专家讲堂 | 食药用真菌抗肿瘤机制及临床应用研究进展（上）
肿瘤是威胁人类健康的重大疾病，从天然活性物质中寻找具有抗肿瘤活性，且毒副作用小的活性成分，探索其作用机制是开发新的潜在抗肿瘤药物的有效途径。笔者从直接作用和间接作用两方面综述了食药用真菌中活性成分的抗肿瘤作用机制，总结了已应用于临床研究的食药用真菌活性成分，对开发来源于食药用真菌的抗肿瘤药物进行了展望，以期为食药用真菌抗肿瘤活性成分的进一步研究及开发利用提供参考。
肿瘤已经成为严重威胁人类健康的疾病，也是死亡率最高的疾病之一[1]。传统治疗肿瘤的方法主要包括手术切除、放疗和化疗、手术与放化疗相结合。然而，手术切除对已发生转移的癌症的总体预后效果较差，而放疗和化疗在杀死肿瘤细胞的同时也杀死健康细胞，并可产生疲劳、疼痛、腹泻、脱发、白细胞降低等严重副作用，对患者造成不可逆的损伤[2]。近几年，多种肿瘤创新疗法被广泛运用于临床治疗。例如，靶向治疗和免疫治疗分别通过精准针对肿瘤患者的基因突变位点和激活患者免疫反应，可延长肿瘤病人的存活时间和提高生活质量。目前，从天然活性物质中寻找具有抗肿瘤活性，且毒副作用小的活性成分，及探索其分子机制，仍是发掘潜在新靶向抗肿瘤先导化合物的重要途径[3]。
食药用真菌作为传统保健食物和药物已有上千年的使用历史[4]。迄今为止，已发现2000多种食药用真菌，包括灵芝、云芝、黑木耳、银耳、金针菇、刺芹侧耳、香菇、茯苓、猴头菌、灰树花、姬松茸和桑黄等[5]。据文献报道，这些食药用真菌含有复杂多样的生物活性成分，其活性包括抗病毒、抗肿瘤及治疗糖尿病等[5-7]。食药用真菌的抗肿瘤作用已在肺癌、肠癌、肝癌及乳腺癌等多种体外和体内模型中得以验证。大量研究揭示，食药用真菌中的活性成分具有多种不同的抗肿瘤机制，包括直接作用于肿瘤细胞，或通过调节免疫系统等方式间接抑制肿瘤细胞生长[7]。笔者总结了食药用真菌中活性成分的抗肿瘤机制、已用于临床实验的抗肿瘤成分，并对食药用真菌活性成分开发为抗肿瘤药物的前景进行展望。
1
抗肿瘤机制
目前，已报道的食药用真菌的抗肿瘤活性成分对肿瘤细胞的直接作用机制包括诱导细胞凋亡和自噬、阻滞细胞周期完成、抑制肿瘤细胞转移。
1.1.1 诱导肿瘤细胞凋亡和自噬
细胞凋亡（apoptosis）是由基因严格调控的细胞程序性死亡方式，分为内源性凋亡和外源性凋亡两条途径，受多种抗凋亡蛋白和促凋亡蛋白影响[8]。发生凋亡的细胞首先收缩变圆，与周围细胞相分离；然后细胞核和细胞质浓缩，细胞膜内陷将细胞分割为凋亡小体（apoptosis body）；最后被巨噬细胞吞噬降解[8]。凋亡细胞的凋亡小体有膜包被，内容物不外渗，不会引起炎症反应[9]。通过细胞凋亡，机体可消除有缺陷的受损细胞，调控发育中肢体形态变化。细胞凋亡是阻止癌症发生的主要原因之一[10-11]，诱导肿瘤细胞发生凋亡可实现对癌症的治疗[12]。因此，是否能诱导肿瘤细胞凋亡成为大多数食药用真菌活性成分是否具抗肿瘤活性的重要指标之一。细胞凋亡信号通路上的主要调控蛋白Caspase-3、Caspase-9、Bax、PARP、Cytochrome C及Fas等表达上调或被激活，以及细胞凋亡抑制信号Bcl-2及Bcl-xL等因子表达下调或被抑制已成为检测细胞凋亡的主要指标[13]。研究发现，食药用真菌中的活性成分可调节细胞凋亡信号通路上的信号分子（图1）[12,14-20]，如赤芝多糖可提高裸鼠体内的促凋亡基因Bax表达、降低抗凋亡基因Bcl-2的转录水平，诱导肝癌细胞凋亡[14]；桦褐孔菌子实体的三萜类化合物能激活多种肺癌细胞的Caspase-3，诱导肿瘤细胞凋亡[15]；香杉芝发酵液既可促进细胞内Proaspase-3转变成Caspase-3，激活细胞内源性凋亡，同时也可上调FasL和Fas表达，提高Caspase-8活性，激活Fas介导的外源性凋亡[16]。表1总结了近五年来发表的源于食药用真菌的诱导细胞凋亡的活性成分[12,15-22]。
