME的主要間質(zhì)細(xì)胞成分,可直接或間接地與腫瘤細(xì)胞相互作用。

        CAF是轉(zhuǎn)化生長因子β (transforming growthfactor-β,TGF-β)、趨化因子、VEGF和白細(xì)胞介素等多種生長因子的重要來源,也是誘導(dǎo)或表達(dá)免疫檢查點(diǎn)配體以及抑制TME免疫應(yīng)答的重要參與者[60]。放療在有效殺死癌細(xì)胞的同時,也可誘導(dǎo)CAF功能表型改變,進(jìn)而促進(jìn)免疫抑制細(xì)胞的浸潤和活化[61]。課題組前期研究[62]證實(shí):放療可誘導(dǎo)CAF形成一種既不增殖也不凋亡的“僵尸樣”細(xì)胞群,這類CAF細(xì)胞依然能夠促進(jìn)OSCC細(xì)胞獲得放療抵抗,并持續(xù)促進(jìn)細(xì)胞增殖、侵襲和遷移。PI3K/Akt 信號通路與CAF 功能密切相關(guān)??谇籆AF高表達(dá)促癌因子整合素β2,通過激活PI3K/Akt/mTOR 通路增強(qiáng) CAF的糖酵解活性和乳酸釋放從而促進(jìn)OSCC細(xì)胞增殖[63]。而成纖維細(xì)胞衍生的胰島素樣生長因子-1可通過激活OSCC的非典型hedgehog信號通路并維持Akt活性,進(jìn)而促進(jìn)腫瘤侵襲[64]。

        TEC位于血漿與血管組織之間,是腫瘤血管形成的主要細(xì)胞[65]。抑制mTOR可通過旁分泌方式改變HNSCC內(nèi)皮細(xì)胞形態(tài),阻礙腫瘤細(xì)胞生長,這與黏著斑激酶活性磷酸化和遷移行為的增強(qiáng)有關(guān)[66]。在OSCC中,可激活PI3K/Akt/mTOR信號通路的信號蛋白4D和VEGF均已證實(shí)參與TEC對腫瘤發(fā)生發(fā)展的調(diào)節(jié),或可成為未來潛在的治療靶點(diǎn)[67]。

        2) 免疫細(xì)胞。各類免疫細(xì)胞共同維持TME免疫狀態(tài)以調(diào)控腫瘤對放療的響應(yīng)模式。研究[68]發(fā)現(xiàn):電離輻射可促進(jìn)調(diào)節(jié)性T細(xì)胞(regulatory Tcell,Treg) 的增殖和活性,且被募集至輻射區(qū)域以降低效應(yīng)T細(xì)胞(effector T-cell,Te) 功能,導(dǎo)致放療敏感性下降。增強(qiáng)CD8+ T細(xì)胞的抗腫瘤免疫反應(yīng)對HPV陽性O(shè)PSCC患者的放療預(yù)后有積極作用[69]。PI3K信號傳導(dǎo)能夠減弱調(diào)節(jié)主要組織相容性復(fù)合體(major histocompatibility complex,MHC) Ⅰ類和Ⅱ類表達(dá),進(jìn)而促進(jìn)免疫逃逸[70]。小鼠實(shí)驗(yàn)[71]揭示:PI3K通路在HNSCC中通過Treg的功能狀態(tài)促進(jìn)免疫抑制反應(yīng),進(jìn)而減弱效應(yīng)CD8+ T細(xì)胞依賴性抗腫瘤免疫和局部照射后的遠(yuǎn)隔效應(yīng)。

