修回日期: 2015-07-17
接受日期: 2015-08-10
在线出版日期: 2015-10-28
肿瘤微环境调控侵袭转移的研究以往多聚焦基质细胞、免疫细胞、细胞因子、趋化因子等生化因素, 而对肿瘤物理微环境, 尤其是基质蛋白大量沉积及交联导致的基质硬度/弹性力学特征, 在肿瘤侵袭转移中的作用却长期被忽视. 近年来, 随着模拟基质硬度的系列细胞培养平台建立, 基质硬度物理力学因素影响、调控肿瘤侵袭转移分子机制的相关研究取得了明显进展. 本文拟从基质硬度影响肿瘤上皮间质转化(epithelial-mesenchymal transition)发生、迁移运动、整合素、侵袭转移基因、干性特征等几个方面进行综述, 以期说明基质硬度力学物理信号在参与肿瘤侵袭转移调控中, 是一个不容忽视的重要因素.
核心提示: 本文从细胞外物理力学因素-基质硬度角度出发, 对影响肿瘤侵袭转移的系列证据及相关机制进行深入探讨, 为未来针对肿瘤物理微环境-基质硬度进行干预开辟新思路.
引文著录: 郑琼丹, 游洋, 崔杰峰. 胞外基质硬度: 肿瘤侵袭转移不可忽视的因素. 世界华人消化杂志 2015; 23(30): 4778-4784
Revised: July 17, 2015
Accepted: August 10, 2015
Published online: October 28, 2015
It has been well documented that biochemical factors of tumor microenvironment like stromal cells, immune cells, cytokines, and chemokines contribute to the regulation of tumor invasion and metastasis. However, the roles of physical factors, especially matrix rigidity or elasticity resulting from abundant matrix protein deposition and cross-linking, remain largely unexplored. Lately, with the establishment of a series of cell culturing platforms mirroring matrix stiffness, a giant leap has been witnessed in the research into mechanisms of matrix stiffness-mediated effects on tumor invasion and metastasis. This article reviews the impact of matrix stiffness on epithelial-mesenchymal transition (EMT), motility, integrin, invasion and metastasis genes, and stemness in tumors, to illustrate that matrix stiffness is also an important factor in the regulation of tumor invasion and metastasis.
- Citation: Zheng QD, You Y, Cui JF. Extracellular matrix stiffness: An important regulatory factor in tumor invasion and metastasis. Shijie Huaren Xiaohua Zazhi 2015; 23(30): 4778-4784
