Advances in Clinical Medicine
Vol.05 No.04(2015), Article ID:16549,8 pages
10.12677/ACM.2015.54032

Chronic Inflammation and Colorectal Cancer Microenvironment

Wenrui Lian1, Dongmei Ma2, Peide Dong1*

1Department of General Surgery, Affiliated Hospital, Inner Mongolia Medical University, Hohhot Inner Mongolia

2Department of Vasculocardiology, Zibo Coal Central Hospital, Zibo Shandong

Received: Nov. 25th, 2015; accepted: Dec. 14th, 2015; published: Dec. 18th, 2015

Copyright © 2015 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

ABSTRACT

Inflammation is a very common and important basic pathological process, mainly by the pathogen, physical or chemical damage caused. The course of the disease is divided into two broad categories: acute inflammation and chronic inflammation. The main function of acute inflammation is to eliminate infection of the organization, to maintain the physiological balance in the body. Chronic inflammation can cause cell malignant transformation, resulting in the occurrence of cancer. The existing research results show that many inflammatory cytokines play an important role in the process of development and cancer initiation, such as IL-6, TNF-alpha and TGF-beta. In this review, we argue that these inflammatory factors have played a very important role in the process of induced cancer. At the same time, we analyzed its effect of the process of the inflammatory cytokines in proctitis related colorectal cancer.

Keywords:Chronic Inflammation, Colorectal Cancer, Inflammatory Cytokines, IL-6, TNF-α, TGF-β

慢性炎症与结直肠癌微环境

廉文瑞1,马冬梅2,董培德1*

1内蒙古医科大学附属医院普通外科,内蒙古 呼和浩特

2淄矿集团中心医院血管内科,山东 淄博

收稿日期:2015年11月25日;录用日期:2015年12月14日;发布日期:2015年12月18日

摘 要

炎症是由病原体的侵袭,物理性或者化学性的损伤引起的十分常见而又重要的基本病理过程,通常可依病程经过分为两大类:急性炎症(acute inflammation)和慢性炎症(chronic inflammation)。急性炎症主要的功能是消除感染损伤的组织,维持体内的生理平衡,慢性炎症却可以引起细胞的恶性转化,进而引起癌症的发生。已有研究结果表明许多的炎症细胞因子在癌症的起始和发展过程中起着很重要的作用,如IL-6,TNF-α和TGF-β等。在本综述中,我们认为这些炎症因子在诱导癌变的过程中发挥了很重要的作用,同时我们分析了这些炎症细胞因子在结直肠炎相关结直肠癌发生过程中的作用。

关键词 :慢性炎症,结直肠癌,炎症细胞因子,IL-6,TNF-α,TGF-β

1. 介绍

早在1863年,Rudolf Virchow首次阐述了炎症与癌症的关系,提出癌症起源于炎症的假设。近来,大量的报道揭示感染和慢性炎症会促进癌症的发展和恶化,进而支持了Virchow的假设[1] -[3] 。炎症反应是一种正常的免疫反应,通常情况下,炎症是有益的,是人体的自动的防御反应,但如果未能及时制止,急性炎症将会发展成为慢性炎症。慢性炎症可以促进癌症的发生和发展,并参与癌症的发生、生长和转移的各个病理过程[4] 。所以有人提出,癌症也是一种慢性炎症性疾病[5] [6] 。现已发现一些炎症促进肿瘤发生的传导途径和关键分子,如NF-κB/IKK、STATs、PPAR、AID等,应用一些抗炎剂和炎症细胞因子靶向药物可以控制肿瘤的发生和发展[7] -[11] 。

2. 慢性炎症是癌症的始作俑者

大量的报道揭示慢性炎症会促进癌症的的发生、生长和转移[12] 。现在人们普遍认为急性炎症如未能及时控制,即会发展为慢性炎症,而慢性炎症可能会增加患癌症的风险。流行病学研究证实,25%的肿瘤由炎症发展而来,例如:溃疡性结肠炎患者发生结肠癌的概率是正常人的10倍[13] ,并且有数据表明:20%的溃疡性结肠炎患者在发病30年后进展为结肠癌[14] 。

