董 剛(綜述) 張 瑞 陳榮新(審校)

(復(fù)旦大學(xué)附屬中山醫(yī)院肝癌研究所 上海 200032)

肝癌非手術(shù)治療“治療抵抗”的研究進(jìn)展

董 剛(綜述) 張 瑞 陳榮新△(審校)

(復(fù)旦大學(xué)附屬中山醫(yī)院肝癌研究所 上海 200032)

肝癌具有高度惡性和預(yù)后不良的特點(diǎn)。肝移植和肝切除只適用于少部分腫瘤局限的患者。由于起病隱匿,絕大部分肝癌患者被診斷時已為中晚期或者合并嚴(yán)重肝硬化,臨床治療以非手術(shù)為主,如經(jīng)導(dǎo)管肝動脈化療栓塞(transarterial chemoembolization,TACE)、局部消融、放療、靶向藥物等;治療方式雖然多樣,但肝癌復(fù)發(fā)轉(zhuǎn)移的發(fā)生率很高。非手術(shù)治療效果不理想,可能存在肝癌對每種治療方式有一定的“治療抵抗”。積極改進(jìn)現(xiàn)有的治療方案,對延長患者的生存期、提高患者的生活質(zhì)量具有重要的意義。

肝癌; 非手術(shù)治療; 治療抵抗

肝癌是世界最常見的腫瘤之一,具有高度惡性和預(yù)后不良的特點(diǎn)。近年來由于人們生活環(huán)境和飲食習(xí)慣的改變,肝癌發(fā)病率逐年上升,2012年全球約74.6萬人死于肝癌,其中50%以上死亡病例發(fā)生在我國,并集中在東南沿海地區(qū)[1]。肝炎-肝纖維化-肝癌被認(rèn)為是肝癌經(jīng)典的演變過程,慢性乙型肝炎病毒感染是主要的危險(xiǎn)因素。肝移植能最大限度的切除腫瘤和硬化的肝臟,是最佳的治療手段,但要遵循嚴(yán)格的適應(yīng)證。肝移植病例中,復(fù)發(fā)率為10%～15%[2]。由于供肝短缺,臨床上難以廣泛推廣。肝切除術(shù)是治療肝癌的有效方法,據(jù)統(tǒng)計(jì)只有15%的患者能獲得最佳的切除術(shù)[3]。不少患者因手術(shù)時肝外已有轉(zhuǎn)移或者手術(shù)操作造成腫瘤細(xì)胞擴(kuò)散,高達(dá)40%肝癌患者于肝癌切除術(shù)后1年內(nèi)復(fù)發(fā)[4]。對于不能切除的中晚期肝癌可采用經(jīng)導(dǎo)管肝動脈化療栓塞(transarterial chemoembolization,TACE)延緩病情進(jìn)展,但多重耐藥(multidrug resistant,MDR)和缺氧的適應(yīng)性改變成為TACE治療肝癌的主要難點(diǎn),盡管基礎(chǔ)和臨床研究進(jìn)展迅速,肝癌的預(yù)后仍然很差[5]。一般情況較好且腫瘤局限患者,還可采用射頻、放療等治療方式;嚴(yán)重者可考慮靶向藥物(如索拉非尼)治療;不過這些治療效果并不顯著。肝癌經(jīng)過積極治療,效果不明顯甚至進(jìn)展惡化我們可稱之為“治療抵抗”。雖有文獻(xiàn)報(bào)道,但對不同治療方式其抵抗機(jī)制的解釋不夠充分。現(xiàn)綜述肝癌非手術(shù)治療“治療抵抗”的研究進(jìn)展。

TACE 在肝癌的治療過程中,許多患者經(jīng)過根治性切除后依然復(fù)發(fā),以至于沒有更有效的治療方式可以提供。TACE則是一種重要的替代治療方法[6]。根據(jù)美國國家綜合癌癥網(wǎng)絡(luò)(NCCN)指南,TACE是經(jīng)肝動脈插管將抗癌藥物(如5-氟尿嘧啶、順鉑、阿霉素等)聯(lián)合栓塞劑注入靶病灶的一種治療方式,可以有效地降低腫瘤負(fù)荷,并可逆轉(zhuǎn)部分患者肝癌分期,使不能切除的難治性肝癌轉(zhuǎn)化為可切除的肝癌,延長患者的生存時間,改善生存質(zhì)量。TACE也被建議作為中晚期肝癌患者標(biāo)準(zhǔn)治療,臨床TACE治療的反應(yīng)率是15%～55%。然而,隨著越來越多的患者選擇區(qū)域化療栓塞,TACE引起的臨床難題已經(jīng)引起了大家的關(guān)注:一是多次TACE后,大多數(shù)中晚期肝癌對多種結(jié)構(gòu)和功能不同的化療藥物往往不再敏感,腫瘤甚至?xí)杆龠M(jìn)展[7]。二是栓塞引起的一系列缺血缺氧反應(yīng)增加了后期的腫瘤治療難度。以上兩個方面我們稱之為“TACE抵抗”。

