修回日期: 2022-09-29
接受日期: 2022-10-20
在线出版日期: 2022-10-28
持续血管新生是肝癌、胰腺癌、胃肠道肿瘤等实体瘤常见恶性特征之一, 是肿瘤生长、侵袭和转移的基础, 也是临床肿瘤干预治疗的重要靶点. 肿瘤血管新生多由微环境中生化、缺氧和机械力学因素刺激启动, 其中生化信号及缺氧微环境刺激在肿瘤血管新生中的作用已被广泛报道, 而生物力学信号调控肿瘤血管新生研究近年才逐渐引起关注. 脉管系统具有天然的机械刺激敏感性, 近年研究发现生物力学刺激如基质硬度、流体剪切应力、脉管腔压力等对肿瘤血管表型及功能显示出重要的调控作用. 本文对基质硬度参与肿瘤血管新生调控的一些新进展及其内在机制进行了归纳和总结.
核心提要: 机械力学信号调控肿瘤异常血管新生近年逐渐被关注. 胞外基质硬度改变可引起肿瘤血管内皮细胞机械传感分子表达失调, 血管生成因子表达异常、失衡, 同时招募促血管形成基质细胞, 而导致异常肿瘤脉管系统的生成.
引文著录: 李苗, 赵莹莹, 崔杰峰. 基质硬度参与肿瘤血管新生调控新进展. 世界华人消化杂志 2022; 30(20): 871-878
Revised: September 29, 2022
Accepted: October 20, 2022
Published online: October 28, 2022
Angiogenesis is one of the most common malignant features of solid tumors such as liver cancer, pancreatic cancer, and gastrointestinal tumors, which is the basis of tumor growth, invasion, and metastasis. It is also an important target of anti-tumor therapy. Tumor angiogenesis is usually triggered by biochemical, hypoxic, and biomechanical factors in the microenvironment. The regulation of biochemical signals and hypoxic microenvironment in tumor angiogenesis have been widely documented, but the role of biomechanical signals in tumor angiogenesis has gradually begun to be uncovered in recent years. The vasculature system is naturally sensitive to mechanical stimuli. Recent studies have highlighted the important regulatory effects of biomechanical stimuli, such as matrix stiffness, fluid shear stress, and vascular lumen pressure, on the phenotype and functions of tumor blood vessels. In this paper, we summarize the new progress and internal mechanisms of matrix stiffness-mediated effects on tumor angiogenesis.
- Citation: Li M, Zhao YY, Cui JF. Matrix stiffness in regulation of tumor angiogenesis. Shijie Huaren Xiaohua Zazhi 2022; 30(20): 871-878
- URL: https://www.wjgnet.com/1009-3079/full/v30/i20/871.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i20.871
血管新生是从已存在的血管中形成新血管的过程, 涉及多个步骤, 包括蛋白酶降解基底膜; 内皮细胞(endothelial cells, ECs)迁移到间质出芽; 迁移尖端ECs增殖; 管腔形成, 周细胞募集产生新的基底膜, 形成吻合口, 至新血管系统形成[1]. 血管新生在多种生理和病理过程中都起着十分关键作用. 1971年Judah Folkman首先提出血管新生促实体瘤生长转移理论[2], 该理论是肿瘤抗血管治疗策略形成的基础.目前临床应用的许多肿瘤靶向药物如索拉非尼、仑伐替尼、瑞戈非尼、安罗替尼等, 均重点干预血管生成相关靶点, 包括血管内皮生长因子(vascular endothelial growth factor, VEGF)、血小板衍生生长因子受体(platelet-derived growth factor receptor, PDGFR)、成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)等; 贝伐珠单抗(人源化单克隆抗VEGF-A抗体)用于晚期肿瘤治疗, 同样基于其可显著抑制重要促血管调节因子-VEGF. 尽管抗血管治疗在肿瘤治疗领域显示出良好前景, 但在肝癌、转移性结肠癌中, 索拉非尼、仑伐替尼等靶向药物单药治疗的客观缓解率(objective response rate, ORR)仅为1%-30%[3,4], 而贝伐珠单抗治疗通常在短暂临床获益后会再次出现疾病进展[5,6]. 因此, 从新角度探索肿瘤血管新生机制对发现血管干预新靶点、提高肿瘤抗血管治疗的疗效十分重要.
