锯齿状息肉及传统腺瘤风险因素对比及其发病机制研究

发布时间：2018-05-17 04:17

本文选题：锯齿状息肉 + 传统腺瘤　；参考：《南方医科大学》2017年硕士论文

【摘要】：目的结直肠癌(colorectal cancer,CRC)为消化系统常见恶性肿瘤,为癌症致死的常见病因。大肠息肉为消化系统常见病,与CRC的发生密切相关,其主要包含两种息肉类型,即锯齿状息肉(SPs)和传统腺瘤(CA),其中锯齿状息肉又包含三种亚型:增生性息肉、无蒂平坦型锯齿状息肉伴或不伴细胞异型性及传统锯齿状腺瘤。大多数CRC由传统腺瘤经传统的“腺瘤-腺癌途径”发展而成,而目前有研究认为,大约有1/3的CRC由锯齿状息肉经“锯齿状途径”演变而来。既往已有研究探讨两类息肉的风险因素及其差异,但性别、年龄等因素对疾病的影响仍存在争议。本研究通过分析对比锯齿状息肉及传统腺瘤的风险因素,从病因学角度探讨两类病变间差异,为高危人群的筛查提供参考信息,有利于医疗资源的高效利用,同时,对两类病变高危人群是否需要进行“差异化”管理进行探讨。近来,越来越多的研究表明炎症微环境在肿瘤发生、发展的各个阶段中均发挥着至关重要的作用,这其中也包括了 CRC。活化的炎症细胞可产生活性氧及活性氮介质,并能利用细胞因子使活性氧在周围上皮细胞中聚集。活性氧及活性氮介质可导致DNA的损伤及基因组的不稳定性,增加基因突变率,从而促使肿瘤的发生。另一方面,肿瘤组织中的炎症及免疫细胞可分泌多种炎症介质,这些炎症介质与相应的受体结合,导致JAK-STAT、MAPK等信号通路的持续激活,促进下游Bcl-XL、Bcl-2、MYC、MMP2等靶基因的转录,作用于细胞的增殖、生长过程,从而促进肿瘤细胞的增殖、浸润及转移。炎症微环境可促进晚期CRC的发展,这一观点目前已得到广泛认可,但其与尚处于癌前阶段的大肠息肉之间的关系尚不明确。既往已有多项研究探讨两类病变基因水平发病机制的差异。本研究拟进一步分析炎症微环境与两类病变发生发展的关系,进一步探讨两类病变发病机制的异同,为药物预防CRC提供参考信息。方法风险因素分析:收集南方医院消化内镜中心2012-2015行全结肠镜及息肉病理检查的病例。按病例入组标准从入选病例中随机选取健康对照103例,锯齿状息肉100例(增生性息肉66例,无蒂平坦型锯齿状息肉伴或不伴细胞异型性21例,传统锯齿状腺瘤13例),传统腺瘤115例(轻度不典型增生71例,中度不典型增生34例,重度不典型增生10例)。收集各病例性别、年龄、身高、体重等临床数据用于分析。发病机制研究:选取南方医院消化内镜中心2012年-2016年行结肠镜检查及息肉病理诊断的病例,从中选取锯齿状息肉53例(增生性息肉12例,无蒂平坦型锯齿状息肉不伴细胞异型性17例、伴细胞异型性5例,传统锯齿状腺瘤低级别瘤变11例、高级别瘤变8例),传统腺瘤44例(低级别瘤变26例,高级别瘤变18例)。选取南方医院消化内镜中心2016年11月至12月期间行结肠镜检查且未见异常者11例作为正常粘膜对照。运用免疫组织化学染色法检测石蜡包埋标本中COX-2、IL-6、p-STAT3、Ki-67的表达。结果风险因素分析:SPs平均发病年龄48.87岁(95%CI 47.22-50.52),较CA更早(P=0.038)。以青年组为参照,中年组发生SPs风险增加2.31倍(95%CI 1.46-3.65)、CA风险增加4.10倍(95%CI 2.50-6.72);老年组发生SPs风险增加 2.77 倍(95%CI 1.52-5.04)、CA 风险增加 6.00 倍(95%CI 3.26-11.05)。其中,年龄与CA的发生较SPs关系更为密切(老年组:OR=2.14,95%CI 1.21-3.78,P=0.009)。男性较女性SPs发病风险增加2.75倍(95%CI 1.50-5.07)、CA增加2.19倍(95%CI 1.22-3.95)。BMI每增加1个单位,SPs发病风险增加1.18倍(95%CI 1.06-1.30)、CA 增加 1.20 倍(95%CI 1.09-1.32)。发病机制研究:COX-2、IL-6、p-STAT3、Ki-67在传统腺瘤中的表达均强于正常粘膜(COX-2:P=0.004;IL-6:P=0.004;p-STAT3:P=0.001;Ki-67:P=0.018)。而在锯齿状息肉中,仅p-STAT3的表达强于正常粘膜,余均无显著性差异(COX-2:P=0.881;IL-6:P=0.484;p-STAT3:P=0.001;Ki-67:P=0.287)。传统腺瘤与锯齿状息肉进行比较,COX-2、IL-6、Ki-67在传统腺瘤中的表达均高于锯齿状息肉(COX-2:P=0.003;IL-6:P=0.0.044;Ki-67:P=0.029),而p-STAT3在两者中的表达并无显著性差异(P=0.991)。COX-2、IL-6、p-STAT3、Ki-67在锯齿状息肉不同亚型中的表达并无显著性差异(COX-2:P=0.534;IL-6:P=0.369;p-STAT3:P=0.054;Ki-67:P=0.601)。COX-2、IL-6、p-STAT3、Ki-67在无蒂平坦型锯齿状息肉不同发展阶段中的表达无显著性差异(COX-2:P=0.359;IL-6:P=0.649;p-STAT3:P=0.319;Ki-67:P=1.000);在传统锯齿状腺瘤不同发展阶段中的表达无显著性差异(COX-2:P=0.152;IL-6:P=0.177;p-STAT3:P=0.129;Ki-67:P=0.051);在传统腺瘤不同发展阶段中的表达无显著性差异(COX-2:P=0.189;IL-6:P=0.283;p-STAT3:P=0.512;Ki-67:P=0.896)。结论两类息肉风险因素均为年龄、男性、BMI,仅年龄与传统腺瘤的发生关系更为密切,对两类息肉高危人群的筛查可考虑使用同一方案。SPs平均发病年龄早于50岁,而其具有快速进展的潜能,建议50岁前即开始进行CRC筛查。炎症微环境可促进肠上皮细胞的增殖;炎症微环境参与了传统腺瘤及锯齿状息肉的发生发展,抗炎药物或可抑制大肠息肉的发生发展;NSAIDs类抗炎药物或仅对传统腺瘤的发生发展具有抑制作用,而对锯齿状息肉不具有抑制作用。对于锯齿状息肉,p-STAT3或为更值得考虑的药物作用靶点。
[Abstract]:Colorectal cancer (CRC) is a common malignant tumor of the digestive system. It is a common cause of cancer death. Colorectal polyps are common diseases of the digestive system. It is closely related to the occurrence of CRC. It mainly contains two types of polyps, namely, serrated polyps (SPs) and traditional adenomas (CA), of which serrated polyps include three subtypes: hyperplasia Sexual polyps, no pedicle type serrated polyps with or without cell heterotypic and traditional serrated adenomas. Most of the CRC is developed by traditional adenoma adenocarcinoma pathway. Currently, some studies have