除诱导细胞凋亡外，食药用真菌活性物质也可通过调控细胞自噬（autophagy）这种细胞程序性死亡方式诱导肿瘤细胞死亡。自噬已被证实与肿瘤的发展密切相关[23]。不同于形成凋亡小体，最后由巨噬细胞吞噬的细胞凋亡过程，在自噬死亡过程中，细胞主要形成自噬体，由自噬体转运细胞内物质到胞内溶酶体进行降解。自噬死亡途径主要由mTOR（mammalian target of rapamyein）、磷酸肌醇3-激酶（PI3K/Akt）及Beclin-1等信号通路及信号分子调控[23]。牛樟芝的活性成分By-1（3-isobutyH-met hoxy-4-[4-（3-methyl but-2-enyloxy） phenyl]-1 H-pyrrole-2，5-dione）能诱导肿瘤细胞发生自噬，从而抑制肺癌细胞增殖[24] ；牛樟芝的活性成分antrodin C可影响Akt/mTOR等自噬信号通路上的关键调控分子，从而抑制肺癌细胞增殖[25-26]。
1.1.2 阻滞细胞周期完成
细胞周期指细胞从上一次有丝分裂结束到下一次有丝分裂结束所经历的整个过程。细胞周期分为G1（准备期）、S（DNA合成期）、G2（有丝分裂准备期）和M（分裂期）四个阶段[27]，是细胞正常生命活动的基本特征。细胞周期的静息和启动控制细胞生长和增殖。细胞周期蛋白（cyelins）、细胞周期蛋白依赖性激酶（cyelin-dependent kinases，CDKs）和细胞周期蛋白依赖性激酶抑制剂（eyclin-dependent kinase inhibitor，CDKI）等多种细胞周期调控蛋白相互协调，调控整个细胞周期有序进行[28]，实现细胞稳态[27,29-30]。恶性肿瘤中，CDK等相关细胞周期蛋白过度表达，导致细胞周期的协调作用失衡[29]。已报道的多种食药用真菌中所含活性成分均能够诱导肿瘤细胞周期停滞而抑制肿瘤细胞增殖[19,31-33]。例如，云芝糖肽能够抑制CDK4的表达而使肿瘤细胞停滞于G1期[34]；牛樟芝中的硫酸多糖SPS，能够阻滞肿瘤细胞周期于G2/M期[19]。
1.1.3 抑制肿瘤转移
肿瘤转移（cancermetastasis）指肿瘤细胞从原发病灶位置扩散到远处器官的过程，是癌症恶化的主要标志之一[35-36]。肿瘤转移过程包括以下几个步骤：①肿瘤细胞黏附性下降，从原发部位脱离，穿过细胞外基质（extracellular matrix，ECM）向血液迁移；②迁移的肿瘤细胞通过血液和淋巴循环进入到其他器官，并黏附于器官的血管内皮细胞；③黏附的肿瘤细胞增生，形成新血管供养并快速生长，最终形成新的肿瘤转移灶[36-38]。因此，细胞黏附性对肿瘤细胞迁移至关重要。影响肿瘤细胞黏附性的关键分子包括上皮性钙粘着蛋白（epithelial cadherin， E-cadherin）和整合素（integrin）。E-cadherin水平升高能使肿瘤细胞之间的同质黏附作用增强，难以脱离原发瘤[39-40]。整合素与肿瘤细胞与细胞外基质之间的异质黏附作用相关。整合素与黏着斑激酶（focal adhesion kinase，FAK）结合后，促使FAK发生磷酸化，激活PI3K/Akt、MAPK等信号通路上的下游信号分子，促进肿瘤细胞与细胞外基质之间形成粘着斑，增加肿瘤细胞的迁移和侵袭[39]。