胰腺癌神經(jīng)浸潤的分子機制

沈孝陵 張筱鳳

胰腺癌是一類高度惡性的腫瘤，目前只有約7%的胰腺癌能被早期診斷，由于難以早期診斷及頻繁發(fā)生的局部或者遠(yuǎn)處轉(zhuǎn)移，只有15%～20%的患者最終可以接受根治術(shù)。盡管近年來對胰腺癌的研究在基礎(chǔ)和臨床方面均取得進展，但是胰腺癌的預(yù)后仍然嚴(yán)峻，總體5年生存率不到5%。研究表明[1-3]，胰腺癌有很高的神經(jīng)浸潤(perineural invasion，PNI)發(fā)生率，甚至可高達100%[5]。這可能是胰腺癌轉(zhuǎn)移的一種方式，也是胰腺癌復(fù)發(fā)的一個重要原因。PNI陽性患者總是與不良預(yù)后和低存活率相關(guān)[4-5]。

一、PNI定義和浸潤途徑

PNI為癌細(xì)胞侵犯神經(jīng)外膜、神經(jīng)束膜，甚至到達神經(jīng)內(nèi)膜和與之緊密聯(lián)系的施旺細(xì)胞和神經(jīng)元[6]。目前存在的“perineural invasion”和“neural invasion”概念的含義是相同的[7]。胰腺導(dǎo)管腺癌(pancreatic ductal adenocarcinoma，PDAC)是PNI發(fā)生率最高的腫瘤類型[2]，但是腫瘤大小與PNI的發(fā)生無必然聯(lián)系，即使是只有顯微鏡下才可見到的癌仍然可發(fā)生PNI[8]。PNI的發(fā)生與胰腺癌細(xì)胞的親神經(jīng)性和胰腺與神經(jīng)叢的解剖位置極為貼近有關(guān)。神經(jīng)叢的分布使癌細(xì)胞和神經(jīng)之間形成良好的接觸，癌細(xì)胞可以直接侵犯神經(jīng)，也可以通過神經(jīng)上的穿通管道(如血管和網(wǎng)狀纖維的穿透部位)侵入神經(jīng)內(nèi)部[9]。因為神經(jīng)外膜層內(nèi)有淋巴管存在，多年來一直認(rèn)為PNI是淋巴轉(zhuǎn)移的延伸。近年來發(fā)現(xiàn)淋巴管未穿透神經(jīng)外膜，故而排除了PNI與淋巴轉(zhuǎn)移的關(guān)系。

二、PNI的分子機制

1．神經(jīng)營養(yǎng)因子及其受體：胰腺癌的PNI可以發(fā)生于疾病早期，所以推測可能存在某些神經(jīng)分泌的因子在此過程中發(fā)揮作用，神經(jīng)營養(yǎng)因子家族最初被認(rèn)為是這些因子中的一類。神經(jīng)營養(yǎng)因子指的是作用于神經(jīng)系統(tǒng)，影響神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞生長、分化、存活及其細(xì)胞周期的分子。它能增強細(xì)胞分化，誘導(dǎo)增殖，影響突觸功能，防止神經(jīng)細(xì)胞凋亡，具有細(xì)胞因子的多功能性、協(xié)同性和相互依賴性、相互制約性、自分泌和旁分泌性等特點。神經(jīng)營養(yǎng)因子可以分為5大類：①神經(jīng)營養(yǎng)因子(neurotrophins)家族，包括神經(jīng)生長因子(nerve growth factor，NGF )、腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor，BDNF)、神經(jīng)營養(yǎng)素(neurotrophin，NT)-3、NT-4等。②膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子(glial cell line-derived neurotrophic flactor，GDNF)家族，包括GDNF、NTN (neurturin)、PSP(persephin)、ART/RNV(artemin/renovin)。③細(xì)胞因子(cytokines)家族，包括睫狀神經(jīng)營養(yǎng)因子(ciliary neurotrophic factor, CNTF)、白介素-6(IL-6)、白血病抑制因子(leukemia inhibitory factor，LIF)及心肌營養(yǎng)素-1(cardiotrophin-1，CT-1)。④成纖維細(xì)胞生長因子(fibroblast growth factor，F(xiàn)GF)家族：aFGF, bFGF。⑤其他類：包括胰島素樣生長因子(insulin-like growth factors，IGF)、表皮生長因子(epidermal growth factor，EGF)、血小板源性生長因子(platelet derived growth factor，PDGF)等。