“TACE治療抵抗”標(biāo)準(zhǔn) 肝癌早期階段采用合適的診斷和治療方法效果較好;中晚期肝癌TACE治療耐受后,及時調(diào)整現(xiàn)有的治療策略,才能有效延長患者的生存期[8]。如何識別“TACE治療抵抗”很關(guān)鍵;臨床上常根據(jù)影像學(xué)資料定義:連續(xù)2次以上TACE,在化療藥物已更換和/或供血動脈重新定位再栓塞情況下,1～3個月后通過CT或MIR評價治療效果仍不明顯,甚至出現(xiàn)新的病灶[9]。α-甲胎蛋白(alpha-fetoprotein,AFP)、巖藻糖基化-AFP和γ-羧基凝血酶原作為肝癌的腫瘤標(biāo)志物[10],也可用于再行TACE治療的評估,評價肝癌TACE難治性的指標(biāo)有AFP≥100 ng/mL,巖藻糖基化的AFP≥10%,γ-羧基凝血酶原≥100 mAU/mL。然而在不同的病例,3種腫瘤標(biāo)志物在TACE治療后升高水平不一,日本肝癌研究組標(biāo)準(zhǔn)(LCSGJ)提出:TACE治療后即使3種腫瘤標(biāo)志物有過短暫輕微減少,但整體水平持續(xù)升高可作為TACE治療失敗或者抵抗的標(biāo)志[11]。

TACE后的化療抵抗 最近的研究顯示,腫瘤干細(xì)胞(cancer stem cell,CSC)存在于血液系統(tǒng)腫瘤和實(shí)體瘤中[11-13]。CSC假說認(rèn)為腫瘤內(nèi)有一小部分具有自我更新并產(chǎn)生異質(zhì)性腫瘤細(xì)胞能力的亞細(xì)胞群,它們能夠抑制細(xì)胞分化,啟動腫瘤形成,參與化療逃逸[14]。CSC的MDR是中晚期肝癌局域化療失敗的一個重要原因。多種轉(zhuǎn)運(yùn)蛋白的過度表達(dá)與CSC耐藥有關(guān)。其中,P-糖蛋白(P-glycoprotein,P-gp)是多藥耐藥-1基因(MDR1)產(chǎn)物,一種跨膜磷酸糖蛋白,屬于ATP結(jié)合盒(ABC)超家族,它具有能量依賴性“藥泵”功能,與藥物、ATP同時結(jié)合,將細(xì)胞內(nèi)的藥物泵出細(xì)胞外,降低了細(xì)胞內(nèi)的藥物濃度,使細(xì)胞產(chǎn)生耐藥性。因此,P-gp的表達(dá)水平可作為衡量肝癌MDR的一個重要指標(biāo)。ABC超家族亞族G的第2個成員ABCG2,因其介導(dǎo)的多藥耐藥對順鉑、紫杉醇等典型藥物仍然敏感,其所引起的耐藥又稱為非典型耐藥[15]?？朔﨏SC的耐藥機(jī)制,可以顯著提高癌癥的治療效果,減少腫瘤的復(fù)發(fā)和轉(zhuǎn)移。抑制腫瘤細(xì)胞的MDR基因或抑制P-gp可以恢復(fù)其對抗癌劑的敏感性[16]。運(yùn)用納米醫(yī)學(xué)技術(shù)將納米顆粒作為常見化療藥物的遞送載體,通過增強(qiáng)CSC對納米顆粒-藥物復(fù)合體的內(nèi)吞作用,升高腫瘤細(xì)胞內(nèi)部的藥物濃度,達(dá)到殺傷腫瘤細(xì)胞的作用[17]。除了轉(zhuǎn)運(yùn)蛋白,非編碼單鏈miRNA (如miR-130b和let-7等家族成員)也可通過作用于腫瘤蛋白53誘導(dǎo)的核蛋白1(TP53INP1)參與CSC的化療抵抗[18]。CSC耐藥的信號通路主要包括Wnt/β-連鎖蛋白(β-catenin)、轉(zhuǎn)化生長因子-β(transforming growth factor-β,TGF-β)、 Notch 和 Hedgehog等,這些途徑可以作為分子靶點(diǎn)加以阻斷從而作為改善肝癌化療抵抗的策略[19]。