        抗輻射HNSCC細(xì)胞系表現(xiàn)出新型受體酪氨酸激酶/磷脂酰肌醇3激酶/程序性死亡配體1信號軸(receptor tyrosine kinase/phosphatidylinositol 3-kinase/programmed death-Ligand 1 signaling axis,AXL/PI3K/PD-L1),關(guān)聯(lián)了放療后的局部治療失敗[72]。T 淋巴細(xì)胞免疫球蛋白黏蛋白 3 (T cell immunoglobulindomain and mucin domain-3,Tim-3)是在小鼠和人類腫瘤浸潤淋巴細(xì)胞表達(dá)的免疫檢查點(diǎn)受體。PI3K/Akt復(fù)合物介導(dǎo)的T細(xì)胞受體(Tcell receptor,TCR) 信號傳導(dǎo)調(diào)節(jié)了Tim-3介導(dǎo)的程序性死亡受體1 (programmed death-1, PD-1)抑制,受體Tim-3通過蛋白激酶B/核糖體S6激酶(protein kinase B/ribosomal S6 kinase,Akt/S6) 激活下游增殖途徑,并在功能失調(diào)的腫瘤浸潤淋巴細(xì)胞中高表達(dá)[73]。此外,在舌鱗狀細(xì)胞癌中,被證實(shí)具有抗腫瘤和化療/放療增敏作用的番茄紅素可通過 PI3K/Akt和絲裂原活化蛋白激酶激酶/絲裂原活化蛋白激酶激酶激酶/細(xì)胞外信號調(diào)節(jié)激酶信號通路(mitogen-activated protein kinase kinase kinase/mitogen-activated protein kinase kinase/extracellularsignal-regulated kinase signaling pathway,Raf/MEK/ERK) 逆轉(zhuǎn)程序性死亡配體1 (programmedcell death 1 ligand 1,PD-L1) 信號傳導(dǎo)和表達(dá)[74]。

        3) 缺氧/活性氧。放射可直接導(dǎo)致細(xì)胞氧化應(yīng)激損傷累積,導(dǎo)致缺氧的TME形成。缺氧狀態(tài)可促進(jìn)新生血管發(fā)育及CAF代謝活動,可協(xié)助癌細(xì)胞強(qiáng)化生存和增殖相關(guān)信號通路抵抗缺氧,并增強(qiáng)其放射抵抗能力[36]。

        PI3K/Akt/mTOR被認(rèn)為是腫瘤內(nèi)部氧水平的重要調(diào)節(jié)通路之一。在HNSCC中,作為和細(xì)胞生存密切相關(guān)的信號通路,它通過增加VEGF和HIF-1α表達(dá)來提高癌細(xì)胞對缺氧環(huán)境的適應(yīng)力[75-76]。靶向該信號軸可顯著降低線粒體耗氧量、改善腫瘤缺氧,進(jìn)而增加腫瘤對放療的敏感性[77]。在喉癌中,PI3K/Akt/mTOR 通路是輻射下HIF-1α和/或葡萄糖易化擴(kuò)散轉(zhuǎn)運(yùn)蛋白1的正向介質(zhì),并和放射抵抗呈正相關(guān)[78]。缺氧條件下的HNSCC中應(yīng)激激活激酶和PI3K信號通路參與了膠原蛋白ⅩⅧ 和VEGF之間的表型切換,可引起腫瘤體積增加和遠(yuǎn)處轉(zhuǎn)移[28]。OSCC中過表達(dá)的骨橋蛋白作為一種乏氧相關(guān)因子,也可通過激活PI3K/Akt/mTOR途徑誘導(dǎo)細(xì)胞的惡性表型,促進(jìn)細(xì)胞增殖、遷移和侵襲能力增加[79]。

        長期低氧狀態(tài)促進(jìn)了無氧呼吸,也使TME呈現(xiàn)微酸性。暴露于酸性微環(huán)境的OSCC細(xì)胞活力最初降低,隨后可逐漸適應(yīng)并獲得間充質(zhì)樣表型和更高的運(yùn)動指數(shù),最終可被誘導(dǎo)獲得CSC表型和放射抗性[80];在動物模型中磷酸酶和張力蛋白同源物/磷脂酰肌醇-3-激酶信號通路(phosphataseand tensin homolog/phosphatidylinositol 3-kinasesignaling pathway,PTEN/PI3K) 被證實(shí)參與了此過程的調(diào)控[76]。

        4) 代謝重編程。為了適應(yīng)放射帶來的營養(yǎng)枯竭和缺氧的環(huán)境改變,腫瘤細(xì)胞往往會進(jìn)行代謝重編程以獲得快速增殖、轉(zhuǎn)移和逃避免疫系統(tǒng)的能力,這是癌細(xì)胞維持生存的特征之一[81],也是其放射抵抗的基礎(chǔ)。

