肿瘤代谢与肿瘤转移

王祥宇　郑　燕,3　鲁　明 (综述)　钦伦秀,3△ (审校)

(1复旦大学附属华山医院普外科　上海　200040; 2复旦大学肿瘤转移研究所　上海　200040;3复旦大学生物医学研究院　上海　200032)



肿瘤代谢与肿瘤转移

王祥宇1,2郑燕1,2,3鲁明1,2(综述)钦伦秀1,2,3△(审校)

(1复旦大学附属华山医院普外科上海200040;2复旦大学肿瘤转移研究所上海200040;3复旦大学生物医学研究院上海200032)

【摘要】在肿瘤的发生、发展过程中,肿瘤细胞的代谢会改变为特定的谱式以适应肿瘤的快速生长。近年来的研究表明,肿瘤的代谢与肿瘤的转移也存在密切联系。本文主要从肿瘤细胞代谢及肿瘤微环境中的代谢两方面综述肿瘤代谢在肿瘤转移中的作用及机制的研究进展。

【关键词】糖类;氨基酸;胆固醇;脂肪酸;肿瘤微环境;肿瘤转移

*This work was supported by the National Natural Science Foundation of China,Program of International Cooperation and Exchanges (81120108016).

近年来,肿瘤代谢领域的研究受到了越来越多的关注。异常的代谢变化是恶性肿瘤的重要特征,在肿瘤的发生、发展过程中发挥非常重要的作用,肿瘤代谢的研究可为肿瘤的诊疗提供新的指标和干预靶点。转移是恶性肿瘤另一重要的生物学表型,是影响恶性肿瘤预后的首要因素[1]。现在认为,肿瘤转移是一个多因素参与、多阶段发展的动态过程,涉及肿瘤细胞本身、肿瘤与微环境之间相互作用等多方面因素[2]。

有关肿瘤的代谢已有许多相关综述,其中大部份侧重于描述肿瘤的代谢异常及其与肿瘤发生的密切联系[3-5],而对于代谢酶及代谢途径在肿瘤转移的作用及其机制的综述还很少。近年来已有许多研究报道显示,肿瘤本身以及微环境的代谢异常与肿瘤转移存在密切的联系。基于目前的研究现状,本文将主要从肿瘤细胞的关键物质代谢及微环境的异常代谢等方面对肿瘤代谢在肿瘤转移中的作用及其机制的研究进展作一综述。

糖代谢与肿瘤转移葡萄糖是生物体进行糖类代谢的主要原料。与正常组织相比,即使在有氧条件下,肿瘤组织仍然主要以糖酵解方式进行葡萄糖代谢,产生大量乳酸,德国生化学家Otto Warburg发现的这种现象即“Warburg效应”,也称有氧糖酵解[6-7]。该研究还发现,高度恶性或者转移性的肿瘤细胞比低度恶性的肿瘤细胞的糖酵解能力更强,提示了肿瘤异常代谢与其侵袭转移特性可能存在潜在的联系[7]。近年来,人们利用同位素示踪技术证实了“Warburg效应”在肿瘤中普遍存在[8-9],并逐渐揭示了其调控机制。肿瘤特殊的微环境刺激以及癌基因和抑癌基因异常调控,是“Warburg效应”产生的根本原因[5,10-11]。近年来的研究显示,异常的葡萄糖代谢在肿瘤转移过程中也发挥了重要作用。

葡萄糖摄取与肿瘤转移在正常细胞中,葡萄糖是进行能量代谢最主要的原料,而肿瘤细胞摄取大量的葡萄糖进行糖酵解,其中间代谢产物可以通过磷酸戊糖、氨基酸及脂质合成等途径,进行旺盛的生物合成代谢,为肿瘤快速生长提供蛋白质、脂肪及核酸[8]。临床上以此为原理发明的PET-CT,可以利用葡萄糖类似物18-氟脱氧葡萄糖 (2-18F-fluoro-2-deoxy-D-glucose,18FFDG)等为标志物,通过检测转移灶摄取的FDG来诊断肿瘤的远处转移和治疗效果[12-14]。近年来研究发现,在微环境刺激以及癌基因和抑癌基因异常调控下,肿瘤细胞通过异常表达一型葡萄糖转运蛋白 (glucose transporter 1,GLUT1)和二型己糖激酶 (hexokinase 2,HK2)大量摄取葡萄糖[15-20]。而且GLUT1和HK2的异常表达与多种肿瘤的转移呈正相关[21-22],而通过干扰GLUT1和HK2的表达或抑制其活性,可显著降低葡萄糖的摄取而减弱糖酵解作用,进而抑制肿瘤的生长及侵袭转移能力[23-26]。

