修回日期: 2013-10-18
接受日期: 2013-10-19
在线出版日期: 2013-10-28
肝细胞生长因子(hepatocyte growth factor, HGF)/c-Met与人类许多恶性肿瘤的生长、侵袭及转移密切相关, 乳腺癌、卵巢癌、子宫内膜癌、肺癌及消化系肿瘤中均可见HGF/c-Met的激活与过表达. 在肿瘤的生长和转移过程中, c-Met担当了重要的角色, 针对HGF/c-Met通路的抗肿瘤研究也成为当今研究的热点. c-Met在消化系肿瘤中的表达有较多的报道, 本文将相关的最新研究做一系统的阐述, 以使临床工作者对目前的研究现状有系统的了解.
核心提示: 肝细胞生长因子(hepatocyte growth factor, HGF)/c-Met信号传导通路是人体内重要的信号传导通路之一, 广泛存在于各种细胞中, 具有多种功能并对组织器官的发育具有重要的生理调节功能. 当正常细胞过度表达c-Met或HGF时, 会导致细胞发生恶变. 目前有文献报道显示人类多种恶性肿瘤的发生与c-Met蛋白异常表达有关, 这些恶性肿瘤包括甲状腺癌、阴茎鳞癌、乳腺癌、大肠癌、非小细胞肺癌、结肠癌、宫颈鳞状细胞癌等. 关于c-Met蛋白在消化系肿瘤中的表达有较多的报道, 本文将相关报道做一系统的阐述, 以使临床工作者对目前的研究现状有系统的了解.
引文著录: 侯雷, 赵明明, 孙宝明, 邢会军. c-Met蛋白在消化系肿瘤中表达的研究进展. 世界华人消化杂志 2013; 21(30): 3230-3235
Revised: October 18, 2013
Accepted: October 19, 2013
Published online: October 28, 2013
There is a close relationship between HGF/c-Met and many human cancers. The activation and overexpression of HGF/c-Met can cause the growth, invasion and metastasis of breast cancer, ovarian cancer, endometrial cancer, lung cancer, and digestive system tumors. Since c-Met plays an important role in the growth and metastasis of tumors, targeting the HGF/c-Met pathway has become a hotspot for anti-cancer research. Currently, there have been many reports about c-Met expression in digestive tumors. In this paper we try to elaborate the latest progress in research related to c-Met expression in digestive tumors, with an aim to help clinicians gain a systematic understanding of this issue.
- Citation: Hou L, Zhao MM, Sun BM, Xing HJ. Expression of c-Met protein in gastrointestinal tumors: Recent research progress. Shijie Huaren Xiaohua Zazhi 2013; 21(30): 3230-3235
- URL: https://www.wjgnet.com/1009-3079/full/v21/i30/3230.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i30.3230
c-Met是原癌基因编码的蛋白质, 被称为肝细胞生长因子(hepatocyte growth factor, HGF)受体且具有酪氨酸激酶活性[1,2]. 自从1984年Nakamura等从部分肝切除大鼠的血清中分离并命名为肝细胞生长因子后[3-5], 大量的研究已经证实c-Met参与多种肿瘤的病理生理过程[6-8]. Park等[9]报道了c-Met的cDNA序列, 确定了c-Met的产物为跨膜蛋白. HGF/c-Met信号传导通路是人体内重要的信号传导通路之一, 广泛存在于各种细胞中, 具有多种功能并对组织器官的发育具有重要的生理调节功能[10-14]. 当正常细胞过度表达c-Met或HGF时, 会导致细胞发生恶变[15-17]. 目前有文献报道显示人类多种恶性肿瘤的发生与c-Met蛋白异常表达有关, 这些恶性肿瘤包括甲状腺癌[18]、阴茎鳞癌[19]、乳腺癌[20]、大肠癌[21]、非小细胞肺癌[22,23]、结肠癌[24]、宫颈鳞状细胞癌[25,26]等. 关于c-Met蛋白在消化系肿瘤中的表达有较多的报道, 本文将相关报道做一系统的阐述, 以使临床工作者对目前的研究现状有系统的了解.
胃癌是消化系常见的发病率和死亡率均较高的恶性肿瘤, 具有国家和地区差异性. 其早期诊断困难, 大部分患者就诊时已发生淋巴结转移, 手术可切除癌变的病灶仍为目前唯一有希望治愈此病的方法. c-Met在恶性肿瘤中的表达通常伴有预后不良和癌灶的远处转移, 研究胃癌中c-Met的表达及临床病理特征的关系, 揭示c-Met在胃癌发病的转移机制中可能的作用具有深远的临床意义.