suggested that about 1/3 CRC evolved from the serrated path of the serrated polyps. Two types of previous studies have been studied. The risk factors and differences of polyps are still disputed, but the influence of sex, age and other factors on the disease is still controversial. By analyzing and comparing the risk factors of serrated polyps and traditional adenomas, this study explores the differences between the two types of lesions from the point of view of the etiology, and provides information for the screening of high-risk groups, which is beneficial to the efficient use of medical resources, and at the same time, The need for "differential" management of two types of high-risk groups is discussed. Recently, more and more studies have shown that the inflammatory microenvironment plays a vital role in the development of the tumor. It also includes that CRC. activated inflammatory cells can produce living oxygen and active nitrogen medium and can be used. Cytokine causes the accumulation of active oxygen in the surrounding epithelial cells. Active oxygen and active nitrogen medium can cause DNA damage and genomic instability, increase gene mutation rate, and promote the occurrence of tumor. On the other hand, inflammation and immune cells in the tumor tissue can secrete a variety of inflammatory mediators, these inflammatory mediators and corresponding receptors. Combined, it leads to the continuous activation of JAK-STAT, MAPK and other signaling pathways, promoting the transcription of target genes, such as Bcl-XL, Bcl-2, MYC, MMP2, and other target genes in the downstream, acting on the proliferation and growth process of the cells, thus promoting the proliferation, infiltration and metastasis of the tumor cells. The inflammatory microenvironment can promote the development of late CRC. This view has been widely recognized, but it is still in place. The relationship between colorectal polyps in the precancerous stage is not clear. There have been a number of previous studies to explore the differences in the pathogenesis of the two types of lesions. This study intends to further analyze the relationship between the inflammatory microenvironment and the development of the two types of lesions, further explore the similarities and differences of the pathogenesis of the two types of lesions, and provide reference information for the prevention of CRC. Method analysis of risk factors: 2012-2015 cases of total colonoscopy and polyp pathological examination were collected from the digestive endoscopy center of the southern hospital. According to the standard of case entry, 103 cases of healthy control, 100 cases of serrated polyps (66 cases of proliferative polyps, 21 cases of non pedicle saw polyps with or without cell heterotyping) were selected. 