修回日期: 2015-06-18
接受日期: 2015-06-29
在线出版日期: 2015-07-28
结直肠癌作为消化系中常见的恶性肿瘤, 提高早期大肠癌的诊断率一直是其防治的重点. 而大肠黏膜上皮内瘤变及腺瘤被认为是大肠癌最重要的癌前病变. 近年来, 随着对生物医学、遗传、基因学等学科的深入研究发展, 在探索其二者关系的诸多相关领域取得了一些新的研究进展, 为今后的临床筛查处理、定期随访及化学预防等方面提供了一定指导. 然而大肠黏膜上皮内瘤变及腺瘤的产生因素有哪些以及他是如何演变发展为真正的"癌", 这些仍是亟待解决的问题, 需做大量的先进研究工作来积极探索这些未知领域.
核心提示: 从大肠黏膜上皮内瘤变(intraepithelial neoplasia)及腺瘤的分子遗传学改变以及其临床科学的处理措施和预防方法等进行较全面的介绍, 有利于提高临床工作者对于肠癌癌前病变的认知和处理能力. 对于大肠癌的早期防治, 具有积极意义.
引文著录: 刘芳腾, 欧阳喜, 张官平, 罗洪亮. 结直肠黏膜上皮内瘤变及腺瘤的相关研究进展. 世界华人消化杂志 2015; 23(21): 3413-3420
Revised: June 18, 2015
Accepted: June 29, 2015
Published online: July 28, 2015
Colorectal cancer is a common malignant tumor in the digestive system, and the early diagnosis of colorectal cancer has been the focus of its prevention and control. Colorectal intraepithelial neoplasia and adenoma are considered to be the most important precancerous lesions of colorectal cancer. In recent years, with the development of biological medicine, genetics,
and other disciplines, many studies have explored the relationship between intraepithelial neoplasia and adenoma and colorectal cancer, and some new research progress has been achieved to provide some guidance for the future clinical screening, regular follow-up and chemical prevention. However, it remains to be studied how colorectal intraepithelial neoplasia and adenoma form and evolve to colorectal cancer.
- Citation: Liu FT, Ou-Yang X, Zhang GP, Luo HL. Progress in research of colorectal intraepithelial neoplasia and adenoma. Shijie Huaren Xiaohua Zazhi 2015; 23(21): 3413-3420
- URL: https://www.wjgnet.com/1009-3079/full/v23/i21/3413.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i21.3413
大肠癌(colorectal cancer, CRC)是消化系中常见的恶性肿瘤. 最新资料[1]表明, 肠癌在欧美发达国家其发病率和死亡率分别居恶性肿瘤的第4和第2位. 在我国, 肠癌的发病率和死亡率分别居恶性肿瘤的第4和第5位, 且发病年龄明显提前, 大城市的肠癌发病率高于农村[2]. 一般认为结直肠癌的发生是正常上皮-增生/微腺瘤-早/中/晚期腺瘤-癌的过程, 是多基因、多因素、多阶段的动态演变过程, 这一结论, 已得到国内外学者的广泛认可[3,4]. 2000年世界卫生组织(World Health Organization, WHO)在胃肠道肿瘤新分类中, 首次提出上皮内瘤变的定义[5], 现就结直肠黏膜上皮内瘤变及腺瘤的研究进展作简介综述.
Morson于1970年首次在结直肠癌前病变中采用上皮内瘤变的观点[6]. 上皮内瘤变是指肠黏膜上皮结构和细胞学上的异常, 是上皮浸润前的肿瘤性改变. 病理特点包括上皮细胞紊乱和细胞极性丧失; 细胞核不规则、深染, 核质比例增高和核分裂活性增加等. 2000年WHO在出版的国际肿瘤组织学分类中明确对结直肠等器官中的肿瘤统一采用"上皮内瘤变"取代原来所用"异型增生""癌前病变"等的名词, 将上皮内瘤变分为2级, 即低级别上皮内瘤变(low-grade intraepithelial neoplasia, LGIN)和高级别上皮内瘤变(high grade intraepithelial neoplasia, HGIN), 并将未通过黏膜基层浸润到黏膜下层者归为HGIN[5]. 由于结直肠在黏膜层包括黏膜肌层是没有淋巴管的, 当肿瘤穿透黏膜肌层侵入黏膜下层时, 才有可能通过黏膜下层的淋巴管网发生转移, 这时方可诊断为癌[6].