肿瘤微环境中炎症细胞和炎症因子的蓄积具有促进血管生成、促进恶性细胞增殖和转移,促进上皮间质转化(Epithelial-Mesenchymal Transition, EMT),以及逆转获得性免疫反应的作用[13] [15] ,同时也改变了肿瘤细胞对激素和化疗药物的敏感性[16] 。

3. 肿瘤周围的炎症细胞因子

细胞因子大多数为低分子量可溶性蛋白质,具有调节细胞生长、血细胞生成、免疫反应以及损伤组织修复等多种功能。细胞因子可分为淋巴细胞产生的淋巴因子和单核巨噬细胞产生的单核因子等。目前已知白细胞介素(Interleukin, IL),干扰素(Interferon, IFN)、集落刺激因子(Colony Stimulating Factor, CSF)、肿瘤坏死因子(Tumornecrosis Factor, TNF)、转化生长因子(Transforming Growth Foctor, TGF)等均是免疫细胞产生的细胞因子,它们在免疫系统中起着非常重要的调控作用,在异常情况下也会导致病理反应。在肿瘤微环境中的细胞因子通常发挥抗瘤作用,但是在慢性炎症中,表达异常的细胞因子,在癌症发生的早期可以促进周围正常细胞向癌细胞转化,促进癌细胞的生长与发展[17] 。本文主要以与结肠炎和结直肠癌相关的三种细胞因子TNF-α、IL-6、TGF-β为例介绍炎症细胞因子与结直肠癌的关系。

3.1. 肿瘤坏死因子(TNF-α)

如前所述,慢性炎症会促进癌症的发生、生长和转移。TNF-α作为一种炎症介质,在慢性炎症疾病中发挥重要作用,TNF-α在癌症早期阶段发挥重要作用,如血管形成、侵袭。作为一种典型的炎症因子,在癌症发生发展中起双重作用[18] [19] 。

早在1975年,Carswell等接种BCG的小鼠注射LPS后,血清中检测到一种因子可以杀伤某些肿瘤细胞或使体内肿瘤组织发生出血坏死,称为肿瘤坏死因子(Tumor Necrosis Factor, TNF)。直到1985年,Shalaby把巨噬细胞产生的TNF命名为TNF-α[20] 。TNF-α主要由单核巨噬细胞分泌,也可以由中性粒细胞、星状细胞、内皮细胞、平滑肌细胞等细胞产生[21] 。IFN-γ、M-CSF、GM-CSF等在体内可以刺激单核细胞/巨噬细胞产生TNF-α。TNF-α有两种形式:17kD的分泌型TNF-α (sTNF-α)和26kD的膜相关型TNF-α (mTNF-α)。一般认为mTNF-α是sTNF-α的前体,在TNF-α转换酶(TACE)的作用下从膜上裂解脱落生成成熟的sTNF-α,从而发挥生物学效应[22] 。

存在于细胞上的TNF-α受体由信号肽、胞外结构域、跨膜区和胞内结构域4部分组成。主要包含两种:I型TNF-α受体(TNF-α-R1,又被称为TNFRSF1A,CD120a或p55),体内几乎每种细胞均有表达,此型受体可能在溶细胞活性上起主要作用;II性TNF-αR (TNF-αR2,又被称为TNFRSF1B,CD120b或p75),其表达仅仅局限于免疫系统细胞、内皮细胞和神经细胞,此型受体可能与信号传递和T细胞增殖有关[23] 。

TNF-α与TNF-α受体结合后通过募集胞内其它蛋白引发四条下游信号通路:1:TNF-α细胞凋亡的信号通路:TRADD (TNF-Rassociated Death Domain Protein)通过其C端的死亡结构域与TNF-R的死亡结构域结合,形成TNF-R/TRADD复合体,TRADD 又与FADD (Fas Associated Death Domain Protein)结合, 通过Caspase可以诱导细胞凋亡;2:抗凋亡信号通路:通过细胞抑制凋亡蛋白1 (Cellular Inhibitor Of Apoptosis Protein-1, cIAP-1) 等介导;3:NF-κB信号通路:NF-κB在细胞中通常和抑制因子IkB结合,以非活性的状态存在。TNF刺激后,IkB降解,NF-κB激活,启动下游通路,最终进入核内启动转录;4:JNK信号通路TNF-α刺激细胞形成TNFR复合体后,通过一系列蛋白的磷酸化,MAPKKK激活MAPKK,MAPKK进而又激活MAPK,从而激活了JNK信号通路。

