陶倩逸 许尤琪
(1.南京中医药大学,江苏南京210023; 2.南京中医药大学第二附属医院肿瘤科,江苏南京210017)
胃癌是消化系统常见恶性肿瘤,在全球范围内,其发病率和死亡率一直居高不下[1]。2015年中国胃癌发病率为15.8%,死亡率为17.6%,在所有癌症中位居第二[2]。中医药在胃癌术后康复治疗阶段发挥着不可替代的作用,其不仅在改善术后生存状态、提高生活质量方面疗效显著,在抗肿瘤、防复发转移领域也取得了诸多成果,现将中医药防治胃癌术后复发转移机制的实验研究进展概述如下。
胃癌形成与细胞增殖失控、凋亡异常息息相关。许多单味中药及中药复方对胃癌细胞具有抗增殖、促凋亡的作用。研究证实麦冬皂苷对SGC-7901细胞有较强的抗增殖作用,且呈剂量依赖[3]。研究者通过对小鼠人胃癌移植瘤的研究发现三棱提取物通过影响胃癌细胞周期、诱导细胞凋亡抑制肿瘤生长[4]。Gui等[5]经实验证实消痰散结方可以抑制MKN-45细胞的增殖并诱导细胞凋亡。Zhou等[6]发现益气消积方含药血清可抑制胃癌nkn-28细胞生长,且抑制强度取决于药物浓度和作用时间。研究表明乌梅丸能够抑制人胃癌SGC-7910细胞的生长增殖[7]58。Huang等[8]经实验证实蛇床子素可以抑制多种人类恶性肿瘤细胞系,包括胃癌细胞株MKN-45和BGC-823。
细胞黏附分子在肿瘤侵袭与转移中起重要作用,其中跨膜糖蛋白CD44v6与胃癌的复发转移关系密切,是胃癌淋巴结转移的有力预测指标[9]。有研究者发现苦参碱注射能抑制SGC-7901细胞增殖及迁移、抑制细胞黏附能力,其机制可能与下调CD44v6蛋白的表达有关[10]。徐叶峰[11]发现益气补肾方可通过下调CD44的表达抗胃癌细胞增殖。张元清[12]经实验证实健脾养胃方可下调胃癌细胞中CD44v6mRNA的表达,从而降低细胞黏附力,抑制胃癌细胞侵袭转移。颜延凤等[13]通过研究证实胃安宁颗粒能抑制胃癌原位癌的生长,减少转移灶,其作用与下调CD44表达水平有关。
肿瘤的侵袭能力是肿瘤局部侵袭和远处转移的基础,而细胞外基质的重塑是肿瘤细胞侵袭的基础[14]。MMPs能降解各种蛋白成分,破坏组织学屏障,重塑细胞外基质,为肿瘤侵袭转移创造条件。其中MMP-2、MMP-9的表达与胃癌浸润程度及淋巴结转移关系密切[15]。叶冰等[16]发现参术胶囊能显著抑制模型动物MMP-2、MMP-9的表达,证实参术胶囊抗胃癌转移的作用可能与抑制细胞外基质降解有关。潘传芳等[17]经实验证实胃肠安方可通过下调MMP-9蛋白表达抑制胃癌转移。李晶等[18]发现启膈方可降低MMP-2的表达,从而起到抑制肿瘤转移的作用。Xu等[19]发现四君子汤加肉豆蔻和木通果实提取物能调控MMP-2、MMP-9的蛋白表达以发挥其抗癌作用。
肿瘤血管为肿瘤的远处转移提供条件,许多中药可通过抑制肿瘤血管生成发挥抗癌作用。Shi等[20]经研究发现消痰散结方可抑制VEGF-A、VEGFR-1及VEGFR-2mRNA的表达从而抑制胃癌血管生成。研究者通过实验证实健脾解毒方含药血清可下调VEGF表达以抗血管生成,这可能是健脾解毒方的抗癌作用机制之一[21]。Zhang等[22]检测去甲斑鹜素对静脉内皮细胞血管结构形成的影响,发现去甲斑鹜素可通过抑制肿瘤血管生成发挥抗肿瘤作用。