- URL: https://www.wjgnet.com/1009-3079/full/v23/i30/4778.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i30.4778
以往肿瘤侵袭转移研究多聚焦肿瘤细胞自身恶性生物学特征的改变, 包括肿瘤细胞增殖、凋亡、黏附、侵袭、转移、运动、细胞骨架等[1-6]. 近些年, 针对肿瘤微环境中基质细胞、免疫细胞、细胞因子、趋化因子、基质蛋白等组分参与肿瘤侵袭转移调控的相关研究逐渐成为热点[7-15], 其中, 对肿瘤微环境非细胞固态高丰度组分-基质蛋白生物学作用的认识也不断更新. 目前, 基质蛋白的生物学作用已不仅仅局限于支撑、维持肿瘤细胞组织三维形态结构, 以及贮存被分泌的细胞因子等, 其表达、类型的差异同样对肿瘤侵袭转移病理过程存在重要影响[16,17], 基质蛋白, 如层黏连蛋白(Laminin)、纤维黏连蛋白(Fibronectin)和Ⅰ型胶原(CollagenⅠ)被发现可诱导增强卵巢癌细胞趋化性迁移, 而在细胞侵袭实验中, 仅Laminin和CollagenⅠ被观察到诱导卵巢癌细胞侵袭能力的增强, 用针对整合素亚型α3、α6和β1抗体干预, 可抑制基质蛋白对卵巢癌细胞迁移、侵袭的调控[18]. Laminin-5在肝癌组织中高表达, 且与肝癌转移表型关联, 同时其和转化生长因子β1(transforming growth factor-β1, TGF-β1)协同促进肝癌上皮间质转化(epithelial-mesenchymal transition, EMT)发生[19,20]. Laminin-5可影响、调控整合素α3β1和α6β4介导的肝癌细胞黏附、增殖、迁移和侵袭[15]. 除上述基质蛋白类型、表达差异等生化信号在肿瘤细胞恶性生物特征调控中发挥作用外, 由基质蛋白大量沉积及交联导致基质力学特征-硬度/弹性物理信号的变化, 对肿瘤侵袭转移调控的研究近来也引起重视[21-25]. 实际上, 临床很早就注意到, 基质硬度增加与肝癌、乳腺癌等实体肿瘤的发生发展及预后密切关联, 如伴肝硬化背景的肝癌患者中位生存期下降[26], 肝癌患者肝纤维化程度越重, 肝内转移率越高[27], 慢性丙型肝炎患者的肝脏硬度增加为肝癌发生独立危险因素[28], 肝基质硬度改变可用于预测肝癌进展、预后[29,30]. 超30%乳腺癌患者有较高乳腺组织密度[31], 高乳腺组织密度妇女患乳腺癌几率明显增高, 乳腺组织密度是乳腺癌危险性独立预测指标[32,33], 但由于组织基质硬度体外实验模拟的困难, 致使基质硬度参与肿瘤侵袭转移调控研究一直滞后. 随着体外二维、三维不同基质硬度细胞培养体系建立及优化, 基质硬度调控肿瘤细胞恶性特征作用的机制研究开始步入加速期. 本文从基质硬度参与肿瘤侵袭转移的调控的几个方面包括EMT发生、迁移运动、整合素、侵袭转移关联基因表达、干性特征等进行综述, 以期说明基质硬度力学信号在参与肿瘤侵袭转移调控中, 同样是一个不容忽视的重要因素.
EMT发生是癌细胞浸润转移的早期分子病理事件, EMT发生可增强癌细胞侵袭转移能力[34]. 发生EMT的肿瘤上皮细胞去分化, 失去原有上皮细胞形态及排列极性, 失去细胞间紧密结合, 细胞骨架重塑, 转变为梭形间质化外观, 易从原发瘤脱落, 流动性及侵袭性增强, 主要分子特征表现为[35]: (1)上皮标记蛋白表达下调: E-钙黏蛋白(E-cadherin)、角蛋白(Keratin)、紧密连接蛋白(Occludin)、桥粒蛋白(Desmoplakin)、ZO-1等; (2)间质化蛋白表达上调: N-钙黏蛋白(N-cadherin)、波形蛋白(Vimentin)、α-SMA、纤连蛋白(Fibronectin)、玻连蛋白(Vitronectin)等; (3)EMT转录因子表达活性增强或核转位发生, 包括ZEB1/ZEB2、Twist、Snail、Slug、Smad2/3、β-连环蛋白(β-catenin). 