丙酮酸代谢与肿瘤转移在糖酵解过程中,中间产物磷酸烯醇式丙酮酸 (phosphoenolpyruvate,PEP)在丙酮酸激酶催化下产生丙酮酸 (pyruvate)是非常关键的环节。Christofk等[27]发现,正常组织中主要表达M1型丙酮酸激酶 (pyruvate kinase,muscle 1,PKM1),而肿瘤组织异常表达M2型丙酮酸激酶 (pyruvate kinase,muscle 2,PKM2)。后续研究发现,c-Myc基因所介导的选择性剪切是肿瘤特异性表达PKM2的主要原因[28]。PKM2在肿瘤中主要以二聚体形式存在,一方面,可促进糖酵解中间产物进行生物合成代谢,另一方面,二聚体形式的PKM2以磷酸激酶活性的形式参与信号转导[29-30],通过转运进入细胞核与β-catenin、缺氧诱导因子 (hypoxia-inducible factor,HIF)等转录因子共同参与基因的转录调控[31-32]。PKM2的异常表达与多种肿瘤的转移呈正相关[33-35],而干扰PKM2的表达,可显著抑制肿瘤的生长及侵袭转移能力[36]。

乳酸代谢与肿瘤转移丙酮酸激酶催化产生的丙酮酸主要通过A型乳酸脱氢酶 (lactate dehydrogenase A,LDH-A)催化生成终产物乳酸 (lactate),乳酸脱氢酶的表达与肝癌、结直肠癌、前列腺癌、多发性骨髓瘤、肾癌和胰腺癌的侵袭转移密切相关[37-40]。研究表明,LDH-A在肿瘤中的异常激活与癌基因c-Myc以及LDH-A的异常乙酰化修饰密切相关[41-42],而下调LDH-A的表达可以显著逆转肿瘤的“Warburg效应”,并且抑制肿瘤的侵袭转移能力[43-45]。乳酸作为LDH-A的催化产物,可能介导了肿瘤侵袭转移的调控。临床研究发现,肿瘤组织中的乳酸含量也与其转移正相关[46-47],实验研究也证实了乳酸可以促进乳腺癌的侵袭转移潜能[48]。一方面,乳酸可能参与了肿瘤干细胞特性的维持[49],另一方面,最新研究显示乳酸可能参与肿瘤细胞与微环境的相互作用,肿瘤细胞分泌的乳酸可促进微环境中的巨噬细胞向M2型转化,进而促进肿瘤的侵袭转移[50];而微环境中的乳酸也可以通过激活HIF,引起某些类型肿瘤的发生与转移[51]。

氨基酸代谢与肿瘤转移除糖类外,氨基酸类营养物质也是细胞进行合成代谢的重要原料。近年来研究发现,谷氨酰胺、丝氨酸及天冬氨酸等氨基酸的异常代谢对肿瘤的生长及侵袭转移有重要的意义[52-53]。下面主要探讨谷氨酰胺的分解代谢在肿瘤转移中的作用机制。

Roberts等[54-55]很早就发现部分肿瘤中存在异常活跃的谷氨酰胺代谢,这些肿瘤细胞不一定依赖葡萄糖的摄取,却表现出谷氨酰胺依赖性生长,这种现象称为“谷氨酰胺成瘾”[56-57]。谷氨酰胺主要在线粒体内生成α-酮戊二酸 (α-ketoglutarate,α-KG),通过三羧酸循环途径为氧化磷酸化以及脂质合成提供原料。研究表明,在癌基因c-Myc的调控下[58],谷氨酰胺代谢的关键酶谷氨酰胺酶 (glutaminase,GLS)和一型谷氨酸脱氢酶 (glutamate dehydrogenase 1,GDH1)在多种肿瘤中高表达,并且与肿瘤的分级及预后密切相关,而通过降低GLS或GDH1的表达,可以通过抑制脂质合成或者引起细胞内氧化还原压力,引起肿瘤细胞的凋亡[59-61]。最新的研究显示,在肿瘤进展过程中,周围环境变化引起的氧化压力是抑制肿瘤细胞远处转移的重要因素[62-64],而谷氨酰胺代谢的中间产物延胡索酸 (fumarate)可以通过激活谷胱甘肽过氧化物酶 (glutathione peroxidase,GPx),来降低肿瘤细胞内部的活性氧化物 (reactive oxygen species,ROS)水平,维持氧化还原平衡[60],进而可能促进了肿瘤的转移。关于谷氨酰胺代谢在肿瘤侵袭转移中的作用及其具体机制,还有待进一步研究。