TNF-α在肿瘤中的作用仍存在争议:在小鼠模型肉瘤中,高浓度的TNF-α表现出抗瘤作用,外科专家William B. Coley发现:争对TNF-α的全身治疗会出现低血压和器官衰竭等不良反应,故TNF-α腺病毒局部治疗联合化疗效果可能更好[24] [25] 。目前:临床上的TNF-α单克隆抗体等一系列争对TNF-α的药物治疗表现出了可靠疗效,但不同病人对其治疗表现不同。相反,低浓度持续的TNF-α水平促进肿瘤发生。TNF-α促瘤作用主要通过活性氧(Reactive Oxygen Species, ROS)和活性氮(Reactive Nitrogen Species, RNS),ROS和RNS导致DNA损伤,促进了肿瘤的发生。总之,TNF-α发挥促瘤还是抗瘤作用,取决于其产生部位及产生水平[26] 。

3.2. 白细胞介素6(IL-6)

IL-6是另一种典型的症因子,临床试验数据表明:与正常人及良性结直肠息肉患者相比,结直肠癌患者血清中IL-6水平较高,并且IL-6可以作为肿瘤恶性程度的一个预测指标,其敏感性与特异性分别为60%~70%和58%~90%。但对于IL-6是否可以作为一个诊断工具的研究目前较有限[27] 。

白细胞介素(Interleukin, IL)最初是由白细胞产生,因在白细胞间发挥调节作用而命名。后来发现,除白细胞外,其它细胞也可以产生白细胞介素如巨噬细胞、T细胞、B细胞及成纤维细胞等。

IL-6与其受体结合发挥作用。IL-6受体主要由α、β两条链组成的,α链为配基特异性受体,一般称为IL6R;β链为IL-6类型的细胞因子(LIF、OSM、IL-11、CNTF、CT-1)的公共转导子,也称gp130。

IL-6胞内信号转导途径主要有两条:经典信号通路和反式信号通路。经典途径中,IL-6与IL6R结合后经受体相关联的gp130向胞内传递次级信号;反式信号通路中,由IL-6与游离在细胞外液中的亚单位IL-6Rα结合成IL-6/IL-6Rα复合体,其后再结合至膜表面的gp130亚单位上,然后完成信号传递。IL-6主要信号通路是JAK (Janus Kinases) /STAT (Signal Transducers And Activators Of Transcription)。STATs是肿瘤进展中的重要转录因子。同TNF-α一样,IL-6促进非癌症细胞向癌症干细胞转变,而且,非癌症干细胞分泌的IL-6通过活化IL-6R/JAK/STAT3上调OCT4基因,而OCT4功能是控制细胞多能性的决定性因素,对于维持胚胎干细胞的多潜能性和自我更新具有极其重要的作用,OCT4基因上调促进肿瘤的形成[28] 。

Siltuximab (CNTO 328)作为一种抗IL-6的单克隆抗体,临床肺癌治疗中有所运用,作为一种辅助药物运用,效果显著[29] 。

3.3. 转化生长因子-β( Transforming Growth Factor-Β, TGF-β)

TGF-β为一种多效性细胞因子,起到免疫抑制和抗炎作用。生理条件下,TGF-β在癌症细胞分化、凋亡、粘附和侵袭均起作用。

TGF-β分子量为25KD,哺乳动物TGF-β存在三种亚型:TGF-β1、TGF-β2和TGF-β3。目前研究比较清楚的是TGF-β1 [30] [31] 。TGF-β1可由巨噬细胞、淋巴细胞、内皮细胞和软骨细胞等细胞产生,白血病细胞也可产生。

TGF-β家族受体为异源二聚体,主要包括TGF-βRI、TGF-βRII、TGF-βRIII等3种,TGF-βRII胞外端首先与配体结合,其胞内段的Ser/Thr激酶活化,进而TGF-βRI的GS结构域磷酸化,TGF-βRI活化后将信号向细胞内转导[30] -[32] 。