为了更清晰地了解c-Met的表达与胃癌的发病之间的关系, 国内外专家进行了相关的研究, 国内马桂芳等[27]的研究显示c-Met在胃癌、癌周组织的表达(85.74%、83.67%)明显高于正常组织(12.5%), 但在高中低不同分化的研究中, c-Met的表达与胃癌的组织分化程度无明显关系; 胃癌伴有淋巴结转移的患者中c-Met的阳性表达明显高于无淋巴结转移者, 表明c-Met表达与胃癌患者是否伴有淋巴结转移密切相关; 胃癌中肿瘤体积>5 cm与<5 cm的c-Met表达的研究显示, 两者的阳性表达率无显著性差异, 说明c-Met表达与肿瘤大小无关. 国外Chi等[28]对c-Met及整合素α5β1在胃贲门腺癌的表达进行研究, 采用RT-PCR分析两者mRNA的表达、Western blot分析两者蛋白的表达并使用免疫组织化学进行表达模式的鉴定, 结果表明c-Met和整合素α5β1的表达与胃贲门腺癌的分化程度、分期及远处转移显著相关. Ma等[29]评估了结肠癌转移相关基因1(metastasis associated in colon cancer-1, MACC-1)和c-Met在胃癌组织中的表达, 发现MACC-1和c-Met在非癌组织中表达较弱或缺失, 在胃癌组织中呈中重度表达. 最近的研究显示, 可溶性c-Met具有作为胃癌新型生物标记物的潜能, 人类血浆中高浓度的可溶性c-Met成为强有力的支持[30].
食管鳞癌是常见的消化系恶性肿瘤之一, 我国是食管癌的高发国家, 鉴于食管癌早期诊断困难, 80%的患者就诊时已进入中晚期, 因此深入研究食管癌发生发展过程中相关的危险因素及肿瘤标志物, 做到早期发现、早期诊断、早期治疗, 对于提高患者的生存率、改善患者生活质量具有重要的临床价值和意义. c-Met蛋白与多种肿瘤的侵袭和转移密切相关, 因此探讨HGF的受体c-Met在食管鳞癌发生发展中的作用, 可为临床评估预后及开发肿瘤治疗靶点提供帮助.
食管鳞癌的发生与基因的改变具有相关性, 常见的包括P53突变、P120ctn失活及c-Met、表皮生长因子(epidermal growth factor receptor, EGFR)等基因的过表达[31,32]. Grugan等[33]研究发现P53突变激活c-Met酪氨酸激酶受体从而增强肿瘤细胞的侵袭. 在P53表达增强的食管上皮细胞中发现增加的c-Met酪氨酸激酶受体. Herrera等[34]利用免疫组织化学法和RT-PCR方法测定食管腺癌、Barrett食管、正常食管组织中c-Met蛋白和mRNA的表达显示, c-Met在食管腺癌及发育不良的Barrett食管中呈过表达. 国内邹志田等[35]探讨了c-Met基因和COX-2基因在食管鳞癌组织中的表达, 结果示c-Met基因和COX-2基因在食管鳞癌中呈高表达, 而在癌旁正常食管组织中低表达. Ren等[36]利用ELISA方法测定食管鳞癌患者血清中HGF的含量, 结果显示患者血清中HGF较正常显著增高. 因此我们有理由认为c-Met在食管癌的发生、发展、侵袭及转移中发挥了重要作用, 如果能找到有效抑制c-Met表达的途径, 则有望控制肿瘤的生长及转移, 从而阻止肿瘤的恶性生物学行为, 延长患者寿命.
大肠癌是消化系常见的恶性肿瘤, 在其发病过程中存在许多原癌基因的激活和抑癌基因的失活. c-Met蛋白参与细胞信号传导、细胞骨架重排的调控, 是控制细胞增殖、分化和运动的重要因素. 众多研究提示c-Met蛋白在大肠癌发病早期起了重要的作用, 因此深入研究c-Met系统, 将有助于大肠癌的诊断、治疗和预后判断.
c-Met在大肠癌的发生发展中起着重要的作用, 被认为极具吸引力的受体分子治疗靶点[37]. Gao等[38]调查了c-Met的高表达与大肠癌发生的关系, 免疫组织化学检测了大肠癌患者及良性肿瘤患者的c-Met, 发现c-Met的高表达与肿瘤的淋巴结转移及分期有关. 国内荣玮等[39]探讨了c-Met在大肠腺癌组织中的表达, 结果显示c-Met的表达与大肠癌组织的分化程度、浸润深度、淋巴结转移及Duke分期有关, 与国外研究结果一致. 徐伟等[40]研究了重组免疫毒素(immunotoxin, IT)抗c-Met/PE38KDEL对大肠癌细胞增值的抑制作用, 结果显示重组IT抗c-Met/PE38KDEL对大肠癌细胞株有显著的增殖抑制及诱导凋亡的作用. 郭运生[41]通过观察大肠癌组织中肝细胞生长因子及其受体c-Met和微血管密度(microvessel density, MVD), 发现HGF、c-Met蛋白阳性者MVD均显著高于HGF、c-Met蛋白阴性者. 江燕飞等[42]采用免疫组织化学检测c-Met和CXCR4在癌旁正常组织、大肠腺癌中的表达显示c-Met和趋化因子受体4(CXC chemokine receptor-4, CXCR4)的表达存在相关性, 与大肠癌的发生、发展和肝转移有关. Zeng等[43]研究表明大肠癌组织较正常大肠c-Met明显增高, 且与肿瘤进展相关, 提示c-Met激活机制在大肠癌的发生、转移中起着重要作用. Umeki等[44]采用RT-PCR及Southern blot方法对43例大肠癌标本进行c-Met基因扩增与过表达的研究, 认为c-Met基因过表达与大肠癌的发展相关.
