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导 读 每个人一生中最美好的时光，都在和肿瘤战斗。 引子 并非每个人都会患癌，但癌细胞存在于每个人体内。 每个人一生中最美好的时光，都在和肿瘤战斗。 结果，赢了还是输了？ 赢了，放下心中的执念，人生还可以重来；输了，来不及收拾行李，人生就提前谢幕。 数据年年触目惊心，只上不下！ 2个月前，国家癌症中心发布了最新一期的全国癌症统计数据。（来自于全国肿瘤登记中心的2017年数据。由于一般滞后3年，本数据实际为2014年登记资料。） 倒吸一口冷气，数据年年触目惊心，只上不下！ 全国恶性肿瘤新发病例数380.4万例，较去年的368万又有上升。其中男性211.4万，女性169.0万，城市人发病更高。相当于平均每天超过1万多人被确诊为癌症，每分钟有7个人被确诊为癌症。 全国发病率前五位癌症： 肺癌、胃癌、结直肠癌、肝癌、乳腺癌。 全国主要恶性肿瘤死亡前五位： 肺癌、肝癌、胃癌、食管癌、结直肠癌。 年龄别发病率 0-30岁组：恶性肿瘤发病率较低； 30岁后：快速升高； 80岁组：达到高峰，而后有所下降。 年龄别死亡率 0-30岁组：恶性肿瘤死亡率较低； 30岁后：快速升高； 东部、中部男性80岁组：达到高峰，而后有所下降； 西部地区男性及所有地区女性死亡率随年龄增高而持续上升。 从30岁开始，我们就直面癌症，与它争夺生存的权利，年复一年，此消彼长，遗憾的是，恶魔在壮大，我们在透支。 每一天的见面问候，是不是有一天会从“很高兴见到你！”，改成“很高兴还能见到你！”？ 人类在和肿瘤的抗争中，对它的了解也在天天刷新，有些种类的对手脾气早已被摸透，痊愈不是奢望；但是，有些对手依然面目模糊。 为什么，我们还看不透？ 癌症的十大标志 对癌症的了解越多，越说明对手的狡猾，既预示更多的遏制方法，也存在失败的风险。针对癌症的十大标志，研究人员在夜以继日地开发对应药物。 现在，越来越清楚，肿瘤是基因疾病，生物学基础是基因的异常。肿瘤的发生是多基因、多步骤突变的结果。不同基因的突变与不同强度的突变形成了不同的肿瘤，也产生了不同的免疫应答。 这既是一些病例对治疗无效的原因，也是有些病例痊愈的原因。 免疫治疗，会是我们战胜肿瘤的终极武器吗？ 还有肠道微生物，在肿瘤的发生和治疗中都占据重要的一席之地，或许微生物治疗，也是未来克敌制胜的黑马。 《NEOPLASIA》上近期发表了意大利dellaCampania大学学者FlorianaMorgillo等的署名文章，综合分析了炎癌关系和肠道微生物在肿瘤发生发展中的作用。 参考文献169篇，文字达1万多字。我们将分两次发布。 研究人员常从免疫系统、遗传易感性和环境因子等角度解释肿瘤发病机制[1]，炎症和氧化应激反应成了科学界争论不休的重要话题。 炎症是防御组织对干扰人体内环境平衡因素的反应。精妙的调节，可确保对损伤不会过度反应，并能及时修复相关的损伤。不过，“修复机”能否正常运作，取决于平衡的实现，即免疫系统在理化刺激后能够自我激活，而后还能自动关闭回到初始状态，这对保护生物功能至关重要。基因对环境的反应让炎症复杂化，慢性自身免疫性疾病的恢复因此可能受到影响，这是癌症发病的原始诱因，就像炎症性肠病(IBD)[2]。 1863年，鲁道夫·路德维希·维尔乔(RudolfLudwig Virchow)在肿瘤组织中发现了白细胞，首次提出了免疫系统执行“第一顺序（Primary Order）”的假说。