以往细胞EMT发生一般由微环境中可溶性因子信号诱导调控, 近来研究[36-40]显示基质硬度力学信号在疾病进展EMT的调控中同样发挥作用. Lee等[36]发现乳腺生理性组织硬度(软基底硬度)可阻止MMP3诱导EMT发生, 保护上皮细胞样特征, 而模拟乳腺癌组织硬度的硬基底硬度则促进MMP3诱导EMT发生, 胞外硬度信号主要通过控制Rac1b胞膜定位, 与膜上NADPH氧化酶形成复合体促进活性氧产生, 上调Snail表达进而导致EMT发生. 基质硬度增加可促进可溶因子诱导细胞EMT发生进而加速纤维化及肿瘤进展等病理过程. TGF-β在肿瘤发生早期阶段, 具有抑增殖促凋亡作用, 但随着肿瘤进展, TGF-β则呈现促肿瘤作用如EMT发生和细胞运动等. Leight等[37]研究发现基质硬度改变可控制、调节TGF-β1诱导细胞凋亡与细胞EMT之间的转变. 硬度降低增强TGF-β1诱导细胞凋亡, 硬度增加则促进细胞EMT发生, 且硬度信号通过激活PI3K/AKT实现, 而经典的Smad信号通路则未见明显改变. 肌成纤维细胞可由上皮细胞EMT改变而形成, 表现为拉伸形态和骨架蛋白上调, 对周围产生更大收缩力、重塑微环境, 他参与纤维化及肿瘤进展病理过程. 在TGF-β1诱导情况下, 生长于高基质硬度表面的上皮细胞, 较低基质硬度表面生长的上皮细胞, 显示出更多肌成纤维细胞标志, 细胞形态变化和骨架蛋白重塑, 提示硬度可协同促进TGF-β1诱导EMT发生[38]. Schrader等[39]研究发现, 软基底硬度(1 kPa)表面生长的肝癌细胞呈现分化的肝细胞特征, 而硬基底硬度表面(12 kPa)的肝癌细胞呈现不完全间质细胞样改变, 且高硬度信号对TGF-β诱导Smad信号通路的激活远强于软基底表面生长的肝癌细胞. 除了上述基质硬度协同可溶因子诱导细胞EMT发生外, 最近研究显示, 单纯基质硬度因素也可影响肿瘤EMT发生, Wei等[40]在乳腺癌中, 发现高硬度信号刺激, 可使EMT重要转录调节因子TWIST1从其胞浆结合分子G3BP2释放并核转位, 诱导EMT发生促进肿瘤侵袭转移. 上述这些结果, 有力地说明力学基质硬度参与肿瘤细胞EMT分子调节的复杂, 以及物理力学因素在肿瘤侵袭转移调控中的重要性.
基质硬度是影响调节细胞运动迁移的一个重要因素. 一般多数细胞都能够感知基质硬度传递的物理信号, 出现肌动蛋白丝的收缩反应, 而肌动蛋白丝产生的机械力可导致整合素调节的细胞黏附构象发生改变, 进而促进细胞游走和迁移. 细胞在胞外基质环境中往往产生改变基质机械力的倾向, 硬基质由于可塑性低于软基质故需更大的机械力, 因此细胞肌动蛋白产生张力更大, 导致细胞收缩更强, 细胞运动更快. 肌动蛋白是细胞运动迁移的主要承担者, 在细胞边缘聚合形成伪足. 有观点[41,42]认为伪足是独立的具有自我组装能力的个体, 并非细胞固定的组成部分, 在细胞运动或癌细胞侵袭转移中频繁形成, 虽细胞运动伪足形态改变甚少, 但肌动蛋白更新非常旺盛, 提示伪足生成时相当活跃的自我催化生成能力.
伪足伸出在硬度促癌细胞侵袭转移的过程中扮演重要的角色. Ulrich等[42]发现两株胶质瘤细胞U373-MG和U87-MG, 平均迁移速度随基质硬度的升高而增加, 细胞运动的模式也随之发生改变. 当细胞生长于软基质表面时, 其运动呈现出"黏附滑移"模式, 即细胞伸展出细长的丝状伪足, 通过其末端黏附周围环境及伪足的收缩和放松以拖动胞体移动; 而在硬基质表面时, 细胞伸展出宽大的板状伪足, 其肌动蛋白的组装更为活跃, 细胞运动也更为流畅, 说明硬度诱导伪足类型改变是癌细胞侵袭转移的一个重要因素. Alexander等[43]发现, 胞外基质硬度可同时上调乳腺癌细胞侵袭性伪足的数量和活性, 这种效应依赖于细胞收缩机制, 若抑制肌球蛋白Ⅱ, 肌球蛋白轻链激酶和Rho激酶则抑制侵袭性伪足相关的胞外基质降解. 侵袭性伪足中信号蛋白Cas和FAK的磷酸化活跃, 过表达Cas或FAK可增加硬基质表面生长细胞侵袭性伪足的活性, 说明基质硬度可通过Cas/FAK信号通路调控侵袭性伪足的活性.