恶性肿瘤细胞具有强大诱导新生血管形成的能力[7], 持续血管新生被认为是包括肝癌、结肠癌等实体肿瘤的常见恶性特征之一.肿瘤血管结构呈迂曲、扩张及高渗漏性等异常表型[8], 上述肿瘤血管特点有利于输送更多氧气、营养物质给肿瘤细胞, 以促肿瘤生长与进展, 同时富含血管的肿瘤组织中的内皮细胞也可释放生长因子及基质降解蛋白酶, 促进肿瘤细胞侵袭, 此外, 扩张的内皮表面也使肿瘤细胞更易进入循环系统以发生转移[9,10]. 肿瘤血管新生多由微环境中生化、缺氧和机械力学因素刺激启动, 生化因素刺激主要来源于癌细胞及肿瘤相关基质细胞所释放的细胞因子、生长因子、胞外基质蛋白和微泡等[11], 其中VEGF, 成纤维细胞生长因子(fibroblast growth factor, FGF), 血管生长素(angiopoietins, Ang), 血小板衍化内皮细胞生长因子(platelet-derived endothelial cell growth factor, PD-ECGF), 白介素-8(interleukin, IL-8)等, 通过诱导内皮细胞增殖、存活、异常生长和出芽促进血管生成[9], 是调节肿瘤血管新生最重要的途径. 缺氧则主要通过缺氧诱导因子-1(hypoxia inducible factor-1, HIF-1)刺激血管生成因子表达促进肿瘤血管新生[12]. 力学因素刺激对肿瘤血管新生的影响近年才逐渐引起关注, 机械力学因素刺激主要源于流体剪切应力、脉管腔压力及基质硬度等. 除了血液流动导致的剪切及压力外, 血管亦处不同机械性能支撑结构的包围, 包括支持性壁细胞(周细胞和平滑肌细胞)和细胞外基质(基底膜和间质基质)[13]. 同时, 实体瘤随疾病进展常伴基质(extracellular matrix, ECM)重塑及基质硬度增加[14], 而组织硬度力学信号增加可明显改变细胞行为, 包括增殖、迁移和细胞-细胞粘附, 这些生物学行为也是血管生成的必要条件[15]. 此外, 基质硬度力学信号的增加还可调节血管内皮细胞的功能, 在肿瘤进展和促肿瘤脉管系统异常中发挥作用. 最近研究也显示, 基质硬度增加可导致肿瘤对抗血管药物的耐药性, 如基质硬度增加导致肝细胞癌对索拉非尼敏感性降低[16], 而结直肠癌肝转移中, 肝转移瘤组织硬度增加会增强其对贝伐珠单抗治疗的耐药性[17]. 可见基质硬度参与肿瘤血管生成调控. 本文围绕基质硬度参与肿瘤血管新生调控研究的一些新进展进行归纳和总结.
受持续促血管信号的刺激, 肿瘤血管新生不断被激活, 新生血管呈现过度分支、异常凸起和盲端、ECs内衬不连续以及基底膜和周细胞覆盖缺陷等异常表型, 说明肿瘤血管存在明显的成熟受损和血管功能不良[11]. 脉管系统具有天然机械刺激敏感性, 因此生物力学刺激如剪切应力、脉动管腔压力及周围基质硬度等对肿瘤血管异常表型有重要影响[18].