胃肠道"上皮内瘤变"概念的提出,避免了以往因使用"重度异型增生"、" 黏膜内癌"等名词所引起的过度治疗, 纠正了其产生的不良影响[7]. 但仍有大量学者对WHO新分类标准持谨慎态度, 认为其存在一定争议, 特别是对黏膜肌层浸润的早期结直肠癌使用"HGIN"诊断名称, 仍值得商榷并应进一步研究总结[8-11]. 国内外大量资料[8-12]显示, 术前诊断为结直肠HGIN的患者, 很大一部分已存在浸润性癌, 甚至部分已出现局部淋巴结转移或远处转移.
大肠息肉在病理上分为肿瘤性和非肿瘤性两类. 肿瘤性包括管状腺瘤、混合性腺瘤、绒毛状腺瘤, 有恶变倾向; 非肿瘤性包括增生性、炎症性、幼年性和错构瘤性息肉, 但均能分化转变为腺瘤[13]. 大小和组织学类型是息肉发生癌变的两个主要因素, 息肉直径越大, 异型增生程度越高, 癌变的危险性越大[14,15], Pickhardt等[16]认为, 直径超过1 cm的息肉恶变率为10%, 超过2 cm的息肉恶变率则高达30%. 临床上将肠道广泛出现数目多余100颗且具有特殊临床表现的称为息肉病, 包括Peutz-Jeghers综合征、家族性腺瘤性息肉病(familial adenomatous polyposis, FAP)和Gardner综合征等, 他们都和遗传因素密切相关, 癌变倾向明显, 而家族性腺瘤性息肉病癌变率高达25%-100%[17]. 大肠腺瘤作为临床上最常见的一种息肉, 也称为上皮内瘤变, 是重要的癌前期病变, 具有组织结构和细胞学上的异型性. 据统计[17], 3种腺瘤的癌变率分别为: 管状腺瘤为10%-15%; 绒毛状腺瘤为20%-40%; 混合性腺瘤为30%-40%.
随着近年来表观遗传学的迅速发展, 大肠癌的相关演变发展途径已逐渐被人们所认识和揭示出, 认为在散发性大肠癌中至少有3条不同的遗传学途径, 且他们的癌前病变和对治疗的反应均不同. 癌前病变途径包括锯齿状腺瘤途径、管状腺瘤的途径以及绒毛状腺瘤演进途径. 其中, 锯齿状腺瘤(serrated adenoma, SA)作为近年逐渐被认识的一类特殊病理形态的大肠腺瘤[18,19], 被认为是微卫星不稳定性(microsatellite instability, MSI)散发性大肠癌的重要癌前病变. 据报道[20-24], 相对传统腺瘤性息肉, SA癌变率要低0.6%-1.3%. 但仍具有较强合成CEA的能力, 存在一定的癌变潜能.
目前有研究[25]认为, 肿瘤中存在少量不断增殖的、具有促进癌细胞产生作用的干细胞. 这就是肿瘤干细胞(cancer stem cells, CSC)理论, 肿瘤中的干细胞与其耐药性和复发具有密切关系. 而CD44和Lgr5作为结直肠干细胞的标志, 与大肠癌的发生发展密切相关[26]. CD44作为一种细胞表面黏附分子, 在癌细胞的黏附、血管形成和肿瘤增殖浸润等发挥重要作用[27,28]. 有研究[29,30]表明, 在大肠癌发生发展过程中, CD44基因的表达会逐渐上调. 并且发现CD44v6(CD44的同种型变异体)在正常的结肠细胞不表达, 而在肿瘤发展的早期阶段表达增加[31,32]. 而Lgr5作为与肿瘤发生发展相关的重要信号通路(Wnt信号途径)的靶基因, 在恶变前肠腺瘤中有表达[33,34]. 研究[35]表明, 随着增生性息肉-管状腺瘤-绒毛状腺瘤-腺癌的演变推进, Lgr5的表达亦逐渐增强, 且在腺癌中的表达与正常组织相比差异具有统计学意义(P<0.05). 国内外学者的研究结果都显示: Lgr5和CD44作为结直肠干细胞的标志, 与大肠癌的发生发展关系密切[27-35]. 提示着CD44基因是大肠肿瘤发生早期检测的分子标志物, 而Lgr5对于临床早期观察腺瘤进展以及判断息肉恶变风险均具有重要作用, 两者可以联合检测. 随着CSC理论的不断成熟和实验资料的不断积累, 将会为恶性肿瘤的诊治提供新的契机.
