修回日期: 2010-04-16
接受日期: 2010-04-20
在线出版日期: 2010-05-28
血管内皮生长因子(vascular endothelial growth factor, VEGF)特异性地作用于血管内皮细胞, 参与实体瘤血管的新生, 并且与实体瘤的侵袭、转移等生物学行为密切相关. 研究表明VEGF与原发性肝癌(primary hepatic carcinoma, PHC)的发生、发展及转移密切相关. 经导管动脉灌注化疗栓塞(transcatheter arterical chemoembolization, TACE)近期疗效肯定, 被广泛的应用于临床, 成为PHC非手术疗法中的首选方法, 但是, TACE远期疗效却并不理想. 抑制VEGF和(或)VEGFR在PHC中的表达将会给PHC的治疗带来新的突破. 本文复习文献, 综述PHC介入治疗与VEGF的相关研究进展.
引文著录: 任勇军, 杨林, 翟昭华. VEGF在原发性肝癌介入治疗中的价值. 世界华人消化杂志 2010; 18(15): 1582-1587
Revised: April 16, 2010
Accepted: April 20, 2010
Published online: May 28, 2010
Vascular endothelial growth factor (VEGF) is a well-known potent angiogenic factor that correlates with tumor invasion and metastasis. Primary hepatocellular carcinoma (PHC) is a common highly malignant vascular tumor with a very high mortality. Angiogenesis is considered to be important for PHC progression. Transarterial chemoembolization (TACE) has been proved to be effective for unresectable PHC. This paper aims to make a literature review of the recent advances in understanding the clinical value of inhibition of VEGF in PHC after interventional therapy.
- Citation: Ren YJ, Yang L, Zhai ZH. Clinical value of inhibition of vascular endothelial growth factor in primary hepatocellular carcinoma after transcatheter arterial chemoembolization. Shijie Huaren Xiaohua Zazhi 2010; 18(15): 1582-1587
- URL: https://www.wjgnet.com/1009-3079/full/v18/i15/1582.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v18.i15.1582
我国是原发性肝癌(primary hepatic carcinoma, PHC)的高发地区, 每年约有11万人死于肝癌. PHC具有发病隐匿、进展快等特点, 大部分患者(>80%)就诊时已无法手术切除. 经动脉灌注化疗栓塞术(transcatheter arterical chemoembolization, TACE)是治疗中晚期PHC的首选方法[1,2]. 血管内皮生长因子(vascular endothelial growth factor, VEGF)是调节血管新生最重要的细胞因子之一, 他特异性地作用于血管内皮细胞, 参与实体瘤血管生成, 与实体瘤的侵袭、转移等生物学行为密切相关[3-5]. 近年来国内外研究表明VEGF与PHC关系密切. 本文复习文献, 综述PHC介入治疗与VEGF的相关研究进展.
血管生长因子与肿瘤的发生、发展密切相关. 目前研究较多的血管生长因子有: VEGF、碱性成纤维细胞生长因子(basic fibrolast growth factor, bFGF)、血小板衍化内皮细胞生长因子(platelet-derived endothelial cell growth factor, PD-ECGF)等[6]. 其中VEGF对于肿瘤血管生成有着尤为重要的作用. 人的VEGF主要有VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E. 其中VEGF-A有5种异构体, 即VEGF121、VEGF145、VEGF165、VEGF189、VEGF206. 在异构体中, VEGF121、VEGF145 和VEGF165均能诱导血管内皮细胞增殖和新生血管形成, 其中VEGF165的活性最高.
VEGF受体(VEGFR)主要有: VEGFR-1(Flt-1)、VEGFR-2(FLK-1/KDR)、VEGFR-3三种, 属于酪氨酸激酶受体, VEGFR-1(Flt-1)和VEGFR-2(KDR)主要在血管内皮细胞表达、刺激内皮细胞增殖并促进血管形成. 其中, VEGFR-2具有强烈的酪氨酸激酶活性, 并有双重的血管生成调节功能[7]: VEGFR-2可通过其酪氨酸激酶活性区域正性调节血管生成; VEGF与受体胞外区结合后, 诱导酪氨酸磷酸化, 传导胞内信号, 发挥生物学效应, 在肿瘤血管生成中起主要作用. VEGFR-3分布在淋巴管内皮细胞, 调节淋巴管生成.