肝细胞癌、结肠癌、胰腺癌等实体瘤组织硬度通常比相应正常组织硬度更高[19], 胶原沉积和交联增加是导致肿瘤基质硬度增加的主要原因[20]. 研究显示[21,22], 在肿瘤组织质硬的高变形区域, 血管结构表型改变明显, 血管结构变薄, 形状细长, 血管分支形成小的、散布的管腔, 没有完整小管形成, 当抑制肌动蛋白和肌球蛋白致组织无法收缩变形时, 血管结构均匀生长, 变宽、弯曲且方向随机. Bordeleau等[15]研究基质硬度对乳腺肿瘤血管生长和完整性的影响, 发现基质硬度增加能够上调内皮细胞基质金属蛋白酶(matrix metalloproteinases, MMP)活性, 促进血管新生, 且上述改变仅与基质的硬度有关, 而与其密度无关, 同时基质硬度增加还显著影响内皮细胞功能, 导致血管内皮细胞屏障功能受损, 血管内皮钙粘蛋白(VE-Cadherin)定位改变, 使血管通透性增加, 细胞-细胞连接松散, 肿瘤血管呈现畸形、渗透性更强和更迂曲形态改变.
血管芽内皮尖端细胞向外生长标志着血管新生的开始[23], 胞外基质硬度力学信号可调节尖端细胞的形成从而调控新生血管的表型. Guo等[24]发现, 肝癌组织硬化外层CD31表达明显高于周围软组织, 体外实验显示高硬度基底促进ECs球体发芽, 且上调尖端细胞相关基因的表达; 尖端细胞与ECs相比, 表现为细胞刚度增加、肌动蛋白细胞骨架组织增多和Yes相关蛋白(Yes-associated protein, YAP)核转位增强, 基质硬度通过调节粘着斑中黏着斑激酶(focal adhesion kinase, FAK)和桩蛋白(paxillin, PXN)磷酸化, 促进Rac1从非活性状态转变为活性状态, 使YAP激活并转位细胞核, 导致ECs呈现出尖端细胞特性[24]; 而p-Paxillin可使细胞间连接松散, 同样表现为尖端细胞的特性[24]. 血管芽内皮尖端细胞可分泌血小板衍生生长因子B(platelet-derived growth factor B, PDGF-B)募集周细胞到发芽血管中, 周细胞可分泌血管生成素1 (angiopoietin 1, ANGPT 1), 与ECs上的血管生成素酪氨酸激酶蛋白受体2(TEK receptor tyrosine kinase 2, Tie2)结合, 抑制ECs增殖, 使ECs间的连接更加紧密从而稳定新形成的血管, 促进血管成熟[11]; 肿瘤部位VEGFA增加触发内皮细胞表达ANGPT2, 与ANGPT1竞争内皮细胞上的Tie2, 破坏周细胞-内皮细胞相互作用, 导致周细胞从肿瘤血管基底膜上脱离, 诱导新血管生成并促进血管系统的不成熟表型, 表现为血管管腔不规则、渗透性增加、血管灌注不良, 导致新生血管功能失调[11,23,25,26].
肿瘤内皮细胞(tumor endothelial cells, TECs) 常表达多种机械传感分子, 包括离子通道蛋白、G蛋白偶联受体及一些膜蛋白, 如血小板内皮细胞粘附分子-1(platelet endothelial cell adhesion molecular, PECAM-1), VE-Cadherin及整合素(integrin), 这些机械传感分子可感知来自ECM的力学刺激[24,27,28], 使TECs对基质硬度力学信号异常敏感. 肿瘤基质硬度增加可导致TECs机械传感分子表达失调, 进而引起肿瘤血管畸形[29,30].