TACE常用的化療藥物包括順鉑、5-氟尿嘧啶(5-fluorouracil,5-FU)、阿霉素等。順鉑是目前治療肝癌最常見的細(xì)胞毒性藥物之一,其抗藥性的一個重要特征是腫瘤細(xì)胞凋亡減少。在以順鉑為主的聯(lián)合化療患者當(dāng)中,miR-363水平顯著降低。miR-363通過作用于抗凋亡基因髓細(xì)胞白血病基因-1 (Mcl-1),減少肝癌細(xì)胞對順鉑的耐藥[20]。此外,在化療抵抗方面,miR-182卻起著截然相反的作用;上調(diào)miR-182,腫瘤細(xì)胞活力顯著增加,腫瘤抑癌基因P53表達(dá)受到抑制[21]。順鉑與miRNA聯(lián)合應(yīng)用可能是治療肝癌化療抵抗的一種新方法。除了miRNA,越來越多的證據(jù)表明,細(xì)胞周期檢查點(diǎn)激酶也參與順鉑耐藥,并通過調(diào)控肝癌細(xì)胞的潛在相關(guān)耐藥基因(如P-gp)和 有絲分裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路、細(xì)胞外調(diào)節(jié)蛋白激酶/MEK / ERK信號通路促進(jìn)肝癌進(jìn)展[22]。法尼基衍生物X受體(farnesoid X receptor,FXR)歷來被視為膽汁酸受體,參與膽汁酸的平衡調(diào)控,最近發(fā)現(xiàn)FXR也涉及肝癌化療耐受,順鉑可激活FXR的表達(dá),FXR作用于ATP結(jié)合盒轉(zhuǎn)運(yùn)蛋白B4、 轉(zhuǎn)錄延長因子A蛋白2、趨化因子14、趨化因子15和角蛋白13等靶基因,降低順鉑對腫瘤細(xì)胞毒性作用[23]。人膜聯(lián)蛋白在順鉑耐藥的肝癌細(xì)胞中高表達(dá)也曾有報(bào)道[24],作為一種Ca2+依賴的磷脂結(jié)合蛋白,其能促進(jìn)肝癌細(xì)胞侵襲遷移能力[25]。除了順鉑,人膜聯(lián)蛋白過度表達(dá)也會降低肝癌細(xì)胞對5-FU敏感性[26],并通過細(xì)胞周期蛋白D1(cyclin D1)調(diào)節(jié)腫瘤細(xì)胞對5-FU耐藥[27]。5-FU可被用來治療各種類型的癌癥,還兼有免疫抑制特性,發(fā)揮抗腫瘤作用同時會削弱荷瘤宿主的免疫功能和抵抗力,導(dǎo)致腫瘤的惡化和轉(zhuǎn)移。表阿霉素(epidoxorubicin,EPI)是一種廣泛應(yīng)用于腫瘤化療的蒽環(huán)類藥物,通過誘導(dǎo)癌細(xì)胞凋亡達(dá)到治療的目的,但同時又可以誘導(dǎo)腫瘤細(xì)胞產(chǎn)生自噬(autophagy),增加腫瘤細(xì)胞對EPI的抵抗[28]。在正常細(xì)胞和早期癌變階段,自噬具有腫瘤抑制作用,但在腫瘤的發(fā)展過程中,快速增殖和緩慢凋亡需要高的能量代謝,在這種情況下,自噬也可能作為腫瘤細(xì)胞一個重要的生存途徑。許多抗腫瘤藥物的設(shè)計(jì)是基于化學(xué)模擬剝奪營養(yǎng),但饑餓的腫瘤細(xì)胞往往通過自噬消除受損的細(xì)胞器來逃避死亡,并因此產(chǎn)生治療性的抵抗[29]。除了EPI,組蛋白去乙?；敢种苿┖晚樸K也可以通過增加線粒體活性氧(reactive oxygen species,ROS)產(chǎn)生,誘導(dǎo)自噬的發(fā)生?？紤]到在許多情況下,這些治療產(chǎn)生的自噬具有保護(hù)腫瘤細(xì)胞的作用,所以最近提出,通過結(jié)合其他藥物破壞腫瘤細(xì)胞自噬,抗癌藥物有效性可能會增強(qiáng)[30]。例如,烏司他丁通過抑制轉(zhuǎn)錄因子核因子(NF-κB)信號轉(zhuǎn)導(dǎo)通路,抑制表阿霉素等化療藥誘導(dǎo)的肝癌細(xì)胞自噬,促進(jìn)腫瘤細(xì)胞凋亡[31]。

TACE后缺氧引起的治療抵抗 TACE栓塞會引起缺氧;缺氧上調(diào)肝細(xì)胞生長因子受體c-Met表達(dá)[32]。c-Met是一種由原癌基因編碼的蛋白產(chǎn)物,具有酪氨酸激酶活性;c-Met配體是肝細(xì)胞生長因子(hepatocyte growth factor,HGF),HGF/c-Met信號調(diào)節(jié)多種細(xì)胞功能,包括細(xì)胞增殖、細(xì)胞運(yùn)動、細(xì)胞分化和血管生成[33]。在各種癌癥包括肝癌,HGF/c-Met信號通路是腫瘤潛在惡性的標(biāo)志[34]。此外,c-Met表達(dá)與腫瘤治療抵抗、預(yù)后不良相關(guān)[35-36]。有報(bào)道稱,索拉非尼對TACE難治性有幫助,單藥治療可作為肝功能Child-Pugh A的TACE難治性肝癌患者二線治療方案[37]。TACE抵抗可能還與殘余腫瘤的血管生成相關(guān)。在許多腫瘤血管生成的調(diào)控因子中,缺氧誘導(dǎo)因子1α (hypoxia inducile factor 1α,HIF-1α)和血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)尤為重要。缺氧反應(yīng)主要通過HIF-1α調(diào)節(jié),增加腫瘤細(xì)胞對缺氧環(huán)境的適應(yīng)能力。HIF-1α在缺氧條件下高度表達(dá),常氧條件下可保持低濃度水平。在侵襲性腫瘤中HIF-1α表達(dá)增加,是肝癌預(yù)后不良的獨(dú)立預(yù)測因子[38]。TACE引起腫瘤局部缺氧,可誘導(dǎo)VEGF表達(dá),促進(jìn)新生血管形成[39]。由于結(jié)構(gòu)和功能上的缺陷,新生的腫瘤血管會進(jìn)一步加重缺氧,從而形成惡性循環(huán),加劇腫瘤的復(fù)發(fā)和轉(zhuǎn)移。有研究表明,TACE術(shù)后患者血清中HIF-1α和VEGF水平會發(fā)生動態(tài)性變化,并且兩者的變化與患者TACE術(shù)后預(yù)后相關(guān)[40]。