TGF-β与TGF-βRII结合形成复合物,进而改变了TGF-β =构象,被TGF-βRI所识别后结合形成TGF-βRII-TGF-β-TGF-βRI复合物,复合物中的TGF-βRI被TGF-βRII磷酸化,磷酸化的TGF-βRI将信号放大后传递,启动经典Smad信号通路和非Smad 信号通路。

TGF-β信号通路通过两条途径发挥生物效应,1:经典的Smad依赖性信号转导途径:TGF-β受体与受体调节型Smad的HMH2区的SSXS相互作用,使之磷酸化,Smad被激活,通过MH2结构域与Co-Smad结合形成异源复合物,移位至核与其他转录因子结合,进而调节相应靶基因的表达。2:非Smad信号通路。丝裂原活化的蛋白激酶( mitogen activated protein kinase, MAPK)等信号通路相关因子可与Smad共同调节转录,TGF-β活化的MAPK通路亦可调节细胞的生长、分化及凋亡等[33] 。

TGF-β在癌症发生发展中的作用较复杂,不同细胞类型和肿瘤不同阶段起着不同的作用。在早期阶段,TGF-β为肿瘤抑制因子,抑制细胞周期并促进凋亡;中晚期,其通过表皮间质转化(Epithelial-Mesenchymal Transition, EMT)促进瘤细胞侵袭和转移[34] 。在癌症中,TGF-β产生肿瘤抑制作用通过细胞周期蛋白依赖性激酶抑制因子(Cyclin-Dependent Kinase Inhibitor, CKI) p21的上调和c-Myc的下调,运用传统的TGF-βRⅡ敲除小鼠模型,Guasch G.发现,直肠上皮细胞发生了磷状细胞癌并促进了癌症进展,TGF-β缺陷致使Ras突变和凋亡受阻[35] 。还有许多研究表明,在结直肠癌中,TGF-β1 mRNA和蛋白表达增多,TGF-β受体缺失或突变与结直肠癌高侵袭和预后差有关[36] 。

4. 炎症细胞因子与结直肠癌的关系

结直肠癌是世界范围内第三大常见癌症,发达国家发病率高于发展中国家,美国结直肠癌是男性继前列腺癌和肺癌之后的第三常见癌症,而对于女性它是继乳腺癌之后第二常见癌症,男性和女性发生本病后死亡率均为9% [37] [38] ,位居所有癌症第二位。随着经济发展,我国居民饮食结构与生活方式改变、平均寿命提高、环境污染加重、肥胖人群增多,结直肠癌的发病率会进一步上升。众所周知,结直肠癌的发生为多基因多步骤调控的复杂过程,大多遵循“正常肠上皮→增生微腺瘤→早期腺瘤→中期腺瘤→晚期腺瘤→结直肠癌”的模式[39] ,过程中包括:相关基因突变、逃避凋亡、肿瘤微环境中炎症细胞和炎症介质的蓄积等等。近年来,越来越多的研究认为肿瘤微环境中细胞因子起G着举足轻重的作用。

TNF-α是一种重要的促炎因子,结直肠炎患者血液和结肠黏膜中TNF-α水平显著高于普通人群,而临床上将抗TNF-α药物应用于结直肠炎的治疗已取得显著疗效,这提示TNF-α参与了结直肠炎病病程发展。为研究TNF-α的显著升高是否参与了结直肠炎进展为结直肠癌的病理过程,大量基础医学研究结果证实:阻断TNF-α可以抑制实验动物结肠肿瘤的形成,通过葡聚糖硫酸钠(Dextran Sulfate Sodium, DSS)诱导的自发性结肠炎模型和氧化偶氮甲烷(Azoxymethane, AOM)诱导小鼠结直肠肿瘤模型[40] ,Greten等的研究结果表明:NF-κB信号通路与结直肠癌发生和进展密切相关,敲除NF-κB信号通路的关键蛋白IKKβ的小鼠再给予AOM-DSS诱导,小鼠结肠肿瘤的形成被显著抑制。综合上述研究结果表明:TNF-α促进了结直肠炎向结直肠癌的发展,且其作用机制可能与NF-κB信号通路的激活有关[41] 。