大量相关研究也采用这一概念，证实炎症、氧化应激、细胞因子生成、趋化因子和肿瘤生长、侵袭和转移之间存在明显的相互关联[3]。炎癌关系现在已经很清楚了，尤其是消化道肿瘤[4]，据此可以推测大多数肿瘤发展就是因为炎性微环境的变化。 事实上，仅一小部分癌症与种系突变有关，大多数癌症是环境因素与体细胞基因突变共同作用的结果[5]。近年来代谢疾病明显增加，如肥胖和糖尿病，该人群的肿瘤发病率也随之增加。这些疾病的直接致癌作用导致了肿瘤高发。另外，通过消耗抗氧化系统，免疫失调促进了慢性炎症和氧化应激的发生[6]。 此外，老年和细胞衰老也是重要的因素，因为炎症级联失调本身就能产生较高的肿瘤发病倾向。 这些因素也使免疫反应在对抗癌症时效率低下，无法遏制其生长和转移[7]。 越来越多的科学证据表明：胃肠道细菌群落可能在调控与肿瘤发生或发展有关的多种炎症/免疫过程中发挥了作用。肠道菌群是肠道内细菌、病毒和真菌的总和，它是一个由至少500种不同的细菌组成的复杂的生态系统，组成和数量因所处的部位而有很大的不同。胃中细菌不多，主要有乳酸菌、链球菌、葡萄球菌、肠杆菌科和酵母菌。随着部位深入，十二指肠中集落形成单位(CFU/g)从0增加到105，回肠为108CFU/g，结肠为1010CFU/g。结肠中99%以上的微生物严格厌氧，如双歧杆菌、拟杆菌、梭状芽胞杆菌、优杆菌、梭杆菌、梭菌等[8]。肠道菌群因人而异，会随年龄、饮食、出生类型、母乳喂养、回盲瓣效率、以及使用活性药物对抗胃烧灼感和肠胃蠕动等情况而改变[9-12]。 为了解肠道微生物群和癌症之间的联系，首先要清楚：存在益生菌的肠道能抵抗肠道病原体的入侵以避免生态失调。这通过IgA的诱导和分泌的抗菌物质、还有紧密连接、完整结构的调控，当然，最重要的是先天性免疫与特异性免疫的正常发挥[13- 16]。 尽管人们对这一领域兴趣日日渐浓厚，但目前还没有一种研究肠道微生物群与癌症之间关系的标准化方案，特别在如何解释研究结果方面。能体现两者关系的充分证据存在于胃肠道肿瘤中。 本综述从特定角度分析了不同方式是如何诱导炎症和氧化应激，以期解释一些肿瘤发生的内在机制。此外，鉴于文献中已有可信的科学证据，因此我们就把重点放在分析肠胃微生物群在胃肠道肿瘤发生发展中所起的作用上。 肿瘤微环境 诱导慢性炎症和癌症的主要环境因素是慢性感染（如病毒性肝炎导致肝细胞癌，幽门螺杆菌感染导致胃癌和胃粘膜淋巴组织增生、血吸虫导致膀胱癌、拟杆菌感染导致结肠癌）、有毒物质（如烟草，化学制品和石棉）以及打破炎症调节平衡的各种代谢异常[17-19]。 炎癌关系的一个重要概念是：持久的炎症。指的不是炎症反应的强度，而是说慢性轻度炎症的时间比较长，这会造成真核细胞向肿瘤转化或基因的毒性损伤[20]。 需要强调的是，并非所有的慢性炎症都能致癌。实体瘤的发生与一种由促肿瘤微环境维系的内在肿瘤性炎症有关[5]。肿瘤微环境由巨噬细胞、嗜中性粒细胞、肥大细胞、髓源性抑制细胞、树突细胞和自然杀伤细胞组成；此外，还有癌细胞及其周围基质（成纤维细胞、内皮细胞、周细胞和间充质细胞），以及特异性免疫细胞（T和B淋巴细胞）。 这些细胞通过自分泌、旁分泌和内分泌产生介质。介质间互相沟通，控制着肿瘤生长。细胞激活的不同互联方式、等级和类型，调控着免疫系统与肿瘤之间致癌与抗癌的平衡[21,22]。两种组织炎症在肿瘤发生过程应该是可以共存的。肿瘤微环境的特定成分和激活，以某种方式决定了炎症在肿瘤中的作用[23]。 巨噬细胞的作用还存在争议。