放療 除了TACE,放療也是肝癌常用的治療方法之一。電離輻射誘導(dǎo)DNA斷裂引起致死性細(xì)胞損傷,但是腫瘤周圍正常肝細(xì)胞輻射耐受性低,腫瘤細(xì)胞內(nèi)在的放射抵抗等原因使其療效有限。肝癌的放射抵抗與其治療效果無明顯相關(guān)[41]。

正常情況下,DNA修復(fù)系統(tǒng)維護(hù)基因組的穩(wěn)定性和完整性,但在腫瘤細(xì)胞中,DNA損傷修復(fù)通路的高活性卻是導(dǎo)致癌癥放射抵抗的主要因素。人脫氧嘌呤/嘧啶核酸內(nèi)切酶(apurinic/apyrimidinic endonuclease-1,APE1),作為雙功能蛋白,既是DNA堿基切除修復(fù)途徑的關(guān)鍵酶,參與DNA輻射損傷修復(fù),又可以調(diào)節(jié)轉(zhuǎn)錄因子的氧化還原反應(yīng),維持轉(zhuǎn)錄因子與DNA的結(jié)合活性,介導(dǎo)腫瘤細(xì)胞放療抗性的形成[42]。最近的研究表明,miRNA也可能是影響腫瘤細(xì)胞放療抵抗的重要原因之一。miR-20a和miR-17-92等家族的成員,已被證實(shí)在許多人類癌癥(如肺癌、肝癌、胃癌)的放射治療過程中發(fā)揮消極的作用。輻射可以上調(diào)癌細(xì)胞miR-20a的表達(dá)水平,而過表達(dá)的miR-20a則通過激活磷脂酰肌醇3-激酶/絲氨酸/蘇氨酸激酶(PI3K/Akt)信號通路,減少放療引起的癌細(xì)胞損傷[43]。自噬是腫瘤細(xì)胞的一種自我保護(hù)機(jī)制。自噬反應(yīng)不僅影響腫瘤的化療效果,同樣限制了腫瘤放射治療方案的實(shí)施。電鏡證實(shí),電離輻射誘導(dǎo)DNA斷裂,腫瘤細(xì)胞通過DNA片段化,形成酸性囊泡細(xì)胞器,逃避放射損傷。3-甲基腺嘌呤作為自噬抑制劑,在裸鼠移植瘤模型中與電離輻射具有協(xié)同殺傷腫瘤細(xì)胞的作用[44]。極端的生存環(huán)境一方面會驅(qū)使腫瘤細(xì)胞本身發(fā)生變化而產(chǎn)生放射耐受,另一方面環(huán)境本身也會賦予腫瘤某些抗治療的特質(zhì)。比如,放射的敏感性與組織氧分壓(PtO2)有關(guān)。PtO2依賴于組織氧供應(yīng)和氧攝取之間的差異,由于腫瘤血管異常和血液循環(huán)不良,加之本身耗氧量大,導(dǎo)致腫瘤組織內(nèi)部缺氧,使腫瘤對放療的敏感性大大降低[45]。事實(shí)上,正常組織的放射敏感性是氧含量低的腫瘤組織的3倍,如通過閉塞腫瘤上游的側(cè)支動脈,讓血流通過主要動脈集中到下游腫瘤組織,增加腫瘤的動脈血流,再同步放療,便可達(dá)到良好的治療效果[46]。