机械敏感离子通道激活和钙离子内流是ECs对机械力刺激的最早反应之一[31], 多种机械敏感离子通道蛋白参与机械力学因素对肿瘤血管新生的调控. 基质硬度增加可导致机械敏感离子通道表达失调, 进而调控肿瘤血管新生. 机械敏感离子通道蛋白Piezo1是一种ECs力学感应分子, 当细胞受到渗透压、流体剪切应力、基质刚度等机械力刺激时会发生细胞膜形变, 而激活Piezo1离子通道, 导致钙离子流入胞内, 将机械力学信号转化为生化信号[32]. Piezo1在多种肿瘤组织中高表达, 如脑胶质瘤[33]、肝癌[34]、胃癌[35]、前列腺癌[36]等. 研究发现[33,34], 基质硬度增加可上调肝癌细胞和恶性胶质瘤细胞Piezo1表达. 此外, 基质硬度增加可诱导肝癌细胞Piezo1高表达并促进钙离子内流, 进而抑制HIF-1α泛素化导致其下游的促血管生成因子VEGF等表达增加, 而促进肿瘤血管新生[34]. 还有研究发现, 流体剪切应力可触发血管内皮细胞Piezo1介导的Ca2+内流, 而激活MMP2和膜型基质金属蛋白酶1(membrane type 1 matrix metalloproteinase, MT1-MMP), 并协同促进血管出芽[37]. 机械敏感性离子通道瞬时受体电位香草素受体4型通道蛋白(transient receptor potential vanilloid receptor 4, TRPV4)是ECs中普遍表达的非选择性钙离子通道, 研究显示[38], TRPV4可作为ECs中血管变形和剪切应力刺激的感应分子, ECs中TRPV4低表达可调节ECs力学感应而影响肿瘤血管生成与成熟, 在TRPV4敲除小鼠中, TRPV4的缺失导致血管密度增加、血管直径增加和周细胞覆盖率降低, 进而促进肿瘤生长; 体外TRPV4过表达或激活则通过调节Rho活性恢复ECs的力学感应, 促进异常血管的正常化.
G蛋白偶联受体1-磷酸鞘氨醇受体-1(sphingosine 1-phosphate receptor-1, S1PR1)是血源性脂质介质1-磷酸鞘氨醇(sphingosine 1-phosphate, S1P)的受体, 可参与血管系统的调节, 其表达也受机械力学信号影响. 视网膜脉管系统研究发现, S1PR1在体内、外均可对层流剪切应力做出反应, 从生长的血管前端到血管网络的成熟区域, 内皮细胞S1PR1表达逐步增高, 在内皮细胞S1PR1表达缺失的情况下, 内皮细胞粘附连接不稳定, 屏障功能被破坏, 血流受到干扰, 导致血管过度发芽; 而S1PR1的过表达会抑制尖端细胞形成和过度发芽, 提示内皮细胞S1PR1可被层流剪切应力激活进而保持血管的稳态[28].
ECM机械力信号还可通过调节ECs表面膜蛋白, 如integrin及其下游的磷酸化FAK、PXN、VE-cadherin等表达和活性, 参与ECs的增殖、存活、扩散和运动进而影响肿瘤血管新生[39,40].基质硬度增加能够调节ECs中integrin β1表达和活性, 并影响粘着斑(focal adhesion, FA)的组装和周转[41]. FAK是FA中的关键分子, 可动态感知和/或传递机械力, 是最先响应胞外机械力刺激而招募到FA的蛋白分子, FAK磷酸化是诱导细胞粘附和整合素结合反应所必需的[42]. 研究发现[40], 当ECs受到细胞外机械力刺激或细胞粘附到ECM配体时, 衔接蛋白如Shc被募集到integrin, integrin激活丝裂原激活蛋白激酶(mitogen-activated protein kinases, MAPK)和FAK, 导致Src活化并定位到细胞-细胞连接, 随后Src介导VE-cadherin磷酸化以及FA在ECs的外腔侧不断重塑, 促进血管生成. ECM还可通过integrin对ECs的迁移进行调控, ECs迁移对从已有脉管系统中萌发新血管至关重要, 这种趋向性运动严格依赖于ECs对ECM的粘附, 直接受ECM调节, 该调节作用由integrin、ECM/细胞因子甚至纤维胶原驱动[43], ECs通过integrin粘附到ECM是Erk1/Erk2 MAPK信号通路的有效细胞因子激活所必需的, 且该通路的激活是ECs增殖和血管生成所必需的.此外, 胞外机械张力还可控制VE-cadherin复合物组装和拆卸, 硬基底表面生长的血管内皮细胞VE-cadherin磷酸化增加, 其α-连环蛋白解离, 粘附连接破坏, 血管通透性增加[15,41].