13 cases of serrated adenoma, 115 cases of traditional adenoma (71 cases of mild atypical hyperplasia, 34 cases of moderate atypical hyperplasia, 10 cases of severe atypical hyperplasia). The clinical data of sex, age, height, weight, etc. were collected for analysis of the pathogenesis of each case. Study on the pathogenesis of the cancer endoscopy center of the southern hospital in 2012 -2016 and polyp pathological examination 53 cases of serrated polyps (12 cases of proliferative polyps, 17 cases without pedicle flat serrated polyps without cell atypia, 5 cases with cellular atypia, 11 cases of low grade adenoma with traditional serrated adenoma, 8 cases of advanced tumor change), 44 cases of traditional adenoma (26 cases of low grade neoplasia, 18 cases of advanced tumor and 18 cases) were selected from the digestive tract of the southern hospital. The expression of COX-2, IL-6, p-STAT3 and Ki-67 in paraffin embedded specimens was detected by immunohistochemical staining in 11 cases who underwent colonoscopy from November 2016 to December. The results of risk factors were 48.87 years (95%CI 47.22-50.52), compared with CA earlier (P=0.038). In the middle age group, the risk of SPs increased by 2.31 times (95%CI 1.46-3.65), and the risk of CA increased by 4.10 times (95%CI 2.50-6.72); the risk of SPs increased by 2.77 times (95%CI 1.52-5.04) in the elderly group, and CA risk increased by 6 times (95%CI 3.26-11.05). 9. The risk of SPs increased by 2.75 times (95%CI 1.50-5.07), and CA increased by 2.19 times (95%CI 1.22-3.95).BMI in 1 units. The risk of SPs increased by 1.18 times (95%CI 1.06-1.30) and CA increased 1.20 times (95%CI). P=0.004; IL-6:P=0.004; p-STAT3:P=0.001; Ki-67:P=0.018). But in the serrated polyps, only p-STAT3 expression is stronger than normal mucous membrane, and there is no significant difference (COX-2:P=0.881; IL-6:P=0.484; p-STAT3:P=0.001; Ki-67:P=0.287). Traditional adenomas are compared with serrated polyps, COX-2, IL-6, and Ki-67 in traditional adenomas are higher than sawmills. The expression of COX-2:P=0.003 (IL-6:P=0.0.044; Ki-67:P=0.029) was not significant (P=0.991).COX-2, IL-6, p-STAT3, and Ki-67 in different subtypes of serrated polyps (COX-2:P=0.534; IL-6:P= 0.369; p-STAT3:P=0.054; There is no significant difference in the expression of flat serrated polyps at different stages of development (COX-2:P=0.359; IL-6:P=0.649; p-STAT3:P=0.319; Ki-67:P=1.000); there is no significant difference in the expression of the traditional serrated adenoma at different stages of development (COX-2:P=0.152; IL-6:P=0.177; p-STAT3:P=0.129; Ki-67:P=0.051); in the different developmental stages of the traditional adenoma There was no significant difference in expression (COX-2:P=0.189; IL-6:P=0.283; p-STAT3:P=0.512; Ki-67:P=0.896). Conclusion the risk factors of two types of polyps were age, male, BMI, and the age was more closely related to the occurrence of traditional adenomas. The screening of two groups of high-risk groups of polyps could consider the same scheme as the average age of.SPs at the age of 50. With the potential of rapid progress, it is suggested that CRC screening begins before 50 years of age. Inflammatory microenvironment can promote the proliferation of intestinal epithelial cells; inflammatory microenvironment participates in the development of traditional adenomas and serrated polyps, the development of anti-inflammatory drugs or the inhibition of colorectal polyps; NSAIDs antiinflammatory drugs or only the development of traditional adenomas Inhibition has no inhibitory effect on serrated polyps. For serrated polyps, p-STAT3 is a more worthy drug target.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.3;R574

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