胰腺癌神經(jīng)浸潤機(jī)制研究新進(jìn)展

賈如江，王秀超綜述 郝繼輝審校

（1.邯鄲市中心醫(yī)院普外科，河北 邯鄲 056001；2.天津醫(yī)科大學(xué)附屬腫瘤醫(yī)院胰腺腫瘤科，天津 300060）

胰腺癌神經(jīng)浸潤機(jī)制研究新進(jìn)展

賈如江1，王秀超2綜述 郝繼輝2審校

（1.邯鄲市中心醫(yī)院普外科，河北 邯鄲 056001；2.天津醫(yī)科大學(xué)附屬腫瘤醫(yī)院胰腺腫瘤科，天津 300060）

胰腺癌機(jī)制復(fù)雜，致死率高，至今其療效仍較差，5年生存率極低。胰腺癌中PNI發(fā)生率高，是造成胰腺癌術(shù)后局部復(fù)發(fā)的主要因素，是胰腺癌不良預(yù)后因素之一。然而，胰腺癌PNI發(fā)生的分子生物學(xué)原因仍然不清楚，胰腺組織及周圍具神經(jīng)纖維豐富，是胰腺癌PNI的發(fā)生發(fā)展的解剖學(xué)基礎(chǔ)。胰腺癌生長的微環(huán)境，癌組織介導(dǎo)的神經(jīng)重塑，都可能是腫瘤細(xì)胞PNI的原因。胰腺癌乏氧微環(huán)境、慢性炎性微環(huán)境以及高糖微環(huán)境的協(xié)同作用，形成了復(fù)雜的網(wǎng)絡(luò)調(diào)控作用，腫瘤基質(zhì)及腫瘤微環(huán)境的網(wǎng)絡(luò)調(diào)控，使神經(jīng)與腫瘤細(xì)胞之間的相互作用發(fā)生和形成了PNI。

胰腺癌；神經(jīng)浸潤；腫瘤；微環(huán)境

胰腺癌機(jī)制復(fù)雜，致死率高，預(yù)后極差，其發(fā)病隱匿，多數(shù)患者在確診時已處進(jìn)展期，5年生存率低于5%[1]。近年來，胰腺癌治療發(fā)生了顯著變化。外科理念與技術(shù)的顯著進(jìn)步，胰腺癌全系膜切除[2]，動脈優(yōu)先技術(shù)、手術(shù)標(biāo)本三維切緣的病理學(xué)評判等在胰腺癌全系膜切除中積極開展[3-4]，胰腺聯(lián)合血管與臟器切除的開展[5]，使胰腺癌的切除率有了大幅提高。然而，數(shù)十年來胰腺癌患者的總體預(yù)后仍無顯著改善，治療仍極具挑戰(zhàn)性，腺癌的預(yù)后仍然較差，病死率高達(dá)98%[6]。

神經(jīng)浸潤(perineural invasion，PNI)是指在相關(guān)分子生物學(xué)機(jī)制作用下腫瘤細(xì)胞侵犯神經(jīng)的現(xiàn)象。在多種惡性腫瘤中如口腔鱗癌[7]、食管癌[8-9]、胰腺癌、前列腺癌[10]、直腸癌[11-12]、膽管癌[13-14]等均有PNI的發(fā)生。研究顯示，PNI在胰腺癌中發(fā)生率極高，最多可達(dá)80%～100%[15]。PNI與患者不良預(yù)后和低存活率相關(guān)：有研究表明，PNI導(dǎo)致胰腺癌患者生存期明顯縮短，且是胰腺癌疼痛的主要原因之一。PNI可以作為胰腺癌術(shù)后復(fù)發(fā)或預(yù)后不良的重要因素之一[16]。

然而對神經(jīng)侵襲發(fā)生的分子機(jī)制目前尚認(rèn)識不清，PNI既不是淋巴轉(zhuǎn)移的延伸，也不是單純的腫瘤細(xì)胞沿低阻抗平面的遷移。胰腺導(dǎo)管腺癌是PNI發(fā)生率最高的腫瘤類型，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。胰腺組織內(nèi)和胰腺周圍含有豐富的神經(jīng)纖維，胰腺癌細(xì)胞通過較短距離即可到達(dá)周圍神經(jīng)，這是胰腺癌較易發(fā)生PNI的解剖基礎(chǔ)。而腫瘤生長的微環(huán)境，腫瘤介導(dǎo)的神經(jīng)重塑，也都可能是腫瘤細(xì)胞PNI的原因。