神經(jīng)營養(yǎng)因子受體分為兩種，一種是高親和力的酪氨酸激酶受體(tyrosine kinase receptors，Trk)，包括TrkA、TrkB和TrkC；一種是低親和力的受體p75NTR。3種Trk均為跨膜分子，以不同的親和力與NGF、BDNF、NT-3、NT-4相結(jié)合。NGF優(yōu)先與TrkA結(jié)合，而BDNF、NT-4優(yōu)先與TrkB結(jié)合[10-11]，NT-3優(yōu)先與TrkC結(jié)合[12]，三者均能誘導(dǎo)促生存信號。p75NTR是跨膜糖蛋白，隸屬于腫瘤壞死因子超家族，無論TrkA、B、C存在與否，均能促進細(xì)胞生存或誘導(dǎo)細(xì)胞凋亡[13]。

1999年Zhu等[14]第一次證明NGF及其受體TrkA在胰腺癌PNI中起作用，之后陸續(xù)有報道胰腺癌細(xì)胞及其周圍神經(jīng)中神經(jīng)營養(yǎng)因子家族和其受體TRKA、p75NTR表達水平升高[15-16]。Schneider等[16]報道，TrkA在導(dǎo)管、胰島和癌細(xì)胞中均表達，TrkB僅在胰島的α-細(xì)胞中表達，TrkC的著色程度及分布與TrkA相似；p75NTR在神經(jīng)組織中表達，在正常組織中僅散在存在。導(dǎo)管和腺泡細(xì)胞以及神經(jīng)組織和癌細(xì)胞中均有不同程度的NGF表達。NT-3在毛細(xì)血管內(nèi)皮和紅細(xì)胞中表達，NT-4特異性地在導(dǎo)管細(xì)胞中表達。該結(jié)果提示胰腺癌細(xì)胞自分泌NGF增強，通過激活MAPK途徑發(fā)揮有絲分裂效應(yīng)[17]，并通過旁分泌作用促進PNI發(fā)生。Ma等[18]證實胰腺癌中NGF和TrkA過表達能促進神經(jīng)的病理性增長，聯(lián)合抑制NGF和TrkA或許能起到抑制腫瘤的目的。Wang等[19]證實報道，p75NTR的表達水平和胰腺癌PNI之間存在正相關(guān)。將p75NTR轉(zhuǎn)染胰腺癌細(xì)胞后細(xì)胞對化學(xué)趨化性的反應(yīng)性遷移顯著增強，表明p75NTR在胰腺癌細(xì)胞的遷移中起作用，也可能在PNI中起作用。

Ketterer等[24]報道，胰腺癌中BDNF、NT-3和NT-4表達均升高，將T3M4期胰腺癌細(xì)胞與背根神經(jīng)細(xì)胞共培養(yǎng)后癌細(xì)胞強表達TrkB和p75NTR，細(xì)胞增殖明顯增強。但Schneider等[16]報道胰腺癌中BDNF、NT-3和NT-4表達均不升高。

GDNF被認(rèn)為是胰腺癌細(xì)胞的化學(xué)引誘物，在腫瘤的進展、遷移、侵襲的過程中發(fā)揮重要作用[21]。有PNI的胰腺癌GDNF陽性率顯著高于無PNI的胰腺癌[22]。胰腺癌細(xì)胞系SW1990、CAPAN-2、MiaPaCa-2、BxPC3與GDNF共培養(yǎng)后，細(xì)胞對細(xì)胞外基質(zhì)蛋白如Ⅰ型膠原、層黏連蛋白、纖連蛋白等的趨向性增強，整合素的表達增加；使用整合素抑制劑后可以抑制細(xì)胞對細(xì)胞外基質(zhì)的粘附能力，提示GDNF引起的整合素表達改變在胰腺癌的侵襲和轉(zhuǎn)移行為中發(fā)揮重要作用[23-24]。另外，GDNF還可以激活基質(zhì)金屬蛋白酶(MMP)，引起細(xì)胞惡性程度增加。