IL-6是结直肠癌发生发展过程中的关键因子。临床研究表明:在人结肠癌患者血清、腹水、癌组织中均发现了高水平的IL-6;并且在体外实验中,IL-6刺激结直肠癌细胞生长并诱导抗原表达,如CEA、HLA-1 [42] 。IL-6作为炎性细胞因子,主要来源于肿瘤周围基质细胞如巨噬细胞和成纤维细胞等,肿瘤细胞本身不分泌或分泌很少的IL-6。IL-6调节结直肠癌细胞的生物活性,可能导致细胞扩散或远处转移[43] 。IL-6可以通过增强T细胞介导的免疫炎症反应,促进结直肠癌发展。Matsumoto等采用可溶性IL-6受体阻断IL-6与细胞膜表面受体的正常结合,上述结果显示结直肠肿瘤的形成受到显著抑制[44] 。采用IL-6受体干预后的野生型小鼠组织中STAT3磷酸化水平表达抑制,有研究证实IL-6与相应受体结合后刺激结直肠癌增殖与转移[45] 。

TGF-β信号通路对肿瘤的发生有重要的影响,在信号转导途径中,任何一个转导成员表达异常、突变或失活都将使机体细胞丧失TGF-β对细胞增殖调控的生物学效应而导致肿瘤的发生、发展,且与肿瘤细胞的浸润及转移密切相关。

目前各项研究都表明,TGF-β信号通路相关基因确实遭受频繁的突变失活,这种情况在结直肠癌尤其明显,可导致TGF-βRII移码突变,合成非功能性TGF-βRII蛋白,引起细胞对TGF-β抑制作用的不敏感。同样,在结直肠癌TGF-βI的低表达和(或)低活性也与TGF-β抵抗相关。Grady等研究发现,20%~25%结肠癌患者存在TGF-βRII的失火突变。Gulubova以结直肠癌患者为研究对象,利用免疫组化方法发现89.4%患者中结直肠癌细胞胞质中TGFβ1免疫反应阳性,79.5%患者中结直肠癌细胞中检测到Smad4蛋白阳性,77.4%的肿瘤标本中抑制性蛋白Smad7阳性表达,76.3%的患者肿瘤细胞膜上TGFβRII表达[46] 。另有研究表明,越是晚期的肿瘤患者,其肿瘤细胞中TGFβ1的表达越高,TGFβ1的含量与肿瘤进展程度及术后复发率呈正相关。证实了TGF-β信号通路与结直肠癌的发生密切相关[47] 。

总而言之,多种多样的炎症细胞因子在肿瘤的发生与发展过程中起着至关重要的作用,随着研究的深入,肿瘤与炎症反应之间的相关作用机制会更加清晰,为癌症的预防与治疗提供一条新的途径。

5. 展望

肿瘤与肿瘤微环境为一个不可分割的整体,它们相互作用共同促进。肿瘤微环境主要是由肿瘤细胞、周围基质细胞和浸润的炎性细胞共同组成,其为肿瘤细胞增殖、恶性演变提供“肥沃土壤”的同时,也使得肿瘤细胞逃避了免疫监视。目前大量研究文献表明:肿瘤微环境中炎症因子在肿瘤的发生、发展、侵袭和转移中起重要作用。

近些年来,虽然结直肠癌的临床治疗取得了一定实质性的进展,但它仍是工业化国家中癌症相关死亡的主要原因之一。因此,对于中晚期患者的新型疗法仍在加紧研究中。如上所述,TNF-α,IL-6,TGFβ在肿瘤发生、发展过程中扮演了各种角色,大量的研究结果激发了人们把TNF-α,IL-6,TGFβ作为肿瘤靶向治疗靶点的兴趣。临床上已经有一些细胞因子阻断剂和中和抗体阻止微环境中炎症介质的新型药物。Coley甚至提出:可以利用急性炎症去活化抗瘤反应机制。相信随着研究不断的深入,一定可以阻止癌症的发生及发展。

文章引用

廉文瑞,马冬梅,董培德. 慢性炎症与结直肠癌微环境
Chronic Inflammation and Colorectal Cancer Microenvironment[J]. 临床医学进展, 2015, 05(04): 199-206. http://dx.doi.org/10.12677/ACM.2015.54032

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