事实上，获得某种特定的功能表型之后，巨噬细胞可能具有促瘤或抗瘤活性，包括促炎，M1抗瘤表型，抗炎，M2促瘤表型巨噬细胞（它是诱导肿瘤血管生成和侵袭转移的基础）[24]。 T淋巴细胞也有类似的作用。它们分为几个亚型：CD8 细胞毒性T细胞(CTLs)和CD4 辅助T(Th)细胞，包括Th1、Th2、Th17和T调节(Treg)细胞，以及自然杀伤T(NKT)细胞。在有关结肠癌和胰腺癌的几项研究中，肿瘤微环境中CTLs和Th1的增加，似乎患者预后更好。但如果自发性癌症发生率增加或暴露在有毒的环境因素中，其数量都减少[25–27]。不过，也有争议：不包括NKTs，其他T淋巴细胞(CTLs,Th1,Th2和Th17)可能致癌[28-30]。一些癌基因如RAS和MYC能够触发信号转导级联，导致肿瘤区域内白细胞募集、表达炎症细胞因子和趋化因子、产生血管生成因子[31,32]。 通常，实体瘤因快速增长，其核心区域会缺血坏死，诱发释放促炎因子如白介素(IL)-1和高迁移率族蛋白B1(HMGB1)[33]，HMGB1促进血管生成因子释放，直接增加肿瘤组织供氧和营养物质，并间接募集促炎细胞和释放细胞因子，保证肿瘤存活[34]。其他肿瘤能够通过直接产生促炎物质引发炎症，其中一些促炎物质通过与Toll样受体的相互作用激活巨噬细胞(TLR)-2[35]。另一种与肿瘤相关的炎症是由抗肿瘤治疗引起的。组织坏死后，促炎因子随之释放，刺激肿瘤生长。或者也可以是放疗和/或化疗时，肿瘤抗原暴露在免疫系统中而引起的抗肿瘤反应性炎症[36,37]。 炎症系统失调也参与了肿瘤的发生过程。一个与炎症诱导相关的肿瘤发生机制是：激活诱发的胞苷脱氨酶(AID)上调，这是一种能够诱导免疫球蛋白基因类转换的酶[38]。这种酶的表达与一系列的肿瘤相关，与暴露于环境因子如NF-kB或TGF-β依赖通道时炎症信号的激活有关[38]。过度激活和过度表达导致基因不稳定，这是肿瘤发生过程中，尤其是在含有如Tp53、c-Myc和Bcl-6这些关键基因时，DNA新突变形成的基础[39]。此时，基因表达的表观遗传调控也至关重要。慢性炎症导致了如INK4a和APC等抑癌基因的沉默，而包括基于miRNA的基因沉默和DNA甲基化在内的表观遗传机制都受到了慢性炎症的影响[40]，尤其是与肿瘤发生密切相关的异常CpG岛甲基化。 炎症诱导产生的生长因子和细胞因子，是克隆干细胞诱导肿瘤进程和获得无节制复制能力的重要因素。Oguma等人证明，当不存在Wnt/β-粘蛋白通道突变时，TNF-α能在与炎症相关的胃癌中诱发β-粘蛋白的核心渗透[41]。 从外，同样的DNA损伤也能诱发炎症，而炎症又能产生致癌活性。在二乙基亚硝胺诱导的肝癌模型(DEN)中，已证明DNA损伤可导致细胞死亡和坏死，对释放的DAMPs作出反应，从而刺激Toll样受体，激活炎症[42,43]。 不同类型的癌基因蛋白如Ras,Myc和RET的活动也可能激活信号，产生IL-6,IL-8, IL-1β等促炎因子和趋化因子[5]。据此可以清晰看出，炎癌之间的复杂关系是肿瘤发生、发展、转移的基础机制。 慢性炎症性疾病 流行病学研究表明，慢性炎症使人容易罹患各种癌症。据估计，潜在的感染和炎症反应与全球癌症死亡率的15%至20%有关[44]。有许多诱发慢性炎症的因素会增加患癌症的风险，包括微生物感染（例如，幽门螺杆菌感染与胃癌和胃粘膜淋巴瘤相关或丙肝病毒感染与肝细胞癌），自身免疫性疾病（例如，炎症性肠病（IBD）与结肠癌有关）和慢性炎症性疾病如哮喘、慢性阻塞性肺疾病（COPD）。