2．趨化因子：趨化因子是腫瘤炎性環(huán)境的重要組成部分[25]。趨化因子及其受體已經(jīng)被證明在腫瘤細(xì)胞局部侵犯和遠(yuǎn)處轉(zhuǎn)移中起重要作用。趨化因子也能提供增殖信號使得腫瘤細(xì)胞能在遠(yuǎn)處器官中生存。Marchee等[26]報道，PDAC強表達趨化因子受體CX3CR1，而正常胰腺上皮細(xì)胞不表達。CX3CR1高表達與PNI呈相關(guān)，且與術(shù)后早期復(fù)發(fā)相關(guān)。CX3CR1專一性地結(jié)合跨膜趨化因子CX3CL1。神經(jīng)細(xì)胞大量表達CX3CL1，其主要是介導(dǎo)內(nèi)皮細(xì)胞與神經(jīng)細(xì)胞的粘附。CX3CR1陽性表達的PDAC細(xì)胞通過激活Gi蛋白和黏附分子(β1-整合素和黏著斑激酶)向CX3CL1配體遷移，特別是神經(jīng)細(xì)胞[26]。因此，CX3CL1-CX3CR1信號通路可能是將來減少PNI發(fā)生的一個有前景的靶點[27]。

另外，軸突引導(dǎo)分子腦信號蛋白3A(SEMA3A)及其受體神經(jīng)叢狀蛋白A1(PLXNA1)和神經(jīng)纖毛素1(NRP1)在胰腺癌組織中高表達，且與患者生存期縮短和腫瘤侵襲性、轉(zhuǎn)移潛力增強相關(guān)。盡管92%的患者表現(xiàn)出PNI，但SEMA3A表達與PNI狀態(tài)之間未發(fā)現(xiàn)有明顯的關(guān)聯(lián)[28]。

3．基質(zhì)金屬蛋白酶(MMPs)：MMPs幾乎能降解ECM中的各種蛋白成分,破壞腫瘤細(xì)胞侵襲的組織學(xué)屏障，在腫瘤侵襲轉(zhuǎn)移中起關(guān)鍵性作用，Kilian等[29]報道，應(yīng)用MMP抑制劑Ro 28-2653可以有效抑制MMP-2和MMP-9表達，顯著降低胰腺導(dǎo)管腺癌肝轉(zhuǎn)移的發(fā)生。胰腺星狀細(xì)胞是MMP-2的重要來源，可以促進胰腺癌細(xì)胞的侵襲性[30]，也與胰腺癌的PNI有密切關(guān)系[31]。自主神經(jīng)遞質(zhì)去甲腎上腺素也可以通過上調(diào)MMP-2的表達來增強胰腺癌細(xì)胞的侵襲性，啟動神經(jīng)侵犯，激活癌細(xì)胞促生存信號通路[31]。在GDNF和NGF刺激下亦會增強胰腺癌細(xì)胞MMP-2和MMP-9的表達，有助于胰腺癌PNI的發(fā)生[32-33]。

4．有助于PNI的差異化表達基因：通過胰腺癌微陣列分析，比較高頻率PNI和低頻率PNI的胰腺癌細(xì)胞系裸鼠皮下移植瘤組織的差異表達蛋白，發(fā)現(xiàn)高頻率PNI的胰腺癌細(xì)胞系的CD74表達上調(diào)，而低頻率PNI的細(xì)胞系中表達下調(diào)，說明HLA Ⅱ類分子的穩(wěn)定鏈(CD74)可能在PNI過程中起作用[34]。Nagata等[35]報道，PDAC患者的CD74表達水平與PNI相關(guān)，CD74是一個獨立的預(yù)后因素。

其他表達上調(diào)的分子包括絲氨酸蛋白酶組織纖溶酶原激活物和γ-同型核蛋白(γ-synuclein)，后者對維持中樞神經(jīng)系統(tǒng)的功能和發(fā)育有重要作用。它在腫瘤細(xì)胞中異常表達，是患者不良預(yù)后和無病生存期降低的強烈指標(biāo)。應(yīng)用shRNA沉默γ-synuclein的表達可以降低PNI和肝轉(zhuǎn)移的程度。由于在胰腺癌患者的血樣和尿樣中能檢測到，故認(rèn)為γ-synuclein很有可能成為疾病早期診斷標(biāo)志物，當(dāng)然也可能成為疾病治療的靶點。