1 胰腺癌PNI的腫瘤微環(huán)境的變化

1.1 胰腺癌高糖微環(huán)境 胰腺癌損傷正常胰腺組織，造成胰島β細(xì)胞數(shù)量減少和胰島素抵抗，造成高血糖，此比例高達(dá)80%。長期高血糖可導(dǎo)致神經(jīng)細(xì)胞攝糖增加，繼而產(chǎn)生神經(jīng)細(xì)胞的損傷。神經(jīng)細(xì)胞對于葡萄糖的攝取量取決于血糖濃度，神經(jīng)細(xì)胞胞外基質(zhì)中持續(xù)存在的高血糖，可以導(dǎo)致神經(jīng)細(xì)胞葡萄糖調(diào)節(jié)蛋白疲勞和功能不足，促發(fā)神經(jīng)細(xì)胞內(nèi)大量釋放活性氧，造成神經(jīng)細(xì)胞器受損，神經(jīng)細(xì)胞產(chǎn)生水腫、變性、重塑，甚至壞死。有文獻(xiàn)報道，高血糖促使神經(jīng)脫髓鞘反應(yīng)，促進(jìn)腫瘤細(xì)胞PNI，隨浸潤程度的加深，神經(jīng)纖維進(jìn)一步變性壞死，神經(jīng)軸突斷裂，反過來促進(jìn)腫瘤細(xì)胞的侵襲浸潤[17]。高糖微環(huán)境還可以提升腫瘤細(xì)胞的侵襲和轉(zhuǎn)移能力?？傊?，高糖微環(huán)境通過降低神經(jīng)細(xì)胞的自我保護(hù)能力和增強(qiáng)胰腺癌細(xì)胞的侵襲能力，造成PNI，影響胰腺癌的預(yù)后。

1.2 胰腺癌慢性炎癥微環(huán)境 慢性炎癥微環(huán)境是胰腺癌特有的微環(huán)境，慢性炎癥因子的刺激，導(dǎo)致胰腺細(xì)胞發(fā)生異型性改變、惡性變，趨化因子是重要的慢性炎癥因子之一。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。CX3CLl是一種跨膜趨化因子，介導(dǎo)內(nèi)皮細(xì)胞與神經(jīng)細(xì)胞的粘附，神經(jīng)細(xì)胞大量表達(dá)CX3CLl，而PDAC高表達(dá)趨化因子受體CX3CRI，CX3CRl高表達(dá)與PNI呈相關(guān)，且與術(shù)后早期復(fù)發(fā)相關(guān)，PDAC細(xì)胞通過激活Gi蛋白和粘附分子向表達(dá)CX3CLl配體的神經(jīng)細(xì)胞遷移。有研究表明CX3CL1/CX3CR1也與胃癌神經(jīng)浸潤有著明顯的關(guān)系[18]。CX3CLl/CX3CRl信號通路可能是將來減少PNI發(fā)生的一個有前景的靶點(diǎn)[19]。CXCL12/CXCR4傳導(dǎo)信號軸也是廣泛存在的趨化因子信號傳導(dǎo)途徑之一，CXCR4選擇性與CXCL12結(jié)合，CXCL12/CXCR4軸是腫瘤與基質(zhì)相互作用的重要途徑之一，該信號軸在胰腺癌細(xì)胞的增殖和血管形成浸潤轉(zhuǎn)移中起重要作用[20]，并且該信號通路在胰腺癌的神經(jīng)浸潤中起重要作用，CXCR4/CXCL12軸的阻滯劑，能夠減少惡性腫瘤的遠(yuǎn)處轉(zhuǎn)移和局部進(jìn)展[21]。慢性炎性介質(zhì)的刺激可以導(dǎo)致神經(jīng)肥大，興奮性增加促進(jìn)胰腺癌PNI。