此外，影响肿瘤转移过程的其他靶向分子还包括可降解细胞外基质增强肿瘤转移作用的基质金属蛋白酶（matrix metalloproteinases，MMPs）及由肿瘤细胞分泌促进肿瘤周围血管生成的血管内皮生长因子（vascular endothelial growth factor，VEGF）等。目前，食药用真菌中很多活性组分能特异性抑制肿瘤转移过程的关键分子靶点。例如，牛樟芝倍半萜内酯（antrocin）可诱导膀胱癌5637细胞E-cadherin表达增加，降低FAK和桩蛋白（paxillin）的磷酸化水平，抑制肿瘤细胞迁移和侵袭[41]。云芝水提物能降低肿瘤细胞MMP-9蛋白表达水平，抑制4T1乳腺癌细胞迁移和侵袭，从而显著抑制癌细胞在4T1荷瘤小鼠体内转移[42]。云芝子实体多糖可降低VEGF基因在小鼠肝内的表达、减少血管生成，从而抑制肝癌转移[43]。
表皮间质转化（epithelial mesenchymal transition，EMT）与肿瘤转移高度相关。EMT发生过程中，间质细胞分子标志物（如N-cadherin和vimentin）、转录因子（如Snail和Slug等）、黏附分子、细胞骨架等蛋白的表达水平改变，从而导致细胞丧失极性、获得高移动能力及失巢凋亡抗性（anoikisresistance）[44-45]。抑制EMT发生是抗肿瘤药物发挥作用的潜在机制之一。来源于牛樟芝子实体的TMC（2，3，5-trimethoxy-4-cresol）、Anticin-A和来源于L. crinitus的Panepoxydone均可抑制EMT发生，从而表现出显著的抗肿瘤活性[46-48]。
1.2 间接作用
食药用真菌的活性成分除了直接作用于肿瘤细胞，改变肿瘤细胞的信号通路、诱导肿瘤细胞发生凋亡、抑制肿瘤细胞的增殖和转移外，还可以通过其他间接的方式，例如调节机体免疫系统、肠道菌群等来影响肿瘤细胞的生存和迁移。
1.2.1 调节免疫系统
机体免疫系统通过细胞免疫和体液免疫，实现对肿瘤细胞的免疫监视和杀灭作用。在细胞免疫中，各种免疫细胞，如T淋巴细胞、巨噬细胞、自然杀伤细胞（naturalkiller cells，NK细胞）和树突状细胞（dendritic cells，DC细胞）是主要的执行者，通过特异性或非特异性的互相协作来识别和清除肿瘤细胞[49-51]。然而，肿瘤细胞可通过表面抗原分子表达下调，分泌免疫抑制因子、招募免疫抑制细胞等手段抑制免疫系统对肿瘤细胞的清除，逃避免疫监视，从而诱发癌症或引起癌症恶化[52-53]。食药用真菌的一些活性成分可通过增加免疫细胞数量，重新激活机体受抑制的免疫系统，发挥抗肿瘤作用。例如，云芝糖肽PSK和多糖CVE可显著增加小鼠体内CD4+T细胞数量，抑制肝癌细胞生长[43,54-55]。姬松茸水提物andosan促进Th1细胞增殖，可降低小鼠肠道肿瘤的发生[56]。刺芹侧耳菌丝体多肽刺激巨噬细胞释放TNF-a和IL-6，可增强巨噬细胞的吞噬能力[57]。棕榈生微皮伞杂多糖MFPS1刺激NK细胞活化并加强NK细胞与肿瘤细胞结合以杀死肿瘤细胞[58]。金针菇多糖FVPA1可显著增强NK细胞对K562肿瘤细胞的杀伤作用[59]。金针菇多糖FVPB2诱导小鼠脾淋巴细胞的增殖，激活B细胞，促进其分泌IgM和IgG[60]。牛樟芝多糖和灰树花α-葡聚糖YM-2A均直接激活DC细胞，并促进DC细胞的增殖[61-63]。