局部消融治療 隨著醫(yī)學(xué)技術(shù)的進(jìn)步,局部消融已經(jīng)成為肝癌患者一種有效的治療方式,因其微創(chuàng)、毀損徹底的特點(diǎn),廣泛用于治療不能或不愿手術(shù)的小肝癌患者。消融技術(shù)包括射頻消融、微波消融、超聲消融、酒精消融等,其中以射頻消融較為常用,通過局部升高靶病灶溫度(60 ℃以上)破壞腫瘤細(xì)胞,使得腫瘤組織壞死,同時又可以凝固周圍組織,防止腫瘤轉(zhuǎn)移,對腫瘤直徑3 cm以下肝癌的治療效果等同于外科手術(shù)切除[47]。臨床數(shù)據(jù)顯示局部復(fù)發(fā)率為4%～56%[48]。射頻消融抵抗原因包括未達(dá)到最佳消融溫度、熱消融時間不足、附近大血管的“熱沉效應(yīng)(heat sink effect)”等[49]。腫瘤附近肝內(nèi)大血管的循環(huán)血流可以把射頻的大部分熱量帶走,導(dǎo)致腫瘤組織消融不足,腫瘤易殘留復(fù)發(fā)即“熱沉效應(yīng)”。經(jīng)肝動脈導(dǎo)管化療栓塞聯(lián)合射頻消融,可削弱此效應(yīng),改善治療效果[50]。其次,高溫電極極易引起組織碳化,影響熱量傳遞,冷卻電極的應(yīng)用可以更大程度地殺傷腫瘤細(xì)胞[51]。有報(bào)道,高聚焦超聲消融會引起后續(xù)的“治療抵抗”,消融后患者血清中HIF-1α、HIF-2α、VEGF和上皮細(xì)胞激酶(epithelial cell kinase,EphA2)的表達(dá)增加[52]。大量的血管生成相關(guān)基因可直接被HIF-1α誘導(dǎo),如一氧化氮合酶(NOS)和VEGF。當(dāng)前對HIF-2α的研究也集中在血管生成上。EphA2是酪氨酸激酶家族的成員之一,在許多類型的浸潤性腫瘤包括肝癌中高表達(dá),過表達(dá)的EphA2是腫瘤血管生成及侵襲的關(guān)鍵介質(zhì)[53]。

靶向藥物治療 對于晚期肝癌患者來說,如果不積極治療,往往只有6個月的中位生存期。隨著索拉非尼的研制成功,肝癌得治療進(jìn)入了一個新的時期。作為分子靶向藥物,索拉非尼已經(jīng)被證實(shí)延長晚期肝癌患者的生存時間,而且到目前為止,索拉非尼是唯一被美國食品和藥物管理局批準(zhǔn)用于治療肝癌的小分子抑制劑[54]。索拉非尼作為多激酶抑制劑,通過抑制絲氨酸/蘇氨酸激酶、受體酪氨酸激酶,抑制腫瘤血管生成和增殖,而Raf蛋白激酶和VEGF受體(VEGFR)被推定為與索拉非尼抗增殖效應(yīng)密切相關(guān)。臨床數(shù)據(jù)顯示,索拉非尼只對約30%的患者有效,并通常在6個月內(nèi)獲得耐藥性[55]。最近,索拉非尼的療效不穩(wěn)定引起了越來越多研究者的關(guān)注?！八骼悄岬挚埂庇糜诿枋鏊骼悄釋ν砥诟伟┗颊咧委熜Ч幻黠@甚至無效[56]。α晶狀體球蛋白B(αB-crystallin,CRYAB)屬于小熱休克蛋白家族,14-3-3ζ屬于14-3-3蛋白家族,兩者能夠抵抗多種物理、化學(xué)因素誘導(dǎo)的細(xì)胞凋亡,并通過誘導(dǎo)上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition EMT)降低肝癌細(xì)胞對索拉非尼敏感性[57]。同屬于熱休克蛋白家族,葡萄糖調(diào)節(jié)蛋白78 (glucose regulated protein 78,GRP78)在肝癌抵抗索拉非尼治療中同樣發(fā)揮重要作用,GRP78表達(dá)能夠穩(wěn)定線粒體膜電位,抑制線粒體鈣超載,減輕索拉菲尼誘導(dǎo)的ROS產(chǎn)生,同時又可以通過抑制caspase-3、caspase-7的活化,減少索拉非尼引起的腫瘤細(xì)胞凋亡[58]。索拉非尼的長期使用與獲得性耐藥的形成有關(guān)。初次使用索拉非尼,多數(shù)腫瘤細(xì)胞凋亡CSC仍然存在,長時間暴露于索拉非尼,CSC產(chǎn)生大量的耐藥異質(zhì)細(xì)胞,有助于腫瘤的復(fù)發(fā)和轉(zhuǎn)移[59],幸存的肝癌細(xì)胞會激活PI3K/Akt、Janus激酶/信號轉(zhuǎn)導(dǎo)子和轉(zhuǎn)錄激活因子通路(JAK-STAT),促進(jìn)腫瘤細(xì)胞耐藥形成[60]。肝細(xì)胞癌是一種高度血管化的腫瘤,索拉非尼通過抑制VEGF發(fā)揮抗血管生成作用,重復(fù)使用索拉非尼導(dǎo)致腫瘤血管萎縮,氧供減少,缺氧可激活HIF-1α和HIF-2α,參與腫瘤的血管生成、免疫逃避、侵襲轉(zhuǎn)移[61]。單一使用索拉非尼還會激活哺乳動物雷帕霉素靶向基因(mTOR)。mTOR是雷帕霉素(rapamycin)的靶分子,一種絲氨酸/蘇氨酸激酶。上調(diào)mTOR增加蛋白激酶Akt的表達(dá)進(jìn)而引起細(xì)胞自噬。依維莫司是 mTOR 的抑制劑,聯(lián)合索拉非尼早期治療效果令人滿意[62]。肝癌對索拉非尼的獲得性抵抗也涉及EMT過程。EMT階段,E-鈣黏蛋白、細(xì)胞角蛋白、黏附分子表達(dá)下調(diào),在EMT相關(guān)轉(zhuǎn)錄因子(如Snail、Slug、Twist和Zeb)表達(dá)上調(diào)。因?yàn)樯掀ぜ?xì)胞比間充質(zhì)細(xì)胞對索拉非尼治療更敏感,上皮表型轉(zhuǎn)化為間充質(zhì)表型最終導(dǎo)致索拉非尼耐藥[63]。