整合素家族是细胞表面重要的跨膜异二聚体蛋白, 是将胞外基质成分、表达、重塑、硬度等信息改变转化为胞内信号的"桥梁", 迄今已发现, 整合素家族有18种α亚单位和8种β亚单位, 根据不同组合至少构成23种整合素, 其中15种为基质蛋白受体, β1亚单位可与9个α亚单位组成二聚体与ECM不同基质成分结合. 整合素对胞外基质信号的转导实际是双向模式[44], 外向信号传递根据细胞本身功能状态的改变, 将胞内信号事件由胞内区传到胞外, 调节整合素与配体的结合、整合素的聚集及后续形成的黏着斑-细胞骨架蛋白与信号分子复合物, 影响整合素与基质的亲和力及胞外基质的变化. 内向信号传递则是基质蛋白配体与整合素受体结合导致其构象转变, 而激活下游不同信号通路. 黏着斑是整合素聚集部位, 连接着细胞骨架与胞外基质, 为胞外基质提供附着点, 传递细胞与微环境间的生化及力学信号, 是肿瘤细胞增殖、生存和转移信号通路的胞内发出点[45,46]. Bae等[47]发现FAK-Cas-Rac-lamellipodin信号通路参与了胞外机械力学信号传导, 认为胞外基质硬度信号可通过整合素与黏着斑及肌动蛋白骨架的关联, 转变为胞内生化信号. Levental等[24]发现, 胶原交联导致胞外基质硬度增加上调黏着斑表达, 增加PI3K活性及促进癌细胞的侵袭. 抑制整合素信号转导使黏着斑下调, PI3K活性降低, 癌细胞在高硬度基质表面的侵袭能力明显减弱, 而促使胞膜整合素信号放大则引起相反的结果, 即黏着斑上调, PI3K活性升高及癌细胞在高硬度基质表面的侵袭能力增加. Paszek等[48]认为通过整合素聚集以激活ERK及增加ROCK控制的细胞收缩和黏着斑表达, 是基质调控细胞骨架张力的一个途径. Provenzano等[33]发现基质中胶原密度增加导致基质硬度增加, 可独立诱导尚未转化乳腺上皮细胞表达恶性表型, 其机制与胞外力学信号通过整合素上调FAK, 进而激活Rho/ROCK通路并增强胞内收缩力, 产生促进细胞恶性表型有关. 尽管整合素下游信号通路各异影响细胞的不同生物学行为, 但整合素作为硬度信号胞内传递的桥梁作用却被不断证实, 为针对硬度进行干预提供了较好靶点.
基质硬度增加除影响肿瘤细胞表型特征改变, 对一些侵袭转移关联基因表达水平也存在调控, 如前期我们发现, 基质硬度增加可通过激活Integrinβ1-PI3K/AKT而上调肝癌细胞VEGF表达[49]. Mouw等[21]发现基质硬度可通过integrin激活β-catenin和MYC上调miR-18a表达, 而减少靶基因PTEN表达, 进而促进乳腺癌恶性进展. Tang[50]等发现软基质硬度可使结肠癌细胞HCT-8呈现侵袭样基因表达谱, 包括ALDH3A1、TNS4、CLDN2基因表达上调. 但以培养细胞所用的胶低于常规聚苯乙烯基底硬度而将其称为软基质存在争议, 因为20 kPa的胶硬度已远超出正常结肠组织硬度，故所获结果实际上是高硬度诱导出的侵袭样基因表达谱. 上述结果也进一步提示, 基质硬度在肿瘤侵袭转移病理过程中发挥调控作用.