1.3 胰腺癌乏氧微環(huán)境 乏氧性特點(diǎn)是腫瘤難治愈、易復(fù)發(fā)和轉(zhuǎn)移的重要因素之一，乏氧作為胰腺癌腫瘤微環(huán)境特征之一被眾多研究證實(shí)，在人體正常組織平均氧濃度為7%，而在腫瘤組織內(nèi)部平均氧濃度僅有1.5%。HIF-1是調(diào)控乏氧相關(guān)基因的重要轉(zhuǎn)錄因子，在多種惡性腫瘤中高表達(dá)[22]。在胰腺癌中HIF-1α的高表達(dá)對胰腺癌侵襲、神經(jīng)浸潤和血管生成具有重要作用，調(diào)控作用能特異性地結(jié)合于靶基因的啟動子中的低氧反應(yīng)元件(hypoxia-responsive element，HRE)，調(diào)控多種分子的表達(dá)。在胰腺癌組織中，HIF-1α蛋白表達(dá)水平與腫瘤直徑、淋巴結(jié)轉(zhuǎn)移、腫瘤的病理淋巴結(jié)轉(zhuǎn)移階段相關(guān)，在胰腺癌細(xì)胞系和胰腺癌組織中，HIF-1α和CX3CR1的表達(dá)具有相關(guān)性，HIF-1α通過調(diào)節(jié)CX3CR1調(diào)節(jié)胰腺癌的PNI。HIF-1 α通過上調(diào)VEGF、SCF促進(jìn)腫瘤血管新生；通過上調(diào)GLU-1、ENO1增加葡萄糖轉(zhuǎn)運(yùn)，誘導(dǎo)糖酵解酶，通過上調(diào)端粒酶反轉(zhuǎn)錄酶(hTERT)、survivin促進(jìn)細(xì)胞增殖，抵抗凋亡。HIF-1α蛋白分子由于在常氧條件下不穩(wěn)定，通常僅高表達(dá)于腫瘤組織的壞死部位或遠(yuǎn)離中心血管的缺氧組織中。然而，胰腺癌組織卻具有獨(dú)特的組成型表達(dá)HIF-1α的特征，在常氧條件下約75%的胰腺癌細(xì)胞系不同程度的表達(dá)HIF-1α分子。約70%胰腺導(dǎo)管腺癌組織高表達(dá)HIF-1α，而在正常胰腺組織中難以檢測到HIF-1α的表達(dá)，HIF-1α表達(dá)水平與胰腺導(dǎo)管腺癌的病理分級、淋巴結(jié)轉(zhuǎn)移和不良預(yù)后呈正相關(guān)，可能是參與胰腺癌惡性表型的重要轉(zhuǎn)錄因子。

2 腫瘤基質(zhì)

腫瘤基質(zhì)影響腫瘤細(xì)胞的轉(zhuǎn)移和侵襲，胰腺癌細(xì)胞PNI首先要突破細(xì)胞外基質(zhì)構(gòu)成的重要屏障。腫瘤微環(huán)境中包含各種良性基質(zhì)細(xì)胞，如巨噬細(xì)胞、肥大細(xì)胞及胰腺星型細(xì)胞等其在腫瘤的增殖、侵襲和轉(zhuǎn)移及神經(jīng)浸潤有重要作用，并且是預(yù)后不良的重要指標(biāo)[23-24]。胰腺基質(zhì)中神經(jīng)被細(xì)胞毒性T淋巴細(xì)胞、巨噬細(xì)胞、肥大細(xì)胞等浸潤，其比例分別約為35%、39%和21%，而肥大細(xì)胞的浸潤與胰腺癌神經(jīng)疼痛有明顯相關(guān)性[25]。在結(jié)腸癌中腫瘤相關(guān)巨噬細(xì)胞顯著增加HIF-1α和Sema4D的表達(dá)，并能增加結(jié)腸癌細(xì)胞的遷移和侵襲力[26]。