結(jié)語 肝癌的非手術(shù)治療在一定程度上延緩患者的病情進(jìn)展。因?yàn)榇嬖谥委煹挚?患者雖經(jīng)反復(fù)治療或者更換其他治療方式,病情改善仍不理想甚至進(jìn)展惡化。上述的研究成果為探究肝癌非手術(shù)治療與 “治療抵抗”的內(nèi)在聯(lián)系提供了新的思路。然而,目前非手術(shù)治療“治療抵抗”和肝癌治療后的復(fù)發(fā)轉(zhuǎn)移機(jī)制研究還不夠完善,尚需要進(jìn)一步闡明。

[1] 樊嘉,史穎弘.從最新統(tǒng)計(jì)數(shù)據(jù)看肝癌的發(fā)病死亡變化趨勢[J].健康管理,2015(4):53-54.

[2] DUVOUX C,ROUDOT-THORAVAL F,DECAENS T,etal.Liver transplantation for hepatocellular carcinoma:a model including alpha-fetoprotein improves the performance of Milan criteria [J].Gastroenterology,2012,143(4):986-994.

[3] JAKOBS TF,HOFFMANN RT,TATSCH K,etal.Therapy response of liver tumors after selective internal radiation therapy [J].Radiologe,2008,48(9):839-849.

[4] FAN ST,MAU LC,POON RT,etal.Continuous improvement of survival outcomes of resection of hepatocellular carcinoma:a 20-year experience [J].AnnSurg,2011,253(4):745-758.

[5] FERLAY J,SOERJOMATARAM I,DIKSHIT R,etal.Cancer incidence and mortality worldwide:sources,methods and major patterns in GLOBOCAN 2012 [J].IntJCancer,2015,136(5):E359-E386.

[6] ZHOU JJ,DENG XG,HE XY,etal.Knockdown of NANOG enhances chemosensitivity of liver cancer cells to doxorubicin by reducing MDR1 expression [J].IntJOncol,2014,44(6):2034-2040.

[7] BRUIX J,SALA M,LLOVET JM.Chemoembolization for hepatocellular carcinoma [J].Gastroenterology,2004,127(5 Suppl 1):S179-S188.

[8] KADALAYIL L,BENINI R,PALLAN L,etal.A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer [J].AnnOncol,2013,24(10):2565-2570.

[9] KUDO M,MATSUI O,IZUMI N,etal.Transarterial chemoembolization failure/refractoriness:JSH-LCSGJ criteria 2014 update [J].Oncology,2014,87 Suppl 1:22-31.

[10] HIRAOKA A,ISHIMARU Y,KAWASAKI H,etal.Tumor markers AFP,AFP-L3,and DCP in hepatocellular carcinoma refractory to transcatheter arterial chemoembolization [J].Oncology,2015,89(3):167-174.

[11] KUDO M,MATSUI O,IZUMI N,etal.JSH Consensus-Based Clinical Practice Guidelines for the management of hepatocellular carcinoma:2014 update by the Liver Cancer Study Group of Japan[J].LiverCancer,2014,3(3-4):458-468.

[12] YU F,YAO H,ZHU P,etal.Let-7 regulates self renewal and tumorigenicity of breast cancer cells [J].Cell,2007,131(6):1109-1123.

[13] XU XL,XING BC,HAN HB,etal.The properties of tumor-initiating cells from a hepatocellular carcinoma patient′s primary and recurrent tumor [J].Carcinogenesis,2010,31(2):167-174.

[14] DALERBA P,CHO RW,CLARKE MF.Cancer stem cells:models and concepts [J].AnnuRevMed,2007,58:267-284.

[15] HOU H,SUN H,LU P,etal.Tunicamycin potentiates cisplatin anticancer efficacy through the DPAGT1/Akt/ABCG2 pathway in mouse Xenograft models of human hepatocellular carcinoma [J].MolCancerTher,2013,12(12):2874-2884.

[16] RONINSON IB,CHIN JE,CHOI KG,etal.Isolation of human mdr DNA sequences amplified in multidrug-resistant KB carcinoma cells [J].ProcNatlAcadSciUSA,1986,83(12):4538-4542.

[17] WANG X,LOW XC,HOU W,etal.Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells [J].ACSNano,2014,8(12):12151-12166.

[18] MA S,TANG KH,CHAN YP,etal.MiR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1 [J].CellStemCell,2010,7(6):694-707.