原癌基因如Bcl-2、HER-2、c-myc的激活及抑癌基因如P53、BAX的失活是肿瘤发生发展及复发转移的根本原因。研究者发现复方斑蝥胶囊含药血清可致c-myc基因表达下调、p53基因表达上调,从而降低c-myc mRNA的表达水平并增加p53 mRNA的表达水平[23]。Dong等[24]发现白鹤冲剂具有抑制胃癌生长和转移的作用,其机制与下调p53蛋白表达有关。李勇等[7]59经研究证明乌梅丸可抑制人胃癌SGC-7901细胞增殖,其机制可能与下调凋亡抑制基因Survivin表达有关。
机体的免疫状态很大程度影响着肿瘤的复发转移。胃癌患者往往T淋巴细胞免疫低下,研究人员发现参芪扶正注射液可通过影响胃癌患者外周血T淋巴细胞,提高患者的细胞免疫功能,从而预防胃癌复发转移[25]。Guo等[26]经实验证实紫草素在一定浓度范围内能够促进人共刺激细胞增殖并且增强其对NCI-N87、BCC-823、HGC-27细胞的杀伤活性。唐学敏等[27]发现灵芝合剂能提高小鼠脾脏、胸腺指数,促进IL-6和TNF-α的分泌,从而发挥抗肿瘤转移免疫机制作用。Chen等[28]发现蟾酥提取物可增加移植瘤和邻近组织中CD3、CD4、CD8淋巴细胞数,增加免疫细胞的增殖,增强免疫细胞在肿瘤迁移中的作用。
信号通路传导在肿瘤领域方兴未艾,中医药实验研究在这方面取得了一定进展。研究者发现苦参素可诱导胃癌细胞株SGC7901的凋亡,其机制与抑制STAT3信号通路有关[29]。Jing等[30]经研究证实虎杖提取物白藜芦醇能降低细胞周期蛋白D1,抑制人胃癌MGC803细胞周期进展,且这一作用通过调节PTEN/PI3K/Akt信号通路实现。魏征等[31]发现化瘀解毒方可抑制体外人胃癌SGC-7901细胞增殖、黏附,其机制与抑制PI3K/Akt通路有关。黄芪可用于胃癌的辅助治疗,Tian等[32]发现黄芪抗癌的机制与调节NF-KB信号转导通路有关。
肿瘤微环境包括缺氧、酸性、炎症因子聚集、血管生成因子优势等,其在肿瘤生长和预后中起着不可或缺的作用[33]。中药通过改善缺氧、血管生成异常的微环境对抗肿瘤复发转移[34]。研究表明,中药提取物薯蓣皂苷对缺氧微环境中的胃癌细胞BGC-823的生存和侵袭能力有明显抑制作用[35]。崔澂等[36]经实验发现猪苓多糖能够作用于Colon26肿瘤细胞,并且调节肿瘤炎性微环境。许多活血化瘀中药(如三棱、莪术、红花等)通过促进肿瘤微环境中血管正常化达到抗肿瘤目的,其机制可能与抑制血小板聚集,提高纤溶系统活性,抑制癌栓着床等有关[37]。
PD-1表达于活化的T细胞和B细胞、自然杀伤细胞以及髓细胞,是体内的免疫检查点[38]。PD-L1在胃恶性肿瘤患者体内会出现过表达[39],研究显示其在晚期胃腺癌中表达阳性率为40%[40]。Wang等[41]经实验证实黄芪提取物黄芪多糖可明显抑制肿瘤细胞的生长,降低PD-L1mRNA和蛋白在肿瘤中的表达,其机制可能与调节PD-1/PD-L1通路有关。
随着中医药实验研究水平的不断提升及实验经验的不断累积,越来越多的中药被证实有不同程度的抗肿瘤复发转移作用。为了进一步推动中医药抗癌研究进展,今后可在以下方面进行改进:(1)在对单味中药进行研究的同时,应加大中药复方研究比重,利用好现代实验技术,建立更客观更有效的实验研究体系;(2)许多实验表明某味中药具有抗癌防复发转移作用,但对药物的优势效应研究甚少,应完善中药对不同肿瘤细胞的对比作用研究,以发现中药的某些特殊疗效,更好地将其应用于临床;(3)加强中药结合靶向异位点的研究,提高中药抗癌治疗的特异性。笔者相信,伴随科技水平的提高和实验的不断深入,中医药将在抗癌症复发转移领域发挥更大的作用。
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