脂质代谢与肿瘤转移除了糖类和氨基酸代谢的变化外,脂质代谢的改变也是肿瘤代谢的一个重要特征。脂质是一类不溶于水的分子,主要包括三酰甘油、磷脂、鞘脂和固醇等。脂质代谢中还有一种重要的代谢物脂肪酸,脂肪酸是一类由一个末端羧基和一条烃链构成的分子,是包括三酰甘油、磷脂和胆固醇脂在内的脂质分子的重要组分。脂质分子是生物膜的重要结构组分,同时它们在信号转导和激素合成过程中也发挥重要作用[65]。下面着重综述胆固醇代谢和脂肪酸代谢在肿瘤转移中的作用及机制。

胆固醇代谢与肿瘤转移胆固醇 (cholesterol)是细胞膜尤其是细胞质膜的关键成分[66],并且是甾醇类激素、胆汁酸、维生素等的合成前体[67]。已有的研究显示,胆固醇代谢与肿瘤转移存在密切联系。一方面,血浆胆固醇水平与多种肿瘤的发生和发展密切相关[68-69],Alikhani等[70]在乳腺癌动物模型中证实,血浆胆固醇水平异常可促进乳腺癌的转移。另一方面,利用他汀类药物抑制胆固醇合成,可抑制多种肿瘤的侵袭转移[71-74]。

胆固醇代谢影响肿瘤侵袭转移的具体分子机制目前尚不明确。已有的研究工作提示可能有以下几种机制: (1)脂筏 (lipid raft)是细胞质膜上富含胆固醇和鞘脂 (sphingolipid)的微结构域,在细胞信号转导和细胞质膜蛋白质分选等生物学过程中发挥重要作用[75]。作为脂筏的关键组分,胆固醇水平变化可影响脂筏的结构和功能[76]。最近的研究显示,脂筏与多种肿瘤侵袭转移相关的信号转导过程密切相关:骨桥蛋白 (osteopontin,OPN)是重要的促肿瘤转移分子,OPN通过其受体蛋白整合素 (integrin)和CD44激活MAPK、PI3K/AKT以及NF-等信号通路,上调尿激酶型纤维蛋白溶酶原激活物 (urinary plasminogen activator,uPA)、基质金属蛋白酶-2 (matrix metallopeptidase 2,MMP-2)和基质金属蛋白酶-9 (matrix metallopeptidase 9,MMP-9)等基因的表达,促进肿瘤侵袭转移[77]。而Integrin和CD44都定位于脂筏中,其下游信号通路的激活依赖于脂筏[78-79]。Murai等[80]研究发现,降低细胞质膜胆固醇水平破坏脂筏结构,可促进CD44蛋白从细胞质膜上脱落,进而抑制肿瘤细胞的迁移。此外,脂筏在EGFR信号通路的激活过程中也发挥重要作用,而EGFR通路是肿瘤侵袭转移中重要的信号通路[81]。已有的研究显示,EGFR的脂筏定位可促进其配体依赖的磷酸化以及下游AKT的磷酸化[82]。而Irwin等[83]在乳腺癌中研究发现,当EGFR定位于脂筏时,乳腺癌细胞株对EGFR酪氨酸激酶抑制剂表现出耐药性;而利用甲基-β-环糊精或他汀类药物降低胆固醇破坏脂筏,可降低这种抵抗效应。 (2)胆固醇合成代谢的旁路代谢途径中存在两种重要代谢产物焦磷酸法尼酯 (farnesyl pyrophosphate,FPP)和焦磷酸牛儿基牛儿酯 (geranylgeranyl pyrophosphate,GGPP),这两种代谢产物参与了Ras和Rho蛋白的异戊烯化,而异戊烯化修饰是Ras和Rho蛋白与细胞膜结合和激活所必需的[74]。在神经胶质瘤中的研究显示,抑制胆固醇合成会引起FPP和GGPP这两种代谢产物水平的下降,进而抑制Ras-Raf-MEK-ERK信号途径,最终导致神经胶质瘤细胞生长迁移和侵袭能力的下降[84]。 (3)最新研究表明,在乳腺癌中,胆固醇代谢异常引起其代谢产物27-羟胆固醇 (27-HC)的累积,累积的27-HC通过激活雌激素受体 (estrogen receptor,ER)和肝X受体 (liver X receptor,LXR)促进乳腺癌的生长和侵袭转移[85-86]。