PTEN基因是继p53之后发现的又一重要抑癌基因, 也是迄今发现的第一个具有磷酸酶活性的抑癌基因, 他位于10q23.3上[36]. 大量研究[37-40]表明, PTEN在许多恶性肿瘤中都存在突变、缺失等现象, 在大肠癌中亦检测到PTEN表达的异常. 相关研究[41]发现, PTEN蛋白在正常结肠黏膜的阳性表达率为100%, 而在结肠腺瘤、癌旁黏膜、结直肠癌的阳性表达率则明显降低, 依次为76.4%、76.9%和59.1%, 良性结肠黏膜组织PTEN蛋白表达水平高于恶性结肠黏膜组织(r0 = -0.239, P<0.05). 提示PTEN可能在正常上皮-腺瘤-腺癌序列的发展过程中起重要作用, 是大肠癌多步骤演变过程中的早期分子事件. Sun等[42]研究也证实了上述观点, 并且发现PTEN基因通过磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol 3 kinase/protein kinase B, PI3K/Akt)信号通路对大肠癌细胞的增殖、凋亡产生影响, 表明该信号通路在大肠癌的发生发展中扮演着重要角色, 与肠癌演变的关系密切.
结直肠癌缺陷(deleted in colorectal carcinoma, DCC)基因是由Fearon等[43]于1990年确定并命名, 他是目前发现的最长的抑癌基因, 位于染色体18q21.3, 与结直肠癌的发生发展关系密切. Saito等[44]通过检测比较DCC蛋白的表达, 发现癌组织中表达很少或缺失, 腺瘤中表达减少, 而癌旁正常组织中却有很强的DCC蛋白表达, 这可能是由于肿瘤中DCC基因失活, 造成其基因产物低下. 提示DCC基因的改变是肠癌发生过程中的早期基因事件, 其缺失或失活可以促发肠癌的发生发展. 另外, DCC基因201密码子近年来越来越受到研究者的关注, Minami等[45]通过对191例结直肠癌患者的肿瘤组织和30例正常结直肠组织对比分析, 发现201密码子的突变率远高于正常对照组(P<0.05). 这一结果表明, 201密码子的突变可能发生在大肠癌的早期, 且可作为一种生物学标志物, 用于对大肠癌高危组的初步筛选. 另外, 有研究[46]表明, DCC蛋白具有抑制肿瘤转移或局部浸润性生长的作用, 这有助于研究、制定新的肿瘤治疗策略, 给肿瘤的治疗带来了新曙光.
近年来, Kuwata等[47]发现Di-AcSpm在大肠HGIN组织中有不同水平的增加, 另外YB-1和P53蛋白、p110α和p110β也被研究发现在HGIN组织和癌组织中的表达均高于正常组织和LGIN组织(P<0.05)[48,49]. 他们被考虑为组织获得恶性特征的征兆, 可能在大肠癌的发生发展中扮演重要的角色.
大肠黏膜上皮内瘤变及腺瘤的发生还可有其他方面的分子生物学的改变, 包括P53、DNA甲基化、微卫星不稳定, 端粒酶减少等, 而癌基因激活、抑癌基因丢失、错配修复基因突变等在大肠癌的发生发展中亦起重要作用[50,51]. 考虑将异常活化的癌基因、突变失活的抑癌基因等作为早期检测指标和新的治疗靶点, 为及早发现和治疗大肠癌提供新的策略, 而近年来癌基因成瘾性[52]概念的引入, 给恶性肿瘤治疗策略的制定提供了新的研究方向.
大多数学者认为, 大肠癌的发生发展一般经历正常上皮-腺瘤-癌序列过程[53]. 即认为大肠腺瘤属癌前期病变, 有癌变可能[54]. 而腺瘤癌变一般需要10年左右[55]. 这就为大肠癌及其癌前病变的筛查提供了时间. 大便潜血是最常见的大肠癌早期指征之一, 研究[56]表明, 对自然人群先应用便潜血试验(fecal occult-blood test, FOBT)进行筛查, 阳性者再行全结肠镜检查, 可有效提高CRC早期诊断率和长期存活率. Hewitson等[57]4项大型随机临床研究结果和Yang等[58]对大样本人群的CRC筛查结果都显示: 粪便潜血能发现较早期CRC和癌前病变, 可以有效减少CRC的发病率和死亡率. 有学者认为在不具备全结肠镜检查条件的地区单独行乙状结肠镜检查, 亦能有效发现早期CRC和癌前病变, 降低人群的CRC总体死亡率[59]. 目前除了成熟的粪便潜血试验、内镜(纤维乙状结肠镜、全结肠镜等)和影像学(CT结肠成像、腔内超声等)检查外, 突变基因(DSEPT9基因等)和血液标志物(血浆游离甲基化SEPT9、循环微小核酸等)的检测也越来越显现出巨大的潜力, 为CRC的筛查开拓了广阔的空间, 对于提高大肠癌前病变的检出率有着重要意义[60-62]. 然而目前对于如何提高筛查手段和方案的特异性和敏感性, 并且力求简单、经济, 仍然是CRC及癌前病变筛查研究的重要任务.