结直肠癌作为一种严重危害人类健康的消化系肿瘤, 发病率逐年上升[45]. 有研究显示结直肠癌患者中HGF高水平表达且与分期呈正相关, 合并转移的患者较无转移的患者HGF水平更高[45-47]. HGF作为一种多功能生物因子具有诱导血管生成的作用, 异常的HGF/c-Met信号转导通路与肿瘤的发生密切相关[48-50]. 程变巧等[51]研究显示脆性组氨酸三联体基因(fragile histidine triad, FHIT)及c-Met基因的表达与结直肠癌发生发展有关, 两者联合检测可作为结直肠癌预后的判断指标. Chen等[52]研究显示MJ-56通过影响c-Met的衰减潜在的影响结直肠癌转移的治疗.
HGF与c-Met蛋白结合后使细胞外信号调节蛋白激酶(extracellular signal regulated protein kinase, ERK)磷酸化而被激活, 从而增强细胞的运动能力[53]. Otsuka等[54]通过转基因大鼠研究证实了HGF及其受体c-Met在肿瘤发生中的作用. 徐志彬等[55]在构建的家兔口腔颊黏膜鳞状上皮癌前病变模型中, 通过病理检查及免疫组织化学检查c-Met蛋白的表达, 发现c-Met蛋白的表达与HGF呈正相关, 且在肿瘤的早期阶段即对上皮细胞的恶变起到了促进作用.
Nabeshima等[56]发现当人HGF和c-Met同时在NHI3T3细胞中表达时才有致癌作用. Tomita等[57]研究在上皮细胞中HGF能显著增加他本身及其受体c-Met的表达. 恶性肿瘤的侵袭与转移是一个极其复杂的过程, 需要经过肿瘤细胞间黏附力的降低、肿瘤细胞与基底膜的附着、肿瘤细胞的迁移等最终使得肿瘤细胞游走并停留在其他的脏器[58-61]. 在这个过程中c-Met和HGF信号传导通路对肿瘤细胞的许多生物学行为具有影响, 特别是可以促进肿瘤细胞的局部浸润和远处转移[62].
虽然目前对于c-Met蛋白的研究取得了较大的成果, 但仍存在一些不足, 首先, 在肿瘤发生过程中c-Met蛋白的失调, 是met基因的突变、重排或扩增引起的, 还是其他分子失调导致的c-Met蛋白表达的异常需进一步的研究; 其次, 研究c-Met蛋白的空间结构可能为我们研究其致病机制提供线索; 最后, c-Met蛋白与其他致癌基因在肿瘤发生过程中的相互作用尚有待进一步的探讨.
以上为c-Met在消化系肿瘤中的表达现状, 目前的研究表明, c-Met蛋白已经在多种肿瘤细胞中呈现过表达, 可能成为判断肿瘤局部侵袭和远处转移及辅助判断预后的指标之一. 在胃癌、食管癌、大肠癌中c-Met的高表达将为临床工作中分子靶向治疗提供新的治疗位点, 已将成为预测肿瘤治疗效果的生物标志物之一.
胃癌是消化系常见的发病率和死亡率均较高的恶性肿瘤, 具有国家和地区差异性. 其早期诊断困难, 大部分患者就诊时已发生淋巴结转移, 手术可切除癌变的病灶仍为目前唯一有希望治愈此病的方法. c-Met在恶性肿瘤中的表达通常伴有预后不良和癌灶的远处转移, 研究胃癌中c-Met的表达及临床病理特征的关系, 揭示c-Met在胃癌发病的转移机制中可能的作用具有深远的临床意义.
陈钟, 教授, 南通大学附属医院普外科, 南通大学肝胆外科研究所; 张国梁, 主任医师, 天津市第一中心医院消化内科
虽然目前对于c-Met蛋白的研究取得了较大的成果, 但仍存在一些不足, 首先, 在肿瘤发生过程中c-Met蛋白的失调, 是met基因的突变、重排或扩增引起的, 还是其他分子失调导致的c-Met蛋白表达的异常需进一步的研究; 其次, 研究c-Met蛋白的空间结构可能为我们研究其致病机制提供线索; 最后, c-Met蛋白与其他致癌基因在肿瘤发生过程中的相互作用尚有待进一步的探讨.
Nabeshima等发现当人HGF和c-Met同时在NHI3T3细胞中表达时才有致癌作用. Tomita等研究在上皮细胞中HGF能显著增加他本身及其受体c-Met的表达. 恶性肿瘤的侵袭与转移是一个极其复杂的过程, 需要经过肿瘤细胞间黏附力的降低、肿瘤细胞与基底膜的附着、肿瘤细胞的迁移等最终使得肿瘤细胞游走并停留在其他的脏器.
本文阅读了大量文献, 系统阐述c-Met蛋白在消化系肿瘤中的表达, 工作值得肯定, 但新颖性一般.
编辑:郭鹏 电编:闫晋利
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