脂肪酸代谢与肿瘤转移脂肪酸参与了肿瘤细胞的多个生物学过程: (1)脂肪酸是细胞膜重要结构分子磷脂的基本合成组分,因此,肿瘤细胞快速增殖需要大量的脂肪酸[87]; (2)某些类型的肿瘤 (如前列腺癌)主要依赖脂肪酸β-氧化作为能量的主要来源,而并不依赖于葡萄糖摄取的增加[88]; (3)脂肪酸还参与许多重要的促癌脂质信号分子包括磷酸肌醇、溶血磷脂酸和前列腺素的合成[89]。已有的研究显示,在多种肿瘤中观察到脂肪酸代谢途径中的关键基因ATP-柠檬酸裂解酶 (ATP citrate lyase,ACLY)、乙酰辅酶A羧化酶 (Acetyl-CoA carboxylase,ACC)、脂肪酸合成酶 (Fatty acid synthase,FASN)和酰基-辅酶A去饱和酶 (stearoyl-coenzyme A desaturase,SCD)的表达和活性的提高,并且与不良预后密切相关[90-92],通过下调这些代谢酶的表达或利用特异性抑制剂抑制代谢酶活性可抑制肿瘤的生长[93-95]。

近年来的研究表明,脂肪酸代谢在肿瘤转移过程中也发挥重要作用。Budhu等[96]利用配对的肝癌组织和癌旁组织进行代谢组学研究和差异表达基因的筛选,鉴定出与肝癌进展相关的28种代谢物和169个差异表达基因,进一步研究发现,在这些代谢产物和基因中,SCD代谢途径相关代谢物和基因与肝癌进展表现出显著的相关性,进一步研究显示干扰SCD的表达可抑制肝癌细胞的迁移和侵袭能力。Li等[97]的研究显示,在多种肿瘤中高表达的跨膜糖蛋白CD147,也是肿瘤细胞脂肪酸代谢的重要调控因子,其调控的脂肪酸代谢在肿瘤侵袭转移过程中发挥了重要作用。这些研究表明,脂肪酸代谢也在肿瘤细胞迁移和侵袭的过程发挥重要作用,然而其影响肿瘤转移的具体分子机制还需要更深入的研究。

肿瘤微环境异常代谢与肿瘤转移近年来,肿瘤微环境对肿瘤转移的调控作用引起越来越多的关注[98]。肿瘤的快速增殖和异常的血管生成,使肿瘤细胞处于氧和营养物质缺乏的代谢环境,进一步改变了肿瘤细胞的代谢方式。一方面,缺氧的外界信号可以通过激活HIF,使肿瘤细胞的糖酵解能力进一步加强[99];另一方面,恶劣的微环境可以直接刺激肿瘤细胞表达热休克蛋白90 (heat shock protein 90,HSP90),重塑细胞骨架,增强细胞的运动迁移能力,从而促进细胞侵袭转移[100]。

在肿瘤转移过程中,肿瘤细胞可以通过直接摄取转移微环境中的次级代谢产物来实现快速的能量供应,并实现在转移灶的定植。Loo等[101]发现,转移性的结直肠癌细胞可以直接分泌B型肌酸激酶 (creatine kinase,brain,CKB)进入肝脏微环境,将微环境中的肌酸磷酸化为磷酸肌酸,肿瘤细胞又可以通过摄取磷酸肌酸来快速产生ATP,进而增强其侵袭转移的能力。