        OSCC可依賴PI3K/Akt信號通路增加對葡萄糖的攝取以滿足其快速增長的需求[82]。本課題組研究[16]表明:體外構(gòu)建的放射抵抗性口腔癌細(xì)胞系表現(xiàn)出以脂質(zhì)代謝重編程為主的高代謝特征和腺嘌呤核苷三磷酸(adenosine triphosphate,ATP)結(jié)合盒轉(zhuǎn)運(yùn)蛋白的顯著富集,并伴隨了CSC表型和細(xì)胞球形成能力的增加。OSCC中過度表達(dá)的免疫調(diào)節(jié)蛋白B7-H3通過PI3K/Akt/mTOR途徑調(diào)節(jié)HIF-1α,能夠增加葡萄糖攝取和乳酸產(chǎn)生[83]。放射誘導(dǎo)的缺氧也可激活PI3K/Akt來誘導(dǎo)糖酵解相關(guān)酶mRNA水平的上調(diào),增強(qiáng)放射抵抗[84]。此外,PI3K/Akt還可穩(wěn)定限速酶葡萄糖-21-磷酸脫氫酶(glucose-21-phosphate dehydrogenase,G21PD) 來促進(jìn)磷酸戊糖途徑(pentose phosphate pathway,PPP),PPP的代謝產(chǎn)物則反饋性增強(qiáng)Akt活化,而高PPP 水平和放射抵抗呈正相關(guān)[85]。PI3K/Akt/mTOR激活也促進(jìn)癌細(xì)胞對谷氨酰胺的攝取和利用以促進(jìn)細(xì)胞增殖[86],并驅(qū)動癌細(xì)胞中的脂肪生成,介導(dǎo)HNSCC細(xì)胞的放射抵抗[87] (圖1)。

        3 展望

        當(dāng)前,采用手術(shù)聯(lián)合放化療的綜合治療方案仍是大部分OSCC患者的首選,但治療后的較高腫瘤復(fù)發(fā)、甚至轉(zhuǎn)移嚴(yán)重影響患者生命安全。其中,OSCC具有的較高放射抵抗性是主要限制性因素之一。綜上所述,OSCC的放療抵抗可源于癌細(xì)胞自身的較強(qiáng)DDR能力和被誘導(dǎo)獲取的CSC表型,也受到放射擾動TME重塑的調(diào)控,包括CAF功能改變、免疫抑制、缺氧、代謝重編程等;而PI3K/Akt及其上下游信號分子參與調(diào)節(jié)了OSCC放射抵抗的全生物學(xué)過程。

        PI3K/Akt作為一種調(diào)節(jié)癌細(xì)胞生存能力的信號通路,是被廣泛探索的放射增敏靶點(diǎn)之一,在OSCC中也具有重要的臨床應(yīng)用潛能。OSCC細(xì)胞的PI3K/Akt信號激活特征以PIK3CA基因的激活突變或擴(kuò)增為主,PIK3CA特異性抑制劑如Alpelisib、Copanlisib 和AZD8186 等被證實(shí)可以增加包括OSCC在內(nèi)的多數(shù)HNSCC細(xì)胞的放射敏感性[88]。此外,Alpelisib聯(lián)合tipifarnib (特異性抑制mTOR)更是起到了互補(bǔ)作用,在提高HNSCC放射敏感性的同時有助于克服癌細(xì)胞的PI3K耐藥性[88]。在體外實(shí)驗(yàn)中,經(jīng)第2代mTOR抑制劑AZD 2014和電離放射聯(lián)合干預(yù)的OSCC細(xì)胞表現(xiàn)出了顯著的生長抑制和放射敏感性,mTORC1、mTORC2/Akt失活和細(xì)胞周期阻滯的協(xié)同機(jī)制在其中發(fā)揮了主要作用[48]。PI3K和mTOR激酶的雙重阻斷劑BEZ235聯(lián)合電離放射干預(yù)OSCC細(xì)胞,在體內(nèi)外實(shí)驗(yàn)中均證實(shí)可導(dǎo)致G2/M期的細(xì)胞周期停滯并下調(diào)一系列細(xì)胞周期蛋白的表達(dá)[49],從而促進(jìn)放射敏感。

        目前,針對PI3K/Akt信號通路的靶向藥物如何增強(qiáng)傳統(tǒng)放化療的機(jī)制仍有待深入研究,生物安全性和耐藥性是靶向藥物臨床轉(zhuǎn)化的主要限制因素。通過對PI3K/Akt信號通路介導(dǎo)放射抵抗機(jī)制的總結(jié)和討論,或能為探索合適的分子靶點(diǎn)和藥物選擇提供參考,為提高OSCC放療敏感和改善患者預(yù)后提供依據(jù)。

        利益沖突聲明:作者聲明本文無利益沖突。

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        ( 本文編輯 王姝 )

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