与肿瘤细胞迁移、侵袭等恶性特征一样, 肿瘤细胞干性特征的诱导、维持, 对原发肿瘤癌细胞恶性状态维持及进一步转移发生至关重要. 一般肿瘤细胞干性特征主要表现为干性标志物表达[51], 干性相关转录因子表达[52], 化疗耐药[53], 自我更新能力增强[54]等. 目前, 以基质硬度力学物理信号作为始动因素对肿瘤干性特征诱导的研究仅有零星报道. Schrader等[39]研究发现, 生长于低基底硬度(1 kPa)表面的肝癌细胞干性标志物(CD44、CD133、c-kit、CXCR-4、Oct-4、NANOG)表达明显高于生长于高基底硬度表面(12 kPa)的肝癌细胞, 但cisplatin处理后, 生长于高基底硬度胶表面的肝癌细胞较软基底硬度胶表面的肝癌细胞凋亡比率减少, 显示对cisplatin耐受, 该结果不支持高基质硬度胶肝癌细胞呈现低干性标志表达. Tan等[22]对未分化黑色素瘤TRCs细胞自我更新能力维持进行研究, 发现三维纤维蛋白软基质硬度培养可促进TRCs细胞中H3K9去甲基化及SOX2上调表达, 进而维持肿瘤起始细胞的自我更新. 然而, 其他实体瘤基质硬度诱导干性研究中则显示出不一致的结论[55], 我们课题组最近通过对生长于不同基质硬度表面(6、10、16 kPa)肝癌细胞干性特征比较, 发现基质硬度增加可诱导肝癌细胞干性特征增强, 包括CD133+/EpCAM+肝癌细胞数量增加, 表达增加, 化疗耐药增强, 成球能力明显, 证实基质硬度增加激活integrinβ1/AKT/mTOR/SOX2信号通路诱导肝癌干性特征增强. 该研究结果与Schrader报道也不一致, 而造成上述基质硬度对肿瘤细胞干性诱导结果不一致的原因可能与硬度范围的选择有关, 即研究须以体内脏器组织生理病理状况下组织硬度范围作为体外模拟的硬度标准, 而超出组织硬度范围的体外实验设计对反映疾病的生理病理没有意义. 但是尽管硬度对肿瘤干性诱导结果不尽一致, 依然可证明基质硬度力学因素在肿瘤细胞干性特征诱导中所起的重要作用.
随着基质硬度参与实体肿瘤侵袭转移调控的系列证据逐渐增多, 以及新型硬度关联实验动物模型及理想三维硬度培养平台的不断涌现, 必将加速肿瘤基质硬度物理信号参与侵袭转移调控的实验解析及相关机制的最终阐明, 为未来针对肿瘤物理微环境-基质硬度进行干预开辟新的途径.
尽管基质硬度与肿瘤发生进展密切关联, 但由于基质硬度体外实验模拟困难, 致使硬度参与侵袭转移调控研究一直滞后. 近年来, 体外不同基底硬度细胞培养体系建立, 使得基质硬度调控肿瘤恶性特征的机制研究步入加速期.
陈洪, 教授, 主任医师, 硕士生导师, 东南大学附属中大医院消化科; 戴朝六, 教授, 中国医科大学第二临床学院(盛京医院)肝胆外科
肿瘤物理微环境, 尤其是基质蛋白大量沉积及交联导致的基质硬度/弹性力学特征, 在肿瘤侵袭转移中的作用长期被忽视. 本文通过综述基质硬度调控肿瘤侵袭转移相关研究, 证明其是一个不容忽视的重要调控因素.
随着基质硬度参与实体肿瘤侵袭转移调控系列证据的逐渐增多, 为从肿瘤物理微环境角度-基质硬度进行干预以减少、预防肿瘤侵袭转移发生提供了可能, 开辟了治疗新途径.
本文先进性、科学性较好, 属于相关领域的最新进展及研究前沿, 有较好的指导意义.
编辑:郭鹏 电编:闫晋利
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