上皮内瘤变, 特变是HGIN与大肠浸润癌的发生密切相关, 而LGIN腺瘤与浸润癌的发生, 联系较轻微[63]. 大肠癌的发生是多阶段的序列事件结果, 由上皮内瘤变发展为癌的演变观点, 则要求对于大肠病变部位, 能够完整切除, 对多个剖面进行多次取材切片, 综合分析, 做出准确的病理分型和临床诊断. 对于已明确诊断为HGIN, 则按良性肿瘤给予处理, 根据肿瘤病变的大小、位置、基础疾病等, 选择适宜的处理方式. 对内镜诊断难以确定病变性质而又高度猜疑为浸润癌的处理, 特别是伴有癌变高危因素的HGIN及腺瘤, 则提倡应积极处理, 以进一步的病理结果来指导临床外科处理. 对明确诊断为浸润癌, 外科手术仍是最佳的处理方法. 近年来, 内镜黏膜下剥离术(endoscopic submucosal dissection, ESD)日益成熟, 对于只经肛门手术不能达到病变组织的直肠癌早期病变及浸润癌, 不仅疗效好而且安全性较高[64,65]. 而对于早期直肠癌的局部切除, 经肛门内镜的显微手术系统(transanal endoscopic microsurgery, TEM)则拥有独有的优势, 其手术视野暴露好、工作空间宽广, 为肿瘤的完全切除、好的效果创造了良好的条件[66].
近年研究[67]发现, 内镜下摘除大肠腺瘤尤其是进展性腺瘤, 可在一定程度上预防大肠癌的发生, 但腺瘤仍具有明显的再发倾向. Martínez等[68]对9167例切除大肠腺瘤的术后患者, 进行长达4年的随访, 发现再次出现大肠腺瘤的占46.7%, 进展性大肠腺瘤占11.2%, 而最终演变为大肠癌的占0.6%. 我国5个医疗中心的统计结果显示, 进展性大肠腺瘤摘除后1、5年的再发率分别高达59.46%和78.07%[69]. 而间歇期癌[70]概念的提出, 也为大肠腺瘤及癌前病变的定期随访提供了科学依据. 大肠肿瘤病变的不同, 患者术后的随访时间也不一样, 进展性腺瘤患者建议术后行结肠镜检查的时间间隔为3-6 mo, 其他息肉检查时间为每隔12-36 mo 1次. 对已行保肛手术的腺瘤性息肉病患者, 术后结肠镜检查应1年1次[71]. 美国Memorial Sloan-Kettering肿瘤中心的2006年建议指南和美国胃肠病协会(American Gastroenterological Association, AGA)2008年共识中对大肠腺瘤摘除后的随访及监测工作作了详细阐述[72,73]. 而我国的大肠肿瘤摘除或手术后随访时间则应结合国内具体情况, 可参照上述标准并做相应的修订. 有学者建议对于第二次结肠镜检查未发现肿瘤者, 可适当延长后续肠镜复查时间[73].
随着近年来对大肠肿瘤相关流行病学的调查研究, 有学者[74,75]认为幽门螺杆菌(Helicobacter pylori, H. pylori)感染可能是大肠腺瘤发生的一个因素, 发现H. pylori IgG血清阳性的患者结肠腺瘤发病率较正常人明显升高. 提示H. pylori的感染可能和大肠腺瘤或者癌前病变有着关联, 对H. pylori的治疗可能对于预防大肠癌的发生有着积极意义. 有研究[76,77]报道, 应用非选择性非甾体类消炎药(non-steroidal antiinflammatory drugs, NSAIDs)或环氧合酶2(cyclooxygenase 2, COX2)抑制剂可以降低大肠腺瘤发生率, 起到预防大肠癌的作用. 但其相关机制目前仍不甚清楚. 由于上述药物胃肠道和心血管的不良反应较明显或医疗成本较高, 并不适合用于一般危险度人群的预防[78,79]. 另外, 补充钙剂和维生素D、纤维素饮食及其肠道代谢物短链脂肪酸(short-chain fatty acid, SCFA)可能也具有一定的预防大肠癌的作用[80-82], 但目前尚缺乏直接的临床试验对上述药物长期使用的安全性和疗效作相关评价. 进行大规模临床干预试验有着非常重要的意义.