食药用真菌所含活性成分除直接激活免疫细胞外，还可诱导免疫细胞分泌细胞因子、细胞因子受体和趋化因子。细胞因子、细胞因子受体和趋化因子不仅能够调节各种免疫细胞的活力和平衡，某些细胞因子如干扰素γ（IFN-γ）、白介素（IL-2、IL-6、IL-12）、肿瘤坏死因子（TNF）等还能作用于肿瘤细胞对其产生毒性57,63]。灰树花子实体超微粉可增加Hep-A-22荷瘤小鼠血清中IFN-γ和IL-2含量[64]。刺芹侧耳菌丝体多肽刺激巨噬细胞释放TNF-a和IL-6[57]。云芝中活性成分PSK激活DC细胞产生IL-12、TNF-α和IL-6等促炎细胞因子；酸溶性多糖诱导小鼠血清中IFN-γ和TNF-α水平的显著升高；云芝中的蛋白质结合多糖PBP显著上调乳腺癌MCF-7细胞中TNF-α；云芝多糖CVE维持血清IgG水平来影响HepA肝癌细胞生长[43,54,65-66]。棕榈生微皮伞杂多糖MFPS1刺激小鼠巨噬细胞RAW264.7产生细胞因子IFN-γ、IL-6和TNF-α，促进T细胞的活化和成熟，同时也刺激B细胞增殖和分化，进一步参与调节体液免疫[58]。
1.2.2影响胃肠道菌群的生长
驻留在人类肠道中的大量微生物形成的共生菌群与人类疾病关系密切。就胃肠道菌群与肿瘤的关系来说，除已证实某些病原微生物侵染可能直接与肿瘤发生相关外，胃肠道菌群还可直接影响抗肿瘤药物的吸收、代谢、治疗效果和毒副作用[67]。同时，肠道菌群还作为肿瘤微环境中的重要因素，直接影响胃肠道肿瘤细胞的生长和扩散。此外，肠道菌群是黏膜免疫系统的重要组成部分，产生的次生代谢物、对食物的利用分解等可能影响肠道黏膜炎症等疾病的发生[8]。鉴于胃肠道菌群与肿瘤的密切联系，在利用食药用真菌活性组分开发潜在抗肿瘤药物研究中，已有研究者开始关注食药用真菌对胃肠道菌群的影响。
赤芝是重要的药用真菌，已应用于多种肿瘤治疗的临床研究。赤芝子实体来源的高分子量多糖可改变肥胖发病相关的胃肠道微生物的组成[69]。来源于猴头菌的蛋白HEP3可调节胃肠道菌群的组成和次生代谢，激活T细胞的增殖和分化[70]。虽然食药用真菌对微生物组成的影响已有一定的实验证据支持，但造成微生物改变的具体分子机制，及其对肿瘤的发生和治疗的影响还有待进一步深入的研究和探索。
1.2.3抗氧化作用
食药用真菌活性成分还可通过抗氧化作用来发挥其抗肿瘤活性。生物氧化为生物体提供能量[71]。超氧化物歧化酶（superoxide dismutase，SOD）和过氧化氢酶（catalase，CAT）相互作用，快速地消除生物氧化反应中产生的自由基，到达氧化抗氧化的平衡[17]。然而，炎症发生、药物毒理作用、辐射、化学物质等有害刺激可能降低SOD及CAT的活力、打破生物体氧化抗氧化平衡，生物体进入氧化应激（oxidative stress，OS）状态[72]。在氧化应激状态下，体内将产生大量活跃且不稳定自由基。自由基清除不及时，将损害DNA结构，引起基因突变，从而可能导致肿瘤发生[73-75]。
据报道，黑木耳多糖可提高S180荷瘤小鼠血液SOD和CAT活力，消除体内自由基，发挥抗肿瘤作用[73]。金针菇和黑木耳的醇提物可有效地清除DPPH自由基（1，1-dipheny-2-picrylhydrazyl），发挥抗氧化作用[76]。此外，裂盖马鞍菌（巴楚蘑菇）、刺芹侧耳菌丝体多肽、云芝子实体多糖均具有清除自由基的活性[57,74,77]。
（未完待续）
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原文发表于：食用菌学报 2020.27(3):105-114