3 與腫瘤PNI相關(guān)的細(xì)胞因子

神經(jīng)分泌的細(xì)胞因子如神經(jīng)營養(yǎng)素家族：包括神經(jīng)生長因子(NGF)，腦源性神經(jīng)營養(yǎng)因子(BDNF)[27]，膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子(GDNF)[28]，神經(jīng)營養(yǎng)因子3 (NT-3)和神經(jīng)營養(yǎng)因子4/5(NT-4/5)均與PNI有關(guān)。神經(jīng)分泌的GFRα1通過GDNF-RET通路促進(jìn)腫瘤細(xì)胞的PNI[29]。神經(jīng)營養(yǎng)因子家族在多種腫瘤細(xì)胞及其周圍神經(jīng)中高表達(dá)，是PNI神經(jīng)元遷移的關(guān)鍵因素之一。PTN是一種重要的神經(jīng)營養(yǎng)因子，在胰腺癌細(xì)胞中高表達(dá)，癌細(xì)胞發(fā)生壞死時大量的PTN釋放，PTN和結(jié)合于其高親和性受體N-syndecan上，N-syndecan是一種神經(jīng)突促生長因子，PTN與N-syndecan結(jié)合可促進(jìn)胰腺癌的PNI，神經(jīng)和施旺氏細(xì)胞可長生更多的N-syndecan，大量的N-syndecan釋放進(jìn)一步吸引PTN陽性的癌細(xì)胞到達(dá)受損的神經(jīng)部位，形成PNI的惡性循環(huán)，增加的PTN/N-syndecan水平再次導(dǎo)致神經(jīng)損傷，促進(jìn)癌細(xì)胞的沿神經(jīng)浸潤，PTN/N-syndecan信號通路在胰腺癌的PNI中起重要作用[30]。胰腺癌高表達(dá)肝素結(jié)合細(xì)胞因子，該因子具有促進(jìn)胰腺PNI的作用，是胰腺癌預(yù)后不良的標(biāo)志之一[31]。胰腺癌高表達(dá)熱休克蛋白90α[32]、Linc00675[33]、AFAP1-AS1[34]，并且與PNI及胰腺癌預(yù)后有關(guān)。KIF14(有絲分裂驅(qū)動蛋白)下調(diào)、ARHGDβ上調(diào)等均與胰腺癌PNI相關(guān)。

4 軸突誘導(dǎo)因子4D在腫瘤及PNI中的作用

軸突誘導(dǎo)因子可以誘導(dǎo)軸突生長錐的定向生長，對神經(jīng)發(fā)育影響重大。目前研究認(rèn)為Sema4D和其受體的相互作用與腫瘤關(guān)系密切。Sema4D和plexin-B1在許多腫瘤中高表達(dá)，如頭頸鱗狀細(xì)胞癌、乳腺癌、前列腺癌和結(jié)腸癌等[35]。Sema4D受體至少有CD72、plexin-B1和plexin-B2三種，其中plexin-B1為高親和力受體。Sema4D/plexin-B1是一種較為普遍存在的信號傳導(dǎo)系統(tǒng)，參與調(diào)節(jié)不同類型的細(xì)胞的運(yùn)動和粘附，PlexinB1首先在神經(jīng)系統(tǒng)中被發(fā)現(xiàn)，對神經(jīng)元的定向生長發(fā)揮重要作用，Sema4D/plexin-B1在PNI中發(fā)揮重要作用。有研究表明plexin-B1在親神經(jīng)的惡性腫瘤組織和細(xì)胞系高表達(dá)，并且以Rho/Rho激酶依賴的方式吸引其配體Sema4D，神經(jīng)通過該方式吸引腫瘤。這表明plexin-B1和Sema4D在PNI中起重要作用。

5 結(jié) 語

總之，胰腺癌的PNI是一個復(fù)雜的過程，其詳細(xì)機(jī)制還未闡明。復(fù)雜的腫瘤微環(huán)境調(diào)節(jié)著腫瘤的生長、浸潤和轉(zhuǎn)移，導(dǎo)致腫瘤周圍神經(jīng)細(xì)胞變性、重塑等改變，腫瘤的PNI受到腫瘤微環(huán)境的影響和調(diào)控。神經(jīng)的可塑性改變發(fā)生于胰腺癌發(fā)生和發(fā)展的所用階段，甚至在胰腺癌發(fā)生之前已經(jīng)發(fā)生[36]。胰腺癌細(xì)胞與神經(jīng)細(xì)胞通過微環(huán)境的介質(zhì)相互作用，兩者還共同調(diào)節(jié)胰腺癌生長的微環(huán)境。