因此，使用非甾体消炎药治疗可以降低几种肿瘤的发病率和死亡率[45-47]，特别是降低了健康人群的癌症发病率[48]，而塞来昔布对家族性腺瘤性息肉综合征患者的结直肠息肉也有作用[49]。 一个最好的研究例子就是发生于IBD的结肠癌。在IBD中，结肠细胞持续暴露在促生长的炎性细胞因子中[50]。为修复持续炎症所致的单层上皮损伤，慢性增殖就可能增加了IBD患者癌症风险。慢性炎症中，免疫细胞分泌的细胞因子所刺激的通路，也是肿瘤增殖所需的通路[51-53]。 肿瘤坏死因子α(TNFα)在炎症性肠病的炎症中起着基础性作用，也是生物治疗的靶标。TNFα刺激产生IL-1β和IL-6，诱导粘附分子表达、成纤维细胞增殖、促凝血因子激活、导致急性期细胞毒性，引发炎症[54]。TNFα与受体结合，丝裂原活化蛋白激酶(MAPKs)和可能影响屏障通透性的NF- B通路激活。NF-B活化导致促炎细胞因子的转录增加，导致持续炎症，肌球蛋白轻链激酶(MLCK)表达增加[55,56]，MLCK进而刺激肠道屏障而使其通透性增加。此外，TNFα似乎能刺激环氧化酶衍生的前列腺素E2，或许通过WNT信号途径的调控直接影响致癌作用[54]。 另一个参与癌症进展的细胞因子是TGFβ1，它在上皮-间充质转化(EMT)中举足亲重[57,58]，并通过SLUG诱导及随后的L1CAM基因表达，诱导肠上皮细胞的迁移和抗凋亡表型。 有趣的是，有几份报告显示，除了细胞因子的促炎作用，一些分子改变也参与到炎症诱导的致癌作用之中，包括抑癌基因失活、癌基因突变、杂合性丢失、染色体和微卫星失稳(MSI)。 TP53抑癌基因似乎是IBD相关结直肠癌早期的关键，因为它较早出现在IBD患者中，而散发性结直肠癌(CRC)患者的TP53抑癌基因则出现较晚[58]。TP53异常似乎源于炎症，IBD患者的炎性、非增生异常、非癌性结肠黏膜表达TP53增加，支持这一假设[59]。 基因不稳在癌症中出现很早并逐渐增加。的确，IBD亚群患者中，氧化应激的后果是形成炎症环境，产生的活性氧(ROS)破坏结肠上皮，蛋白质和DNA被氧化致使细胞受损。如果不移除或修复活性氧引发的损伤，细胞就可能出现突变或坏死[60]。 在没有编码区突变的情况下，表型常发生变化，表现为异常启动子甲基化，这与抑癌基因沉默有关【例如TP53、Kruppel样因子6(KLF6)、APC、KRAS，这些基因在结直肠癌(DCC)中被删除了】，在IBD相关癌症患者中可以见到这种表型变化[61]。 在IBD患者的炎症过程中，对那些受CpG岛甲基化表型影响的肿瘤来说，DNA甲基化是关键。CpG岛甲基化表型显示出不稳定的表观遗传[62]。此时，IBD相关肿瘤的一个重要特点是DNA错配修复的缺陷，表现为微卫星不稳定(MSI)和错配修复基因MLH1的启动子高甲基化[63]。最近，也证实表观遗传异常和异常甲基化可以改变与干细胞增殖和分化能力相关的信号通路，如WNT、NOTCH和HEDGEHOG通路。特别是在IBD早期，发现了WNT信号基因的甲基化，并且在与IBD相关的CRC进展过程中逐渐升高。 另一种与癌症发展相关的炎性疾病是COPD，表现为肺部对有害颗粒和气体的异常慢性炎症反应。值得注意的是，大约有30%的轻至中度COPD患者死于肺癌[64]，一般认为这与吸烟有关。肺部微环境的慢性损伤可能会促进从化生、异常增生、原位癌，再到恶性转化的肿瘤发展过程[65]。