多种因素可调节VEGF的表达. 缺氧、缺氧诱导因子、细胞因子、细胞内介质、类固醇激素等都可影响VEGF的调控[8,9]. 其中, 缺氧诱导因子1-α(hypoxia-induced factor 1-α, HIF-1α)在VEGF的调控中发挥了重要作用[10,11]. 在缺氧条件下, HIF-1α和HIF-1β二聚化形成转录因子结合到VEGF基因启动子区域的乏氧反应元件(hypoxic response elements, HRE), 在其他激活因子的协同作用下, VEGF、VEGFR-1基因开始转录并活化, 活化的VEGF结合到VEGFR-1和VEGFR-2. VEGF与VEGFR-2发生二聚化、磷酸化反应, Ras-Raf-Mapk-Erk和Mapk通路被激活并调节DNA的复制, 上调VEGF的表达、细胞增殖和细胞的迁移[12]. Elias等[13]通过子宫内膜癌细胞的研究, 证实在低pH环境下调节VEGF-A的剪接, VEGF121显著升高, 这一过程可能是通过激活P38和SR蛋白的参与实现的. Ray等[14]研究了骨髓细胞在环境信号改变下VEGF3'-端非翻译区发生二元构象改变, 认为VEGF3'-端非翻译区的启动更加重要.
VEGF的主要生物学作用[15-19]: (1)细胞质的钙聚集作用, 几秒钟内可使钙离子浓度升高4倍以上. (2)促进内皮细胞增殖. (3)诱导血管生成. (4)增加血管通透性. VEGF具有很强的增加血管通透性的作用, 主要增加毛细血管后静脉和小静脉的通透性. (5)血管保护作用, 表现在抗血栓生成, 抑制血管平滑肌细胞过度生长, 抗内皮细胞损伤和凋亡, 抗炎及改变细胞外基质, 有利于血管以出芽方式向周围生长. (6)神经保护作用, Zachary等[20]认为在活体内VEGF对神经细胞和神经胶质细胞具有神经营养和神经保护功能, 通过直接和间接作用刺激神经干细胞的增殖和生存, 特别是大脑在受伤后促进脑组织血管的生成.
VEGF是体内最强的一种血管生长因子, 在肝癌组织中高表达, 主要来自肝癌细胞和肝星状细胞旁分泌和自分泌[21]. VEGF的增加可以诱导肿瘤血管的生成, 增加肝癌细胞的血供, 增加血管通透性, 促进肝癌细胞浸润和转移[22,23]. Nakamura等[24]研究发现VEGF与VEGFR-1在肝脏不典型增生结节中高表达并与癌前病变相关.
肝癌细胞生长迅速, 对氧和营养的需求量较正常组织大, 导致癌组织内缺血缺氧, 而缺氧是VEGF最强烈的诱导剂, 促使VEGF大量分泌, 并与其受体相结合, 加速血管内皮细胞的增生和分化, 促使新生血管生成, 以满足肿瘤生长的需求[25,26]. 肿瘤的恶性程度越高、体积越大、转移范围越广、浸润程度越深, 对氧的需求越高, VEGF的分泌越多[27]. VEGF可激活血管内皮细胞基因, 增强尿激酶型纤溶酶原激活物(urokinase plasminogen activator, uPA)和组织型纤溶酶原激活物(tissue plasminogen activator, tPA), 并减弱纤溶酶原激活剂抑制物(plasminogen activator inhibitor, PAI-1)的表达, 进而诱导蛋白水解酶间质胶原酶和组织因子的产生, 促进血管形成, 改善癌细胞营养和氧的需求; VEGF促使血管内皮细胞产生基质金属蛋白酶-9(matrix metalloproteinases 9, MMP-9), MMP-9使凝血酶原转化为凝血酶, 激活明胶酶原A, 降解原来的基膜, 促使血管形成, 使肝癌营养和氧供给加大; VEGF可通过细胞内钙调节蛋白及磷酸肌醇途径, 增强NO合酶(nitricoxide synthase, NOS)表达, 导致NO生成增多, 进而促进新生血管网建立和管腔的形成[28-31].