肿瘤血管新生取决于促血管生成因子和抑血管生成因子间的平衡, 目前许多刺激因子包括VEGF, FGF-2, PDGF, Ang, 内皮抑素等已明确参与血管新生调节[44]. 微环境中除了缺氧因素影响外, 硬度力学信号同样也显著调节肿瘤血管生成相关因子表达[45].
2.2.1 ECM储存和释放血管生成相关因子: ECM是生长因子和其他生物活性分子的储存库, 可储存和浓缩促血管生成因子, 并募集促血管生成细胞促进血管新生[11,46-48], 纤溶酶、MMP和其他蛋白酶对ECM水解加工可使促血管生成因子如VEGFA、FGF、PDGFB和转化生长因子β1(transforming growth factor β1, TGF β1)等以生物活性形式释放, 调控肿瘤血管新生[47,49]. 肿瘤细胞也可表达血管生成调节因子, 从ECM中调动血管生成蛋白, 参与肿瘤血管新生过程[8]. 在已报道的促血管生成因子中, VEGF被认为是最重要促血管新生调节因子[10], 在肝癌组织中, VEGF与VEGFR-2结合, 触发酪氨酸激酶信号级联反应, 增加促血管生成因子生成, 促进血管内皮细胞增殖和迁移, 并有利于血管分化成熟[50]. ECM中储存有大量VEGF, 在胰腺神经内分泌肿瘤中, 即使血管丰度较少的胰岛, VEGF在ECM中含量也很丰富[51], 胰腺肿瘤细胞基质金属蛋白酶-9表达上调, 可将VEGF从ECM中释放出来, 使静止血管状态转变为活跃的血管生成状态[52]. 除了MMPs外, 蛋白酶(如纤溶酶)也可将ECM结合的VEGF释放为可溶形式[53]. 多种ECM成分包括纤维蛋白和I型胶原蛋白, 能够通过细胞因子的释放刺激ECs的迁移调控血管新生[43], 这些基质蛋白的浓度梯度本身可独立于细胞因子的刺激驱动ECs的迁移[54]. 此外, 肿瘤ECM中部分基质蛋白具有直接促血管生成活性, 如骨膜素(periostin)、纤连蛋白(fibronectin, FN)、骨桥蛋白(osteopontin)、生腱蛋白C(tenascins C)等, 同时也有部分ECM蛋白发挥血管抑制作用, 如血小板反应蛋白1(thrombospondin 1, THBS1)、骨连接蛋白和核心蛋白聚糖[11]. 肿瘤组织ECM重塑过程中还产生Ⅳ型和ⅩⅧ型胶原蛋白, 上述蛋白生物活性片段与完整胶原纤维竞争性结合于ECs表面的integrin, 抑制肿瘤血管新生[51].