结直肠黏膜上皮内瘤变及腺瘤, 特别是HGIN与大肠癌的发生密切相关. 随着基因分子生物学研究的逐渐深入以及定量分析、基因诊断等新技术的快速发展, 早期肠癌的检出率必定会得到提高, 大肠癌预后也会进一步改善. 这为大肠癌的微观早期诊治提供了新的策略, 指明了新的研究方向. 然而对于如何提高大肠癌前病变及早期癌的检出率、选择最佳合理的临床处理手段以及大肠黏膜上皮内瘤变的预防和诊治方案, 仍需要相应的大量临床研究和高质量的循证医学证据. 另外, 对于LGIN病变的相关研究相对较少, 对于其"发展"为癌一般需多长的时间, 仍需要相应的基础和临床资料研究.
大肠癌在我国的发病率和死亡率均较高, 并且有上升趋势, 且发病年龄提前. 而大肠上皮内瘤变及腺瘤作为肠癌发生前的重要环节, 对其分子遗传学改变及临床处理措施进行综述, 具有重要临床意义.
禹正杨, 副教授, 南华大学附属第一医院
大肠癌发生发展中的具体分子遗传学机制以及早期肠癌的无创性非侵入性诊断方法是其研究热点. 而方便快捷、特异性敏感性高的诊断筛查方法的标准化制定是其研究重点和亟需解决的问题.
黄玮等对大肠腺瘤中的一种新型腺瘤-锯齿状腺瘤进行了研究探讨. 房静远等对大肠癌的相关防治筛查等相关共识进行了系统详实的叙述.
本文对结直肠黏膜上皮内瘤变及腺瘤的局部基因改变、分子宏观通路及肿瘤干细胞理论等方面进行了阐述. 此外, 对其临床科学的处理措施及预防方法进行了介绍, 文章可读性强, 临床意义较大.
将传统的大肠癌筛查方法和最新检查手段相结合, 将有助于提高早期肠癌的检出率, 另外对大肠黏膜上皮内瘤变及腺瘤进行准确的诊断和科学的处理及预防, 同样具有实际指导与借鉴意义.
本文层次清晰, 内容丰富, 重点突出, 文章可读性强, 具有一定的临床指导意义.
编辑: 郭鹏 电编:都珍珍
| 1. | Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108. [PubMed] [DOI] |
| 2. | Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L, He J. Report of incidence and mortality in China cancer registries, 2009. Chin J Cancer Res. 2013;25:10-21. [PubMed] [DOI] |
| 4. | Johnson RL, Fleet JC. Animal models of colorectal cancer. Cancer Metastasis Rev. 2013;32:39-61. [PubMed] [DOI] |
| 5. | Hamilton SR, Aaltonen LA. Pathology and genetics of tumous of the digestive system.1 edition. Lyon: IARC Press 2000; 105-118. |
| 6. | Morson BC. The pathogenesis of colorectal cancer. Introduction. Major Probl Pathol. 1978;10:1-13. [PubMed] |
| 7. | Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut. 2002;51:130-131. [PubMed] |
| 11. | Tanaka S, Haruma K, Oka S, Takahashi R, Kunihiro M, Kitadai Y, Yoshihara M, Shimamoto F, Chayama K. Clinicopathologic features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointest Endosc. 2001;54:62-66. [PubMed] [DOI] |
| 12. | Odze RD, Goldblum JR. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. 2nd edition. Philadelphia: Saunders Elsevier 2009; 498-507. |
| 14. | Arebi N, Swain D, Suzuki N, Fraser C, Price A, Saunders BP. Endoscopic mucosal resection of 161 cases of large sessile or flat colorectal polyps. Scand J Gastroenterol. 2007;42:859-866. [PubMed] [DOI] |
| 15. | Park DH, Kim HS, Kim WH, Kim TI, Kim YH, Park DI, Kim HJ, Yang SK, Byeon JS, Lee MS. Clinicopathologic characteristics and malignant potential of colorectal flat neoplasia compared with that of polypoid neoplasia. Dis Colon Rectum. 2008;51:43-49; discussion 49. [PubMed] [DOI] |
| 16. | Pickhardt PJ, Hain KS, Kim DH, Hassan C. Low rates of cancer or high-grade dysplasia in colorectal polyps collected from computed tomography colonography screening. Clin Gastroenterol Hepatol. 2010;8:610-615. [PubMed] [DOI] |
| 18. | Szylberg Ł, Janiczek M, Popiel A, Marszałek A. Serrated polyps and their alternative pathway to the colorectal cancer: a systematic review. Gastroenterol Res Pract. 2015;2015:573814. [PubMed] [DOI] |
| 19. | Aust DE, Baretton GB. Serrated polyps of the colon and rectum (hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed polyps)-proposal for diagnostic criteria. Virchows Arch. 2010;457:291-297. [PubMed] [DOI] |
| 21. | Sweetser S, Smyrk TC, Sugumar A. Serrated polyps: critical precursors to colorectal cancer. Expert Rev Gastroenterol Hepatol. 2011;5:627-635. [PubMed] [DOI] |
| 22. | Makkar R, Pai RK, Burke CA. Sessile serrated polyps: cancer risk and appropriate surveillance. Cleve Clin J Med. 2012;79:865-871. [PubMed] [DOI] |
