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)科大學附屬腫瘤醫(yī)院胰腺腫瘤科,天津 300060)
胰腺癌神經(jīng)浸潤機制研究新進展
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)科大學附屬腫瘤醫(yī)院胰腺腫瘤科,天津 300060)
胰腺癌機制復雜,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,是造成胰腺癌術后局部復發(fā)的主要因素,是胰腺癌不良預后因素之一。然而,胰腺癌PNI發(fā)生的分子生物學原因仍然不清楚,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)展的解剖學基礎。胰腺癌生長的微環(huán)境,癌組織介導的神經(jīng)重塑,都可能是腫瘤細胞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,形成了復雜的網(wǎng)絡調控作用,腫瘤基質及腫瘤微環(huán)境的網(wǎng)絡調控,使神經(jīng)與腫瘤細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
胰腺癌機制復雜,致死率高,預后極差,其發(fā)病隱匿,多數(shù)患者在確診時已處進展期,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。外科理念與技術的顯著進步,胰腺癌全系膜切除[2],動脈優(yōu)先技術、手術標本三維切緣的病理學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后仍無顯著改善,治療仍極具挑戰(zhàn)性,腺癌的預后仍然較差,病死率高達98%[6]。
神經(jīng)浸潤(perineural invasion,PNI)是指在相關分子生物學機制作用下腫瘤細胞侵犯神經(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80%~100%[15]。PNI與患者不良預后和低存活率相關:有研究表明,PNI導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可以作為胰腺癌術后復發(fā)或預后不良的重要因素之一[16]。
然而對神經(jīng)侵襲發(fā)生的分子機制目前尚認識不清,PNI既不是淋巴轉移的延伸,也不是單純的腫瘤細胞沿低阻抗平面的遷移。胰腺導管腺癌是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。胰腺組織內和胰腺周圍含有豐富的神經(jīng)纖維,胰腺癌細胞通過較短距離即可到達周圍神經(jīng),這是胰腺癌較易發(fā)生PNI的解剖基礎。而腫瘤生長的微環(huán)境,腫瘤介導的神經(jīng)重塑,也都可能是腫瘤細胞PNI的原因。
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細胞數(shù)量減少和胰島素抵抗,造成高血糖,此比例高達80%。長期高血糖可導致神經(jīng)細胞攝糖增加,繼而產(chǎn)生神經(jīng)細胞的損傷。神經(jīng)細胞對于葡萄糖的攝取量取決于血糖濃度,神經(jīng)細胞胞外基質中持續(xù)存在的高血糖,可以導致神經(jīng)細胞葡萄糖調節(jié)蛋白疲勞和功能不足,促發(fā)神經(jīng)細胞內大量釋放活性氧,造成神經(jīng)細胞器受損,神經(jīng)細胞產(chǎn)生水腫、變性、重塑,甚至壞死。有文獻報道,高血糖促使神經(jīng)脫髓鞘反應,促進腫瘤細胞PNI,隨浸潤程度的加深,神經(jīng)纖維進一步變性壞死,神經(jīng)軸突斷裂,反過來促進腫瘤細胞的侵襲浸潤[17]。高糖微環(huán)境還可以提升腫瘤細胞的侵襲和轉移能力??傊咛俏h(huán)境通過降低神經(jīng)細胞的自我保護能力和增強胰腺癌細胞的侵襲能力,造成PNI,影響胰腺癌的預后。
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,導致胰腺細胞發(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)被證明在腫瘤細胞局部侵犯和遠處轉移中起重要作用。CX3CLl是一種跨膜趨化因子,介導內皮細胞與神經(jīng)細胞的粘附,神經(jīng)細胞大量表達CX3CLl,而PDAC高表達趨化因子受體CX3CRI,CX3CRl高表達與PNI呈相關,且與術后早期復發(fā)相關,PDAC細胞通過激活Gi蛋白和粘附分子向表達CX3CLl配體的神經(jīng)細胞遷移。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[19]。CXCL12/CXCR4傳導信號軸也是廣泛存在的趨化因子信號傳導途徑之一,CXCR4選擇性與CXCL12結合,CXCL12/CXCR4軸是腫瘤與基質相互作用的重要途徑之一,該信號軸在胰腺癌細胞的增殖和血管形成浸潤轉移中起重要作用[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處轉移和局部進展[21]。慢性炎性介質的刺激可以導致神經(jīng)肥大,興奮性增加促進胰腺癌PNI。