在神經(jīng)細(xì)胞和腫瘤細(xì)胞共培養(yǎng)的PNI體外模型中觀察到胰腺癌細(xì)胞定向向神經(jīng)元遷移，神經(jīng)元也向胰腺癌細(xì)胞的方向生長出突觸。進一步通過與神經(jīng)元突出相接觸的胰腺癌細(xì)胞的基因表達譜的分析[48]，發(fā)現(xiàn)了一些促生存基因表達上調(diào)，如黏膜相關(guān)淋巴組織淋巴瘤易位基因1(mucosa-associated lymphoid tissue lymphoma translocation gene 1，MALT1)和腫瘤壞死因子受體相關(guān)因子(tumor-necrosis-factor-receptor-associated factor，TRAF)[36]，同時癌細(xì)胞增殖增加，凋亡減少，這些基因可能有助于癌細(xì)胞的神經(jīng)侵犯。

Abiatari等[37]檢測了PNI體外共培養(yǎng)體系中的癌細(xì)胞的轉(zhuǎn)錄組表達譜。他們發(fā)現(xiàn)驅(qū)動蛋白家族成員14(kinesin family member 14，KIF14))表達顯著下調(diào)，RHO-GDP 解離抑制劑-β(RHO-GDP dissociation inhibitor-β，ARHGDIbeta)表達上調(diào)，KIF14與PNI呈負(fù)相關(guān)，下調(diào)KIF14的表達會增強細(xì)胞的PNI能力。KIF是一種細(xì)胞分裂驅(qū)動蛋白，在分裂的細(xì)胞中增多，敲除后會導(dǎo)致細(xì)胞多核化和凋亡，在很多惡性疾病中表達上調(diào)，且與不良預(yù)后相關(guān)，這觀點與該實驗結(jié)果不同。猜測可能存在某種負(fù)反饋機制使得KIF14在其他一些惡性疾病中高表達。Abiatari等[37]又發(fā)現(xiàn)敲除ARHGDIβ的癌細(xì)胞的侵襲轉(zhuǎn)移和生存能力未見明顯降低，只是PNI能力明顯降低，認(rèn)為ARHGDIβ在胰腺癌中可以促進PNI。他們還發(fā)現(xiàn)微管相關(guān)蛋白質(zhì)RP/EB家族成員2(microtubule-associated protein RP/EB family member 2，MAPRE2)也在表現(xiàn)出PNI的胰腺癌細(xì)胞克隆中過表達，并且與患者的低生存率有關(guān)[35]。

5．其他一些重要的大分子：文獻報道，在胰腺癌活檢標(biāo)本中發(fā)現(xiàn)了高水平的造血集落刺激因子G-CSF和GM-CSF，且對應(yīng)地在胰腺神經(jīng)中發(fā)現(xiàn)了它們的受體表達(G-CSFR和GM-CSFRα)，說明這些細(xì)胞因子可能在腫瘤與神經(jīng)相互作用的過程中起作用[39]。Swanson等[40]的研究發(fā)現(xiàn)，胰腺癌細(xì)胞中的黏蛋白1(MUC1)和雪旺細(xì)胞中的髓磷脂相關(guān)糖蛋白(MAG)相互作用增強與PNI有關(guān)。除了作為MAG的優(yōu)先配體外，胰腺癌細(xì)胞中MUC1的胞質(zhì)尾區(qū)的差異化的磷酸化導(dǎo)致了細(xì)胞增殖和轉(zhuǎn)移信號通路的激活[57]。因此，MUC1-MAG信號通路不僅導(dǎo)致胰腺癌細(xì)胞侵襲和增殖增強，也通過輔助胰腺癌細(xì)胞和雪旺細(xì)胞之間產(chǎn)生聯(lián)系從而在PNI中起作用。此外，還有報道一些黏附分子如神經(jīng)細(xì)胞黏附分子(NCAM)和L1細(xì)胞黏附分子(L1CAM)也在胰腺癌的PNI中發(fā)現(xiàn)，但至今仍缺乏相關(guān)實驗。

胰腺癌PNI的分子機制及其復(fù)雜，目前已知的仍然很少，而且大多數(shù)實驗關(guān)注的是神經(jīng)與腫瘤細(xì)胞之間的相互作用，很少有人關(guān)注腫瘤基質(zhì)和微環(huán)境的變化。今后還需要更加精確的動物模型來模擬體內(nèi)胰腺癌PNI的生物學(xué)過程，最終將研究成果轉(zhuǎn)化到早期診斷和靶向藥物的開發(fā)上。

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