| 23. | Wada R, Morimoto T, Inayoshi T. Pathological features of the sessile serrated adenoma/polyp with special references of its carcinogenesis. Med Mol Morphol. 2014;47:123-129. [PubMed] [DOI] |
| 24. | Haque TR, Bradshaw PT, Crockett SD. Risk factors for serrated polyps of the colorectum. Dig Dis Sci. 2014;59:2874-2889. [PubMed] [DOI] |
| 25. | Aguilar-Gallardo C, Simón C. Cells, stem cells, and cancer stem cells. Semin Reprod Med. 2013;31:5-13. [PubMed] [DOI] |
| 26. | Davies EJ, Marsh V, Clarke AR. Origin and maintenance of the intestinal cancer stem cell. Mol Carcinog. 2011;50:254-263. [PubMed] [DOI] |
| 27. | Sefah K, Bae KM, Phillips JA, Siemann DW, Su Z, McClellan S, Vieweg J, Tan W. Cell-based selection provides novel molecular probes for cancer stem cells. Int J Cancer. 2013;132:2578-2588. [PubMed] [DOI] |
| 28. | Misra S, Heldin P, Hascall VC, Karamanos NK, Skandalis SS, Markwald RR, Ghatak S. Hyaluronan-CD44 interactions as potential targets for cancer therapy. FEBS J. 2011;278:1429-1443. [PubMed] [DOI] |
| 29. | Zhao LH, Lin QL, Wei J, Huai YL, Wang KJ, Yan HY. CD44v6 expression in patients with stage II or stage III sporadic colorectal cancer is superior to CD44 expression for predicting progression. Int J Clin Exp Pathol. 2015;8:692-701. [PubMed] |
| 30. | Alves CS, Konstantopoulos K. PDGF suppresses the sulfation of CD44v and potentiates CD44v-mediated binding of colon carcinoma cells to fibrin under flow. PLoS One. 2012;7:e41472. [PubMed] [DOI] |
| 31. | Bánky B, Rásó-Barnett L, Barbai T, Tímár J, Becságh P, Rásó E. Characteristics of CD44 alternative splice pattern in the course of human colorectal adenocarcinoma progression. Mol Cancer. 2012;11:83. [PubMed] [DOI] |
| 32. | Garouniatis A, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk. Int J Colorectal Dis. 2013;28:9-18. [PubMed] [DOI] |
| 33. | Baker AM, Graham TA, Elia G, Wright NA, Rodriguez-Justo M. Characterization of LGR5 stem cells in colorectal adenomas and carcinomas. Sci Rep. 2015;5:8654. [PubMed] [DOI] |
| 35. | 柴 宁莉, 张 文成, 王 昭涛, 张 艳娥, 刘 红艳, 万 军, 谭 金华, 王 术勇, 王 揾芳, 裴 雪涛. Lgr5和CD44在肠息肉和结直肠癌中的表达及意义. 南方医科大学学报. 2013;33:972-976. |
| 36. | Johnston SB, Raines RT. Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders. Biochemistry. 2015;54:1576-1582. [PubMed] [DOI] |
| 37. | Mak P, Li J, Samanta S, Chang C, Jerry DJ, Davis RJ, Leav I, Mercurio AM. Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor β repression. Cell Rep. 2015;10:1982-1991. [PubMed] [DOI] |
| 38. | Dean SJ, Perks CM, Holly JM, Bhoo-Pathy N, Looi LM, Mohammed NA, Mun KS, Teo SH, Koobotse MO, Yip CH. Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer. Am J Clin Pathol. 2014;141:323-333. [PubMed] [DOI] |
| 39. | Puchmajerova A, Vasovcak P, Polacek V. [Oncology image. Patient with Cowdenovym Syndrome caused by PTEN mutation]. Klin Onkol. 2014;27:303. [PubMed] |
| 40. | Beg S, Siraj AK, Jehan Z, Prabakaran S, Al-Sobhi SS, Al-Dawish M, Al-Dayel F, Al-Kuraya KS. PTEN loss is associated with follicular variant of Middle Eastern papillary thyroid carcinoma. Br J Cancer. 2015;112:1938-1943. [PubMed] [DOI] |
| 42. | Sun Y, Tian H, Wang L. Effects of PTEN on the proliferation and apoptosis of colorectal cancer cells via the phosphoinositol-3-kinase/Akt pathway. Oncol Rep. 2015;33:1828-1836. [PubMed] [DOI] |
| 43. | Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990;247:49-56. [PubMed] |