PNI過程中包含腫瘤細(xì)胞、神經(jīng)細(xì)胞和基質(zhì)細(xì)胞，及腫瘤微環(huán)境中的其他相關(guān)細(xì)胞等多種細(xì)胞的相互作用，許多細(xì)胞因子、信號通路都參與胰腺癌PNI的發(fā)生與發(fā)展，還可能存在自分泌及旁分泌機(jī)制的作用[37]。腫瘤基質(zhì)及微環(huán)境的協(xié)同作用，各種細(xì)胞因子及信號通路，形成錯綜復(fù)雜的網(wǎng)絡(luò)調(diào)控，使胰腺癌細(xì)胞和神經(jīng)細(xì)胞相互作用，導(dǎo)致PNI的發(fā)生，并且形成惡性循環(huán)。神經(jīng)細(xì)胞變性、重塑改變，可能是神經(jīng)得以受侵襲的外部條件。腫瘤微環(huán)境中的細(xì)胞因子通過一系列配體受體作用和信號轉(zhuǎn)導(dǎo)通路的開放與關(guān)閉，使腫瘤細(xì)胞趨化、侵入受損的神經(jīng)細(xì)胞，高侵襲力的腫瘤細(xì)胞得以在神經(jīng)周圍定植、增殖，導(dǎo)致PNI。胰腺癌PNI發(fā)生是在乏氧微環(huán)境、腫瘤炎性微環(huán)境以及腫瘤高糖微環(huán)境協(xié)同作用，形成的網(wǎng)絡(luò)調(diào)控作用下發(fā)生的。神經(jīng)與腫瘤細(xì)胞在腫瘤微環(huán)境和基質(zhì)中的相互作用中發(fā)生和形成胰腺癌PNI。

揭示胰腺癌PNI的產(chǎn)生機(jī)制能夠?yàn)橐认侔┲委熖峁├碚摶A(chǔ)，有利于改善對胰腺癌的治療及預(yù)后判斷，也為以后的基因治療胰腺癌提供新的方法，以提高胰腺癌手術(shù)術(shù)前評估的水平和價值，改善患者預(yù)后和生存。

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New progress in the study of the mechanism of perineural invasion in pancreatic cancer.

JIA Ru-jiang1,WANG Xiu-chao2,HAO Ji-hui2.1.Department of General Surgery,Central Hospital of Handan,Handan 056001,Hebei,CHINA; 2.Department of Pancreatic Tumor,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,CHINA

Pancreatic cancer is characterized by complex mechanism,high mortality rate,poor treatment effect, and low 5-year survival rate.Perineural invasion(PNI)has a high incidence rate in pancreatic cancer,and it was the main cause of pancreatic cancer after operation.PNI is one of the independent factors of poor prognosis in pancreatic cancer.However,the molecular mechanism of PNI is not clear at present.Abundant nerve fibers in the pancreas gland are the anatomical basis of the occurrence and development of PNI in pancreatic cancer.The microenvironment of tumor growth and the organization of the nerve remodeling mediated by tumor tissue may be the cause of PNI of tumor cells. The synergistic effect among the hypoxic microenvironment of pancreatic cancer,inflammatory microenvironment and high glucose microenvironment forms a complex network regulation and control function.PNI occurs and forms in the interaction between nerve and tumor cells in the tumor stroma and tumor microenvironment.

Pancreatic cancer;Perineural invasion;Tumor;Microenvironment

R735.9

A

1003—6350（2016）20—3370—04

10.3969/j.issn.1003-6350.2016.20.034

2016-05-25)

河北省衛(wèi)計(jì)委計(jì)劃項(xiàng)目（編號：20150457）

賈如江。E-mail：jiarujiang@126.com