1.3 胰腺癌乏氧微環(huán)境 乏氧性特點是腫瘤難治愈、易復發(fā)和轉移的重要因素之一,乏氧作為胰腺癌腫瘤微環(huán)境特征之一被眾多研究證實,在人體正常組織平均氧濃度為7%,而在腫瘤組織內部平均氧濃度僅有1.5%。HIF-1是調控乏氧相關基因的重要轉錄因子,在多種惡性腫瘤中高表達[22]。在胰腺癌中HIF-1α的高表達對胰腺癌侵襲、神經(jīng)浸潤和血管生成具有重要作用,調控作用能特異性地結合于靶基因的啟動子中的低氧反應元件(hypoxia-responsive element,HRE),調控多種分子的表達。在胰腺癌組織中,HIF-1α蛋白表達水平與腫瘤直徑、淋巴結轉移、腫瘤的病理淋巴結轉移階段相關,在胰腺癌細胞系和胰腺癌組織中,HIF-1α和CX3CR1的表達具有相關性,HIF-1α通過調節(jié)CX3CR1調節(jié)胰腺癌的PNI。HIF-1 α通過上調VEGF、SCF促進腫瘤血管新生;通過上調GLU-1、ENO1增加葡萄糖轉運,誘導糖酵解酶,通過上調端粒酶反轉錄酶(hTERT)、survivin促進細胞增殖,抵抗凋亡。HIF-1α蛋白分子由于在常氧條件下不穩(wěn)定,通常僅高表達于腫瘤組織的壞死部位或遠離中心血管的缺氧組織中。然而,胰腺癌組織卻具有獨特的組成型表達HIF-1α的特征,在常氧條件下約75%的胰腺癌細胞系不同程度的表達HIF-1α分子。約70%胰腺導管腺癌組織高表達HIF-1α,而在正常胰腺組織中難以檢測到HIF-1α的表達,HIF-1α表達水平與胰腺導管腺癌的病理分級、淋巴結轉移和不良預后呈正相關,可能是參與胰腺癌惡性表型的重要轉錄因子。
腫瘤基質影響腫瘤細胞的轉移和侵襲,胰腺癌細胞PNI首先要突破細胞外基質構成的重要屏障。腫瘤微環(huán)境中包含各種良性基質細胞,如巨噬細胞、肥大細胞及胰腺星型細胞等其在腫瘤的增殖、侵襲和轉移及神經(jīng)浸潤有重要作用,并且是預后不良的重要指標[23-24]。胰腺基質中神經(jīng)被細胞毒性T淋巴細胞、巨噬細胞、肥大細胞等浸潤,其比例分別約為35%、39%和21%,而肥大細胞的浸潤與胰腺癌神經(jīng)疼痛有明顯相關性[25]。在結腸癌中腫瘤相關巨噬細胞顯著增加HIF-1α和Sema4D的表達,并能增加結腸癌細胞的遷移和侵襲力[26]。
神經(jīng)分泌的細胞因子如神經(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],膠質細胞源性神經(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。神經(jīng)分泌的GFRα1通過GDNF-RET通路促進腫瘤細胞的PNI[29]。神經(jīng)營養(yǎng)因子家族在多種腫瘤細胞及其周圍神經(jīng)中高表達,是PNI神經(jīng)元遷移的關鍵因素之一。PTN是一種重要的神經(jīng)營養(yǎng)因子,在胰腺癌細胞中高表達,癌細胞發(fā)生壞死時大量的PTN釋放,PTN和結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結合可促進胰腺癌的PNI,神經(jīng)和施旺氏細胞可長生更多的N-syndecan,大量的N-syndecan釋放進一步吸引PTN陽性的癌細胞到達受損的神經(jīng)部位,形成PNI的惡性循環(huán),增加的PTN/N-syndecan水平再次導致神經(jīng)損傷,促進癌細胞的沿神經(jīng)浸潤,PTN/N-syndecan信號通路在胰腺癌的PNI中起重要作用[30]。胰腺癌高表達肝素結合細胞因子,該因子具有促進胰腺PNI的作用,是胰腺癌預后不良的標志之一[31]。胰腺癌高表達熱休克蛋白90α[32]、Linc00675[33]、AFAP1-AS1[34],并且與PNI及胰腺癌預后有關。KIF14(有絲分裂驅動蛋白)下調、ARHGDβ上調等均與胰腺癌PNI相關。
軸突誘導因子可以誘導軸突生長錐的定向生長,對神經(jīng)發(fā)育影響重大。目前研究認為Sema4D和其受體的相互作用與腫瘤關系密切。Sema4D和plexin-B1在許多腫瘤中高表達,如頭頸鱗狀細胞癌、乳腺癌、前列腺癌和結腸癌等[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系統(tǒng),參與調節(jié)不同類型的細胞的運動和粘附,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胞系高表達,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。
總之,胰腺癌的PNI是一個復雜的過程,其詳細機制還未闡明。復雜的腫瘤微環(huán)境調節(jié)著腫瘤的生長、浸潤和轉移,導致腫瘤周圍神經(jīng)細胞變性、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]。胰腺癌細胞與神經(jīng)細胞通過微環(huán)境的介質相互作用,兩者還共同調節(jié)胰腺癌生長的微環(huán)境。
PNI過程中包含腫瘤細胞、神經(jīng)細胞和基質細胞,及腫瘤微環(huán)境中的其他相關細胞等多種細胞的相互作用,許多細胞因子、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制的作用[37]。腫瘤基質及微環(huán)境的協(xié)同作用,各種細胞因子及信號通路,形成錯綜復雜的網(wǎng)絡調控,使胰腺癌細胞和神經(jīng)細胞相互作用,導致PNI的發(fā)生,并且形成惡性循環(huán)。神經(jīng)細胞變性、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)境中的細胞因子通過一系列配體受體作用和信號轉導通路的開放與關閉,使腫瘤細胞趨化、侵入受損的神經(jīng)細胞,高侵襲力的腫瘤細胞得以在神經(jīng)周圍定植、增殖,導致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)絡調控作用下發(fā)生的。神經(jīng)與腫瘤細胞在腫瘤微環(huán)境和基質中的相互作用中發(fā)生和形成胰腺癌PNI。
揭示胰腺癌PNI的產(chǎn)生機制能夠為胰腺癌治療提供理論基礎,有利于改善對胰腺癌的治療及預后判斷,也為以后的基因治療胰腺癌提供新的方法,以提高胰腺癌手術術前評估的水平和價值,改善患者預后和生存。
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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)計委計劃項目(編號:20150457)
賈如江。E-mail:jiarujiang@126.com