2.2.2 基质硬度可调控肿瘤细胞和血管内皮细胞血管生成因子的表达及活性: 除ECM中部分基质蛋白本身生化因素的影响外, 由基质蛋白沉积、交联增强所致的肿瘤基质硬度增加, 同样参与调控肿瘤细胞和血管内皮细胞血管生成因子的表达活性. Rivron等[21,55]研究发现, 肿瘤组织基质硬度增高、组织收缩性增强, ECs感知这些微环境力学特性, 调节VEGF和VEGFR2表达直接影响肿瘤血管生成. 硬化的ECM通过促进内皮细胞迁移和通过诱导GATA2和转谷氨酰胺酶2(transglutaminase 2, TFII-I)转录, 增加内皮细胞生长及VEGFR2受体表达来促进血管生成[56,57]. 还有研究发现[50], 基质硬度力学信号既可通过激活integrin β1/PI3K/Akt信号通路上调肝癌细胞VEGF表达, 又可激活integrin αVβ5/Akt/Sp1通路上调血管内皮细胞VEGFR2的表达, 促进肝癌血管生成[58]. 基质硬度增加还可通过激活肝癌细胞HepG2中Wnt-β/catenin信号通路促进血管生成相关基因HIF-1α、VEGF的表达, 从而促进血管新生[59]. 赖氨酰氧化酶(lysyl oxidase, LOX)可催化ECM中胶原蛋白和弹性蛋白的交联, 在调控基质硬度方面发挥重要作用[60]. 在肝癌[61]、胃肠道肿瘤[60]和胰腺肿瘤[62]等肿瘤组织中LOX呈高表达, 其高表达可促进Ⅰ型胶原的表达和交联导致ECM硬度增加, 进而激活多种信号通路, 促进肿瘤血管新生. 在肝癌组织中, LOX高表达介导ECM硬度增加, 一方面通过激活丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)复合物以及PI3K和Akt过度磷酸化刺激肝癌细胞VEGF的表达; 另一方面, 在PDGFRβ的刺激下, 促进Akt信号通路, 上调VEGF表达, 促进肿瘤血管新生[60]. VEGF表达升高又可反过来促进基质硬度的增高, 研究发现[63], VEGF可通过上调尿激酶型纤溶酶原激活剂(urokinase plasminogen aetivator, uPA)/uPAR介导蛋白水解诱导基质降解, 致使ECM中胶原蛋白沉积并导致硬度增加, VEGF表达升高还可直接导致层粘连蛋白基质沉积, 诱导细胞外基质局部硬化并产生刚度梯度. 基质硬度增加还伴随血管生成相关细胞因子定位增加和MMP产生增加, 可以促进血管ECs的迁移, 而增加血管新生进程[54]. 此外, ECM机械力传递可通过细胞间粘附分子PECAM-1实现, 研究发现组织收缩时, 外围高变形区域PECAM-1+细胞区域VEGFR2表达水平增加, 明显高于受组织收缩影响较小的中心区域, 且高变形区域细胞VEGF表达量明显高于中心区域; 当收缩受损时, 细胞VEGFR-2/PECAM-1+表达下降, 因此组织收缩性通过调节VEGF和VEGFR-2的空间差异表达, 诱导ECs增殖局部差异促进血管结构的形成[55].
也有研究显示基质硬度增加抑制肿瘤血管新生. Li等[64]对神经母细胞瘤(neuroblastoma, NB)研究发现, 血管长度与NB组织的硬度呈负相关, 高基质硬度抑制YAP表达和核内聚集, 通过Runt相关转录因子2(Runt-related transcription factor 2, RUNX2)调节丝氨酸/精氨酸剪接因子1(serine/arginine splicing factor 1, SRSF1)的表达, 抑制NB肿瘤细胞VEGF165的表达和分泌, 从而抑制肿瘤血管生成. VEGF与VEGFR2的结合可被多种共受体蛋白修饰, 包括HSPG、NRP-1和integrin β1, 细胞-ECM相互作用可通过改变VEGF受体的迁移率和接近度以及VEGF内吞所需的其他细胞表面蛋白影响VEGF的结合与内化[65,66]. SACK等研究了ECM刚度对VEGF结合、加工和信号传导能力的影响, 发现ECM结合是VEGF内化所必需的, 连接于FN的integrin β1以硬度依赖的方式调节VEGF的摄取, 软基质上生长的血管内皮细胞integrin β1活化水平升高, VEGF基质结合增加, 形成更多FN-integrin β1-VEGF复合物, 促进VEGF内吞作用和细胞内信号的增强[67]. 还有研究显示[45], 高硬度基质会损害血管完整性并激活MMP, 上述研究提示基质硬度改变对不同肿瘤类型的血管新生调控存在促进或抑制的相反作用, 可能与肿瘤所处的不同病理微环境特征有关.