支气管上皮的形态学改变伴随着杂合性丢失和区域性癌变的增加，包括突变的积累，最终易于患上肺癌[66-68]。与肠内IBD相关的致癌作用类似，TP53突变表现为吸烟者气道的鳞状上皮化生，并发生在转化早期[66]。微卫星不稳定(MSI)在COPD的非恶性支气管上皮中很常见，并与EGFR扩增有关[69]。 COPD的上皮细胞中，EGFR表达增加[70]和EGFR转录激活，增强并延长了由病毒和细菌感染引起的支气管上皮细胞炎症反应[71,72]。同样，PIK3CA/PTEN/Akt/mTOR信号失调，也可以在吸烟者结构异常的支气管气道中观察到，这会促进肿瘤生存、代谢、转移和血管生成，提示它们在癌变早期就被激活[73]。事实上，在鳞状细胞癌(SCC)中，经常出现PIK3CA扩增，但与功能突变相比，频率还是要低得多[74]。在高侵袭性的非小细胞肺癌(NSCLC)中，已认定PTEN蛋白表达或PTEN启动子甲基化的缺失为一个预后不良的独立因素[75-77]。 需要区别对待诱发癌症的炎症和肿瘤引发的炎症，后者发生在恶性肿瘤已经出现并促进了侵袭和转移发生的时候。事实上，可以把炎癌关系视为双向的：外在途径由增加癌症风险的炎症(如IBD和COPD)驱动；内在渠道由引起炎症的基因改变(如致癌基因)驱动。在后者，导致肿瘤发生的基因事件也产生炎症环境。人类肿瘤中，最常见的突变致癌基因是以MYC和RAS家族为代表。RAS–RAF信号通路的组件反过来能诱导促癌炎症趋化因子和细胞因子的产生(32、78、79)，还包括重建细胞外微环境，如诱导血管生成(31,80)。 人乳头状甲状腺癌可以用于探讨癌基因与炎性微环境之间关系。其发病机制就是早期频繁的RET基因重排，这是该癌症发生的必要和充分条件。RET基因的激活可诱导一种与炎症发生时类似的转录程序，包括提高白细胞生存能力并将其从血液募集到组织的集落刺激因子(CSFs)、白介素-1β(IL-1β)、环氧合酶2(COX2)、能够吸引单核细胞和树突细胞(CC-趋化因子配体2(CCL2)和CCL20)的趋化因子、促进血管生成的趋化因子(如IL-8，又称CXC-趋化因子配体8(CXCL80))、与CXCL12结合的CXC-趋化因子受体4(CXCR4)、胞外基质降解酶、粘附分子淋巴细胞选择素(L-选择素)。这些结果表明，早期基因事件对于人类肿瘤的发展是必要和充分的，能直接促进炎症微环境的形成。 炎癌之间外在或内在通道哪一条更重要，可能取决于肿瘤类型，又或者两条通道都不可或缺。这是小鼠胰腺癌模型中的情况，该模型中经常可见胰腺炎和K-RAS基因突变，两者对诱发胰腺上皮内瘤变和浸润性导管癌都是必须的[78]。因此，尽管RAS-RAF通路[32,79]能推动促癌炎症反应，但仍需要一种外在的炎症条件(胰腺炎)来引发小鼠发生肿瘤，或许人类中也是如此。 很可能所有的促癌炎症，不管是在肿瘤发生之前还是之后，都是对损伤和感染的正常反应，而这些，早已被癌细胞坐收渔利。    参考文献： Carcinogenesisas a Result of Multiple Inflammatory and Oxidative Hits: aComprehensive Review from Tumor Microenvironment to Gut Microbiota,DOI:10.1016/j.neo.2018.05.002 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