[19] OISHI N,WANG XW.Novel therapeutic strategies for targeting liver cancer stem cells [J].IntJBiolSci,2011,7(5):517-535.

[20] OU Y,ZHAI D,WU N,etal.Downregulation of miR-363 increases drug resistance in cisplatin-treated HepG2 by dysregulating Mcl-1[J].Gene,2015,572(1):116-122.

[21] QIN J,LUO M,QIAN H,etal.Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1 [J].Gene,2014,538(2):342-347.

[22] ZHAO W,LIU S,DOU Q,etal.The role and mechanism of WEE1 on the cisplatin resistance reversal of the HepG2/DDP human hepatic cancer cell line [J].OncolLett,2015,10(5):3081-3086.

[23] VAQUERO J,BRIZ O,HERRAEZ E,etal.Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds [J].BiochimBiophysActa,2013,1833(10):2212-2219.

[24] PAN QZ,PAN K,WENG DS,etal.Annexin A3 promotes tumorigenesis and resistance to chemotherapy in hepatocellular carcinoma [J].MolCarcinog,2015,54(8):598-607.

[25] ZHANG W,ZHAO P,XU XL,etal.Annexin A2 promotes the migration and invasion of human hepatocellular carcinoma cells in vitro by regulating the shedding of CD147-harboring microvesicles from tumor cells [J].PLoSOne,2013,8(8):e67268.

[26] TONG SW,YANG YX,HU HD,etal.Proteomic investigation of 5-fluorouracil resistance in a human hepatocellular carcinoma cell line [J].JCellBiochem,2012,113(5):1671-1680.

[27] WANG C,GUO Y,WANG J,etal.Annexin A2 knockdown inhibits hepatoma cell growth and sensitizes hepatoma cells to 5-fluorouracil by regulating beta-catenin and cyclin D1 expression [J].MolMedRep,2015,11(3):2147-2152.

[28] SUN WL,CHEN J,WANG YP,etal.Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development [J].Autophagy,2011,7(9):1035-1044.

[29] CHEN N,KARANTZA-WADSWORTH V.Role and regulation of autophagy in cancer [J].BiochimBiophysActa,2009,1793(9):1516-1523.

[30] CAREW JS,NAWROCKI ST,KAHUE CN,etal.Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance [J].Blood,2007,110(1):313-322.

[31] SONG B,BIAN Q,SHAO CH,etal.Ulinastatin reduces the resistance of liver cancer cells to epirubicin by inhibiting autophagy [J].PLoSOne,2015,10(3):e120694.

[32] HARA S,NAKASHIRO K,KLOSEK SK,etal.Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells [J].OralOncol,2006,42(6):593-598.

[33] MIYAMOTO M,OJIMA H,IWASAKI M,etal.Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma [J].BrJCancer,2011,105(1):131-138.

[34] BALAN M,MIERY TERAN E,WAAGA-GASSER AM,etal.Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression [J].JBiolChem,2015,290(13):8110-8120.

[35] GHOLAMIN S,FIUJI H,MAFTOUH M,etal.Targeting c-MET/HGF signaling pathway in upper gastrointestinal cancers:rationale and progress [J].CurrDrugTargets,2014,15(14):1302-1311.

[36] KAJIHARA J,TOMIMARU Y,EGUCHI H,etal.The clinical impact of transcatheter arterial chemoembolization (TACE)-induced c-Met upregulation on TACE refractoriness in hepatocellular carcinoma [J].DigDisSci.2016,61(6):1572-1581.

[37] KUDO M,UESHIMA K.Positioning of a molecular-targeted agent,sorafenib,in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan [J].Oncology,2010,78 Suppl 1:154-166.

[38] XIANG ZL,ZENG ZC,FAN J,etal.Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1alpha,VEGF,and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma [J].ClinCancerRes,2011,17(16):5463-5472.

[39] JIA ZZ,JIANG GM,FENG YL.Serum HIF-1alpha and VEGF levels pre- and post-TACE in patients with primary liver cancer [J].ChinMedSciJ,2011,26(3):158-162.

[40] RANIERI G,AMMENDOLA M,MARECH I,etal.Vascular endothelial growth factor and tryptase changes after chemoembolization in hepatocarcinoma patients [J].WorldJGastroenterol,2015,21(19):6018-6025.

[41] RODEMANN HP.Molecular radiation biology:perspectives for radiation oncology [J].RadiotherOncol,2009,92(3):293-298.

[42] ROBERTSON KA,BULLOCK HA,XU Y,etal.Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation [J].CancerRes,2001,61(5):2220-2225.

[43] ZHANG Y,ZHENG L,DING Y,etal.MiR-20a induces cell radioresistance by activating the PTEN/PI3K/Akt signaling pathway in hepatocellular carcinoma [J].IntJRadiatOncolBiolPhys,2015,92(5):1132-1140.

[44] TSENG HC,LIU WS,TYAN YS,etal.Sensitizing effect of 3-methyladenine on radiation-induced cytotoxicity in radio-resistant HepG2 cellsinvitroand in tumor xenografts [J].ChemBiolInteract,2011,192(3):201-208.