总之, 肿瘤微环境中ECM一方面可充当促血管生成因子和抗血管生成因子的储存库, 通过释放这些血管生成调控因子调控血管新生, 另一方面, 由ECM所致的硬度力学信号可调控肿瘤细胞和血管内皮细胞血管生成因子的表达及活性, 导致肿瘤组织中血管生成信号失衡, 对血管生成的调节呈现促血管新生和抑血管新生的双重作用. 但是, 基质硬度对血管生成因子的调控是一个复杂的过程, 其作用还需更多的研究加以明确.
基质细胞在ECM内的迁移、增殖和分泌活动是维持器官组织正常功能所必需的, 在肿瘤进展中具有重要作用[26,68]. 基质细胞具有ECM重塑性[26,68], ECM可释放多种细胞因子, 如TGF β1, 调节基质细胞的功能, 募集并诱导成纤维细胞分化为肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、募集诱导巨噬细胞分化为肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)、诱导内皮细胞和上皮细胞(上皮-间质转化)及内皮细胞和周细胞的反应, 间接促进血管生成[21,46,55,69].
CAFs是肿瘤微环境中丰度较高的基质细胞群, 是一种具有机械活性的基质细胞, CAFs可通过生长因子信号传导、基质重塑和收缩行为促进血管生成. CAFs可分泌释放多种血管生成因子, 如VEGF, 肝细胞生长因子(hepatocyte growth factor, HGF)、FGF和CXCL12等, 当CAFs暴露于循环应变力或压缩力后, 会增加包括VEGF-A和基质细胞衍生因子1(stromal cell-derived factor, SDF-1)等生长因子的表达, 从而导致血管生成增加[70]. 此外, CAFs在TGFβ影响下可获得强大的基质蛋白生物合成和沉积能力, CAFs分泌LOX和羟化酶, 可催化胶原蛋白与弹性蛋白和其他ECM分子的交联, 通过控制肿瘤基质的生物力学特性, 包括基质硬度、弹性和间质液压力, 间接调节肿瘤中的血管形成和血流[11].
ECs分泌单核细胞趋化蛋白1(monocyte chemoattractant protein-1, MCP-1)可促进单核细胞趋化迁移, 研究发现基质硬度改变对ECs表面ICAM-1和VCAM-1表达存在明显的调节, 8 kPa和40 kPa硬度基质促进内皮细胞ICAM-1和VCAM-1表达, 而20kPa硬度基质抑制内皮细胞ICAM-1和VCAM-1表达, 基质硬度调控内皮细胞ICAM-1和VCAM-1表达增加, 可诱导单核细胞的趋化性迁移和粘附, 粘附的单核细胞迁移到内膜, 分化为巨噬细胞, 介导血管壁的重塑[71,72].
总之, 基质细胞对肿瘤血管生成的调节是生物力学信号和生化信号互作的高度复杂的分子病理过程, 在解析硬度力学信号调控血管生成机制时, 应综合考虑这些因素.
微环境中基质硬度增加不仅显著影响肿瘤血管出芽模式及血管密度, 同时改变血管内皮细胞间连接及血管的通透性, 表明生物力学因素在调控肿瘤血管新生及功能中发挥重要作用. 然而, 目前力学信号调控肿瘤血管新生的确切机制及相关干预研究依然面临很多困难, 包括体外如何模拟血管及硬度力学微环境, 如何构建理想硬度关联动物模型, 如何建立硬度力学信号、流体剪切力及管腔压力对肿瘤TECs协同作用体系, 以及关键力学感应分子的筛查及鉴定, 硬度力学信号的干预靶点等. 虽然阻断硬度力学信号的药物, 如整合素抑制剂、Hippo/YAP通路抑制剂等临床试验已开展[73], 但最终能否实现临床应用尚需进一步的数据支撑. 令人倍感振奋的是, 一些新技术手段如微流控芯片、血管三维模拟、体内示踪技术、新型硬度基底细胞培养平台及不同硬度背景肿瘤动物模型的涌现, 必将逐步解决制约基质硬度调控肿瘤血管及其内在机制研究的瓶颈, 为未来基于硬度力学信号分子的诊疗应用带来希望.
学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
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科学编辑:张砚梁 制作编辑:张砚梁
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