| 44. | Saito M, Yamaguchi A, Goi T, Tsuchiyama T, Nakagawara G, Urano T, Shiku H, Furukawa K. Expression of DCC protein in colorectal tumors and its relationship to tumor progression and metastasis. Oncology. 1999;56:134-141. [PubMed] |
| 45. | Minami R, Aoyama N, Honsako Y, Kasuga M, Fujimori T, Maeda S. Codon 201Arg/Gly polymorphism of DCC (deleted in colorectal carcinoma) gene in flat- and polypoid-type colorectal tumors. Dig Dis Sci. 1997;42:2446-2452. [PubMed] |
| 46. | Hedrick L, Cho KR, Fearon ER, Wu TC, Kinzler KW, Vogelstein B. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 1994;8:1174-1183. [PubMed] |
| 47. | Kuwata G, Hiramatsu K, Samejima K, Iwasaki K, Takahashi K, Koizumi K, Horiguchi S, Moriya SS, Kobayashi M, Kawakita M. Increase of N1, N12-diacetylspermine in tissues from colorectal cancer and its liver metastasis. J Cancer Res Clin Oncol. 2013;139:925-932. [PubMed] [DOI] |
| 50. | Arvelo F, Sojo F, Cotte C. Biology of colorectal cancer. Ecancermedicalscience. 2015;9:520. [PubMed] [DOI] |
| 51. | Migliore L, Migheli F, Spisni R, Coppedè F. Genetics, cytogenetics, and epigenetics of colorectal cancer. J Biomed Biotechnol. 2011;2011:792362. [PubMed] [DOI] |
| 52. | Pagliarini R, Shao W, Sellers WR. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep. 2015;16:280-296. [PubMed] [DOI] |
| 53. | Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-337. [PubMed] [DOI] |
| 54. | Chaptini L, Laine L. Can I improve my adenoma detection rate? J Clin Gastroenterol. 2015;49:270-281. [PubMed] [DOI] |
| 55. | Foda AA, El-Hawary AK, Abdel-Aziz A. Matrix metalloproteinase-13 expression in the progression of colorectal adenoma to carcinoma: Matrix metalloproteinase-13 expression in the colorectal adenoma and carcinoma. Tumour Biol. 2014;35:5653-5658. [PubMed] [DOI] |
| 56. | Leggett BA, Hewett DG. Colorectal cancer screening. Intern Med J. 2015;45:6-15. [PubMed] [DOI] |
| 57. | Hewitson P, Glasziou P, Irwig L, Towler B, Watson E. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2007;CD001216. [PubMed] [DOI] |
| 58. | Yang HY, Ge ZZ, Dai J, Li XB, Gao YJ. [The effect of immunofecal occult blood test on colorectal cancer screening]. Zhonghua Nei Ke Za Zhi. 2008;47:642-645. [PubMed] |
| 59. | Laiyemo AO, Doubeni C, Pinsky PF, Doria-Rose VP, Sanderson AK, Bresalier R, Weissfeld J, Schoen RE, Marcus PM, Prorok PC. Factors associated with inadequate colorectal cancer screening with flexible sigmoidoscopy. Cancer Epidemiol. 2012;36:395-399. [PubMed] [DOI] |
| 60. | Shaukat A, Church TR, Shanley R, Kauff ND, O'Brien MJ, Mills GM, Jordan PA, Allen JA, Kim A, Feld AD. Development and validation of a clinical score for predicting risk of adenoma at screening colonoscopy. Cancer Epidemiol Biomarkers Prev. 2015;24:913-920. [PubMed] [DOI] |
| 61. | Gattolliat CH, Uguen A, Pesson M, Trillet K, Simon B, Doucet L, Robaszkiewicz M, Corcos L. MicroRNA and targeted mRNA expression profiling analysis in human colorectal adenomas and adenocarcinomas. Eur J Cancer. 2015;51:409-420. [PubMed] [DOI] |
| 62. | 王 侦, 陈 嘉昌, 何 琼, 彭 焕玉, 朱 振宇, 陈 华云, 李 明. MS-HRM检测游离甲基化SEPT9在结直肠癌早期诊断中的应用. 广东医学. 2012;33:1732-1734. |
| 63. | Ikeda Y, Mori M, Shibahara K, Iwashita A, Haraguchi Y, Saku M. The role of adenoma for colorectal cancer development: differences in the distribution of adenoma with low-grade dysplasia, high-grade dysplasia, and cancer that invades the submucosa. Surgery. 2002;131:S105-S108. [PubMed] |