微环境中的间质细胞同样可以通过异常代谢促进肿瘤的侵袭转移。一方面,肿瘤相关成纤维细胞 (cancer-associated-fibroblast,CAF)可以通过快速的脂肪分解及葡萄糖酵解产生酮体及乳酸等物质,并将其分泌到微环境中,而肿瘤细胞可以大量摄取这类营养物质[102-103]。同样,微环境中的脂肪细胞也可直接将脂质等物质传递给肿瘤细胞[104]。这些物质都可以为肿瘤细胞快速提供能量,并促进癌细胞的增殖及侵袭转移能力。除此之外,最新研究发现,肿瘤细胞通过外泌小体携带的miR-122抑制转移灶间质细胞 (主要是成纤维细胞)的葡萄糖摄取能力,间接地改造转移灶微环境的代谢状态来促进其在转移灶中的生存以及定植能力[105]。

另一方面,微环境中的免疫细胞的代谢异常则介导了肿瘤的免疫逃逸。树突状细胞是机体内重要的抗原呈递细胞,其在抗肿瘤免疫中扮演了重要角色,Herber等[106]发现,肿瘤微环境中的树突状细胞存在大量脂肪的累积,减弱了其抗原呈递的能力,进而使其抗肿瘤免疫的作用受到抑制,通过清除树突状细胞内累积的脂肪可以明显增强其对肿瘤的免疫反应。而正常的葡萄糖代谢也是效应T细胞发挥功能的前提条件[107],最新研究发现,肿瘤细胞通过竞争性摄取葡萄糖,限制了T淋巴细胞对葡萄糖的吸收,使其肿瘤杀伤作用受到抑制,引起了肿瘤的免疫逃逸,进而促进了肿瘤的侵袭转移[108-109]。

综上所述,从“Warburg效应”的提出开始,肿瘤代谢领域的研究已历经多年的发展。近十年来,随着代谢组学以及肿瘤基因组学的发展,人们对代谢调控在肿瘤发生发展过程中的作用机制正逐步加深了解。现在观点认为,外部环境的刺激以及癌基因和抑癌基因的异常调控,是肿瘤细胞采取异常的物质及能量代谢方式的根本原因,这一方面满足了肿瘤快速生长的需求,另一方面对于肿瘤的侵袭转移也有深远的影响。此外,肿瘤微环境中间质细胞及免疫细胞的代谢改变,也参与了肿瘤转移的调控过程。所有这些发现,都为肿瘤代谢以及肿瘤转移研究提供了新的研究方向。此外,由于肿瘤代谢与正常代谢的显著差异,肿瘤细胞及其微环境特异性的异常代谢途径有望成为抗肿瘤转移的新靶点,通过筛选针对这些代谢途径中的代谢酶的抑制剂或小分子化合物,可能为抗肿瘤转移的治疗带来根本性的变革。

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Cancer metabolism and metastasis

WANG Xiang-yu1,2,ZHENG Yan1,2,3,LU Ming1,2,QIN Lun-xiu1,2,3△

(1DepartmentofGeneralSurgery,HuashanHospital,FudanUniversity,Shanghai200040,China;2CancerMetastasisInstitute,FudanUniversity,Shanghai200040,China;3InstituteofBiomedicalSciences,FudanUniversity,Shanghai200032,China)

【Abstract】Metastasis and metabolic deregulation are two of the major essential hallmarks of cancer.In the initiation and development of cancer,tumor cells are known to undergo metabolic alterations to sustain faster proliferation.Recent studies indicated that metabolic changes of tumors are also closely related to tumor metastasis.In this review,we summarize the research progress about the roles and related mechanism of tumor metabolism in tumor metastasis from the aspects of both the tumor cell and microenvironment.

【Key words】carbohydrate;amino acid;cholesterol;fatty acid;tumor microenvironment;cancer metastasis

【中图分类号】R730

【文献标识码】B

doi:10.3969/j.issn.1672-8467.2016.01.016

(收稿日期:2015-11-06;编辑:张秀峰)

国家自然科学基金国际(地区)合作与交流项目(8112108016)

△Corresponding authorE-mail:qinlx@fudan.edu.cn