VEGF促进肝癌细胞浸润和转移机制: (1)VEGF能促使血管内皮细胞产生基质降解蛋白酶类(如基质金属蛋白酶-2/MMP-2), 可降解血管基底层和细胞外基质, 增强血管壁的通透性, 加之新生的肿瘤相关血管的结构不完善且通透性强, 部分肿瘤细胞可以穿过血管壁进入血管向远处转移, 故加速了肿瘤浸润和转移; (2)VEGF还可以通过结合分布于肝癌细胞膜上的VEGFR, 促进肝癌细胞自身生长, 并使肝癌细胞的伪足增长、增多, 使之移动能力加强. 通过直接黏附或吞噬靶细胞的方式增强癌细胞的浸润和转移能力; (3)VEGF作用于肝癌细胞后能降低癌细胞的同质黏附性, 使之更易发生分离脱落, 与基质胶原纤维黏附后利于其运动和转移, 此现象与VEGF的剂量及作用时间呈依赖关系. 因此, VEGF在整个肝癌发生发展过程和抗血管生成治疗中占有十分重要的地位.
肝脏是双重血供器官. 肝动脉是肝脏的营养血管, 内含丰富的氧和营养物质, 供给肝脏的物质代谢, 其血流量约占肝脏全部血流量的20%-30%. 门静脉是肝脏的功能血管, 其供血量占全肝血供量的70%-80%. PHC的血供全部或大部分来自肝动脉, 较少来自门静脉, 与正常肝实质相反.
TACE正是利用PHC的血供特点, 经靶动脉灌注化疗药物、栓塞剂, 使肿瘤组织因缺血、缺氧而坏死, 而对于正常肝组织的影响却很小[4,33,34]. TACE近期疗效肯定, 被广泛的应用于临床, 成为PHC非手术治疗的重要及首选方法[4,5]. TACE远期疗效不理想的原因[35,36]在于: 栓塞后侧枝循环形成使病灶逐渐扩大, 甚至发生转移; 栓塞后缺氧可以诱导细胞因子的表达, 增加VEGF基因转录, 使VEGF mRNA的稳定性增加, 上调VEGF mRNA及其受体的表达, 以及癌细胞和内皮细胞之间的相互影响、双向旁分泌VEGF, 从而促进血管的生成; TACE所致的组织缺氧和营养缺乏等改变还可以诱导血管内皮细胞和肝癌细胞分泌VEGF, 分泌的VEGF促进肿瘤血管生长因子的过量表达, 使肿瘤血管增生; VEGF诱导新生的血管基底膜极其不完整, 缺乏血管壁的屏障作用, 肿瘤细胞极易通过基底膜而进入血液循环发生转移.
VEGF不仅与原发性肝癌的血管发生、增殖有关, 而且直接同肿瘤的浸润和转移有关. 血清VEGF水平与肿瘤的临床分期、肿瘤直径、门静脉癌栓、远处转移明显相关; 随着疾病的进展, 血清VEGF水平逐渐升高, 合并有肝外转移者, 其血清VEGF水平明显增高, 与其他期别肿瘤患者的血清VEGF水平具有显著性差异; 肿瘤患者血清VEGF的表达与其年龄、性别、HBV感染、HCV感染、肝硬化、肿瘤部位、组织学类型、病理分化程度、肝功能等临床病理特征无相关性[37,38].
资料[26,27]表明监测接受TACE治疗患者血清中VEGF水平可以判断TACE疗效. TACE后诱导癌基因Bcl-2的表达上调, 在肿瘤浸润的边缘和包膜附近均可看到VEGF强表达, 可能与这些区域发生缺氧有关. TACE后VEGF升高者可能会在治疗后较早出现癌细胞扩散或转移.
肿瘤血管的生成对于实体瘤的发生、发展起着重要的作用, 是影响肿瘤生物学行为和转移潜能的重要因素. 对肝细胞癌免疫组织化学以及VEGF的定量研究表明, VEGF是肝细胞癌复发、远处转移以及预后的有效指标[39,40]. 血清中VEGF的水平是确定癌变以及转归的有效指标, 其特异性、敏感性、准确性都已经达到了临床的需要标准[41,42].
根据肿瘤血管形成机制, 抑制血管内皮细胞对血管生成的作用, 阻断或减少肿瘤组织的血管生成, 就能有效的抑制肿瘤的生长和转移, 就能达到治疗肿瘤的目的[43-45]. 抑制TACE后肝组织中VEGF的上调或者抑制VEGFR, 就能减缓或终止肿瘤血管的生长, 有望更好地中断PHC的血供, 杀死肿瘤细胞, 抑制肿瘤细胞的复发和转移. TACE治疗后, 应用VEGF和(或)VEGFR抑制剂就能有效地治疗PHC[42,46].