| 64. | Kim YJ, Kim ES, Cho KB, Park KS, Jang BK, Chung WJ, Hwang JS. Comparison of clinical outcomes among different endoscopic resection methods for treating colorectal neoplasia. Dig Dis Sci. 2013;58:1727-1736. [PubMed] [DOI] |
| 65. | Saito Y, Otake Y, Sakamoto T, Nakajima T, Yamada M, Haruyama S, So E, Abe S, Matsuda T. Indications for and technical aspects of colorectal endoscopic submucosal dissection. Gut Liver. 2013;7:263-269. [PubMed] [DOI] |
| 67. | Seo JY, Chun J, Lee C, Hong KS, Im JP, Kim SG, Jung HC, Kim JS. Novel risk stratification for recurrence after endoscopic resection of advanced colorectal adenoma. Gastrointest Endosc. 2015;81:655-664. [PubMed] [DOI] |
| 68. | Martínez ME, Sampliner R, Marshall JR, Bhattacharyya AK, Reid ME, Alberts DS. Adenoma characteristics as risk factors for recurrence of advanced adenomas. Gastroenterology. 2001;120:1077-1083. [PubMed] |
| 69. | Gao QY, Chen HM, Sheng JQ, Zheng P, Yu CG, Jiang B, Fang JY. The first year follow-up after colorectal adenoma polypectomy is important: a multiple-center study in symptomatic hospital-based individuals in China. Front Med China. 2010;4:436-442. [PubMed] [DOI] |
| 70. | Pullens HJ, Siersema PD. Quality indicators for colonoscopy: Current insights and caveats. World J Gastrointest Endosc. 2014;6:571-583. [PubMed] [DOI] |
| 71. | 房 静远, 郑 树, 姜 泊, 来 茂德, 房 殿春, 韩 英, 盛 建秋, 李 景南. 中国大肠肿瘤筛查、早诊早治和综合预防共识意见. 胃肠病学和肝病学杂志. 2011;20:979-995. |
| 72. | Rex DK, Kahi CJ, Levin B, Smith RA, Bond JH, Brooks D, Burt RW, Byers T, Fletcher RH, Hyman N. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer. CA Cancer J Clin. 2006;56:160-17; quiz 160-17;. [PubMed] [DOI] |
| 73. | Levin B, Lieberman DA, McFarland B, Andrews KS, Brooks D, Bond J, Dash C, Giardiello FM, Glick S, Johnson D. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008;134:1570-1595. [PubMed] [DOI] |
| 74. | 王 韶英, 惠 萍萍, 叶 荣菊, 吴 剑, 王 娜, 陈 锡美. 幽门螺杆菌感染与结肠息肉关系的研究. 同济大学学报(医学版). 2009;30:55-58. |
| 75. | Hong SN, Lee SM, Kim JH, Lee TY, Kim JH, Choe WH, Lee SY, Cheon YK, Sung IK, Park HS. Helicobacter pylori infection increases the risk of colorectal adenomas: cross-sectional study and meta-analysis. Dig Dis Sci. 2012;57:2184-2194. [PubMed] [DOI] |
| 76. | Wender RC. Aspirin and NSAID chemoprevention, gene-environment interactions, and risk of colorectal cancer. JAMA. 2015;313:1111-1112. [PubMed] [DOI] |
| 77. | Han YD, Hong YK, Kang JG, Choi YJ, Park CH. Relation of the expression of cyclooxygenase-2 in colorectal adenomas and adenocarcinomas to angiogenesis and prognosis. J Korean Soc Coloproctol. 2010;26:339-346. [PubMed] [DOI] |
| 78. | Rostom A, Dubé C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146:376-389. [PubMed] |
| 79. | Ruder EH, Laiyemo AO, Graubard BI, Hollenbeck AR, Schatzkin A, Cross AJ. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol. 2011;106:1340-1350. [PubMed] [DOI] |
| 80. | Mizoue T, Kimura Y, Toyomura K, Nagano J, Kono S, Mibu R, Tanaka M, Kakeji Y, Maehara Y, Okamura T. Calcium, dairy foods, vitamin D, and colorectal cancer risk: the Fukuoka Colorectal Cancer Study. Cancer Epidemiol Biomarkers Prev. 2008;17:2800-2807. [PubMed] [DOI] |
| 81. | Bhatnagar N, Li X, Chen Y, Zhou X, Garrett SH, Guo B. 3,3'-diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. Cancer Prev Res (Phila). 2009;2:581-589. [PubMed] [DOI] |