[45] MOELLER BJ,RICHARDSON RA,DEWHIRST MW.Hypoxia and radiotherapy:opportunities for improved outcomes in cancer treatment [J].CancerMetastasisRev,2007,26(2):241-248.

[46] REYAL J.Arterial flow focalization could increase tissue oxygen partial pressure,or trigger endothelial shear stress-a new concept to overcome cancer hypoxia-induced radiotherapy resistance,or stimulate liver regeneration during fulminant hepatitis[J].MedHypotheses,2010,74(2):301-308.

[47] LU MD,KUANG M,LIANG LJ,etal.Surgical resection versus percutaneous thermal ablation for early-stage hepatocellular carcinoma:a randomized clinical trial [J].ZhonghuaYiXueZaZhi,2006,86(12):801-805.

[48] FERNANDES ML,LIN CC,LIN CJ,etal.Risk of tumour progression in early-stage hepatocellular carcinoma after radiofrequency ablation[J].BrJSurg,2009,96(7):756-762.

[49] HARRISON LE,KONERU B,BARAMIPOUR P,etal.Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma [J].JAmCollSurg,2003,197(5):759-764.

[50] LU DS,RAMAN SS,VODOPICH DJ,etal.Effect of vessel size on creation of hepatic radiofrequency lesions in pigs:assessment of the “heat sink” effect [J].AJRAmJRoentgenol,2002,178(1):47-51.

[51] MIAO Y,NI Y,YU J,etal.A comparative study on validation of a novel cooled-wet electrode for radiofrequency liver ablation [J].InvestRadiol,2000,35(7):438-444.

[52] WU L,FU Z,ZHOU S,etal.HIF-1alpha and HIF-2alpha:siblings in promoting angiogenesis of residual hepatocellular carcinoma after high-intensity focused ultrasound ablation [J].PLoSOne,2014,9(2):e88913.

[53] YANG P,YUAN W,HE J,etal.Overexpression of EphA2,MMP-9,and MVD-CD34 in hepatocellular carcinoma:Implications for tumor progression and prognosis [J].HepatolRes,2009,39(12):1169-1177.

[54] LLOVET J M,RICCI S,MAZZAFERRO V,etal.Sorafenib in advanced hepatocellular carcinoma[J].NEnglJMed,2008,359(4):378-390.

[55] CHENG AL,KANG YK,CHEN Z,etal.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma:a phase III randomised,double-blind,placebo-controlled trial [J].LancetOncol,2009,10(1):25-34.

[56] CHEN J,JIN R,ZHAO J,etal.Potential molecular,cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma [J].CancerLett,2015,367(1):1-11.

[57] HUANG XY,KE AW,SHI GM,etal.alpha B-crystallin complexes with 14-3-3zeta to induce epithelial-mesenchymal transition and resistance to sorafenib in hepatocellular carcinoma [J].Hepatology,2013,57(6):2235-2247.

[58] CHIOU JF,TAI CJ,HUANG MT,etal.Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma [J].AnnSurgOncol,2010,17(2):603-612.

[59] XIN HW,AMBE CM,HARI DM,etal.Label-retaining liver cancer cells are relatively resistant to sorafenib [J].Gut,2013,62(12):1777-1786.

[60] CHEN KF,CHEN HL,TAI WT,etal.Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells [J].JPharmacolExpTher,2011,337(1):155-161.

[61] WU XZ,XIE GR,CHEN D.Hypoxia and hepatocellular carcinoma:The therapeutic target for hepatocellular carcinoma [J].JGastroenterolHepatol,2007,22(8):1178-1182.

[62] SHIMIZU S,TAKEHARA T,HIKITA H,etal.Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma [J].IntJCancer,2012,131(3):548-557.

[63] GROS J,TABIN CJ.Vertebrate limb bud formation is initiated by localized epithelial-to-mesenchymal transition [J].Science,2014,343(6176):1253-1256.

Research advances in “treatment resistance” of non-operative therapies for hepatocellular carcinoma

DONG Gang, ZHANG Rui, CHEN Rong-xin△

(LiverCancerInstitute,ZhongshanHospital,FudanUniversity,Shanghai200032,China)

Hepatocellular carcinoma (HCC) has the characteristics of high malignancy and poor prognosis.Liver transplantation and hepatectomy are applied in a small portion of patients with localized disease.Due to the hidden onset,HCC is usually diagnosed at an intermediate-advanced stage or with advancing cirrhosis.In most cases,various non-operative treatments are applied,including transarterial chemoembolization (TACE),local ablation,radiotherapy and molecular targeted drugs.The therapeutic effect of non-surgical treatments is not always ideal because the incidence of recurrence and metastasis after treatment is high.It also may be associated with “treatment resistance” of HCC to non-operative treatments.Optimizing the current management schemes has great significance in improving patients′ quality of life and prolonging their survival.

hepatocellular carcinoma; non-surgical treatment; treatment resistance

R735.7

B

10.3969/j.issn.1672-8467.2017.03.021

2016-06-01;編輯:段佳)

△Corresponding author E-mail:chen.rongxin@zs-hospital.sh.cn