近年来发现比较重要的血管抑制因子有血管内皮抑素(Endostatin-恩度)、肿瘤抑素(Tumstatin)[47]、血小板反应素-1(Thrombospondin-1, TSP-1)[48]、烟曲霉醇(TNP-470)、贝伐单抗(Bevacizumab)、舒尼替尼(Sunitinib)等. 直接作用于血管生成的抑制剂主要有: Endostatin、Tumstatin、TNP-470、TSP-1等. 间接作用于血管生成的抑制剂主要有: Bevacizumab、Sunitinib等. Bevacizumab[49,50]是第一个被美国FDA(Food and Drug Administration)批准的抑制血管生成的抗癌药物. Tyagi[51]认为Bevacizumab及5-FU是治疗转移性结肠癌的一线药物. Finn等[52]通过对人肝细胞癌株小鼠模型的研究, 认为作为VEGF靶点治疗药物的Bevacizumab能有效治疗原发性肝细胞癌. Siegel等[53]认为Bevacizumab治疗未转移、不能手术的原发性肝癌疗效明显. Endostatin是我国自主研发的世界第一个重组人血管内皮抑制素并上市, 研究发现[54-58] Endostatin可以干扰VEGFR-2, 抑制内皮细胞的活性和增殖能力, 与金属蛋白酶-2牢固结合, 干扰催化作用, 诱发黏附激酶和桩蛋白的酪氨酸磷酸化干扰细胞和基质的作用; 在促进细胞凋亡方面, Endostatin下调Bcl-2、Bcl-xL、Bad等抗凋亡蛋白从而通过活化caspase-9, 激活促凋亡通路. Huang等认为Endostatin可以使肺癌血管及微环境正常化, 血管结构变规则[48,59]. Norén-Nyström等[60]认为TNP-470对各种内皮细胞具有强力的生长抑制能力. 体外培养和体内动物实验证实通过抑制血管生成, 有效的抑制肿瘤生长和转移. 体内抗肿瘤生长机制主要是TNP-470抑制肿瘤组织新生血管的生成, 使肿瘤细胞周期阻滞、加速凋亡. TNP-470不良反应较轻, 主要表现为眩晕、疲劳、焦虑、体质量下降、减少髓外红细胞生成等. Zhu等[61]研究证实Sunitinib在治疗PHC上取得了较好疗效.
TACE直接将化疗药物经供瘤动脉注入, 肿瘤药物浓度明显高于静脉化疗, 而全身药物浓度较低. 这为经供瘤动脉注入血管抑制因子抗肿瘤血管生成提供了理论支持. 目前, 经导管动脉灌注血管抑制因子治疗PHC的文献报道较少. 杜海军[62]经肝动脉灌注Endostatin化疗栓塞治疗中晚期肝癌, 1年生存率显著提高, AFP下降明显, 肿瘤新生血管、转移抑制明显, 并且安全. 文献报道经导管灌注非血管抑制因子治疗PHC亦取得一定疗效, 如灌注131I-肝癌抗体片断[63-65]、CIK细胞[66-68]、中药[69-71]等.
TACE在治疗PHC中发挥了重要作用,TACE后PHC的复发和转移越来越受到重视. VEGF在PHC的生长、转移、预后等方面起重要的作用. 研究发现, 抑制或减少VEGF和(或)VEGFR在PHC的表达将会给PHC抗血管生成治疗带来新的突破. 目前经动脉灌注抗VEGF药物治疗PHC临床研究较少. 相信随着研究的不断深入, 将进一步阐明PHC介入治疗后VEGF变化及机制, 在提高PHC介入治疗疗效等方面发挥更加重要的作用.
血管内皮生长因子(VEGF)是调节血管新生最重要的细胞因子之一, 他特异性地作用于血管内皮细胞, 参与实体瘤血管生成, 与实体瘤的侵袭、转移等生物学行为密切相关. 近年来国内外研究表明VEGF与PHC关系密切. 本文复习文献, 综述PHC介入治疗与VEGF的相关研究进展.
龙学颖, 副主任医师, 中南大学湘雅医院放射科.
TACE在治疗PHC中发挥了重要作用, TACE后PHC的复发和转移越来越受到重视.
Nakamura等研究发现VEGF与VEGFR-1在肝脏不典型增生结节中高表达并与癌前病变相关.
本文立题有一定新颖性和重要性, 具有可读性.
编辑: 李军亮 电编: 何基才
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