阿司匹林抑制食管癌发生与增强顺铂疗效的研究

发布时间：2018-05-27 20:41

本文选题：食管癌 + 阿司匹林　；参考：《北京协和医学院》2016年博士论文

【摘要】：我国恶性肿瘤发病率持续上升,严重影响我国居民健康,对医疗造成巨大负担。食管癌是最为常见的消化道恶性肿瘤之一,其发病率占恶性肿瘤第八位,死亡占第五位。我国是食管癌高发国家,其中90%以上病理类型为鳞状细胞癌(Esophageal squamous cell carcinoma, ESCC),因此食管鳞癌研究对我国居民健康具有重要意义。食管癌是预后较差的恶性肿瘤。由于通常难以早期发现,患者多在晚期就诊,故手术切除率低。食管癌对化疗较不敏感,近年来始终未能取得突破,总体疗效较差,5年生存率仅23%。阿司匹林在预防结直肠癌中的作用已得到一致肯定。其对恶性肿瘤治疗的辅助作用也越来越受到关注。临床研究表明,结直肠癌患者坚持服用阿司匹林能够降低复发和转移,延长患者生存；也有研究提示阿司匹林能够降低食管癌风险。然而尚无明确证据证明明阿司匹林能够预防食管癌发生或提高食管癌治疗效果,阿司匹林提高恶性肿瘤治疗效果也缺乏理论基础。本研究中,我们通过NMBA诱癌模型和裸鼠移植瘤模型证实阿司匹林能够抑制食管癌的发生和生长,对食管癌有一定的预防作用。通过体外实验证实,阿司匹林能够降低食管癌细胞克隆形成能力和成球能力,降低肿瘤干细胞特性。此外,与顺铂联用时,阿司匹林能够显著提高顺铂对食管癌治疗效果。阿司匹林通过多种途径降低食管癌耐药性,促进顺铂诱导的细胞凋亡：抑制ATM磷酸化,抑制肿瘤细胞外排作用,以及抑制肿瘤细胞ALDH1活性。在多株食管癌细胞中,我们检测到阿司匹林对PI3K/Akt信号途径的抑制作用。综上所述,我们的研究表明,阿司匹林能够抑制食管癌的发生和发展,同时能够通过多种机制降低食管癌细胞化疗耐药性,提高顺铂以及其他化疗药物的疗效。我们的实验揭示了阿司匹林在食管癌预防和治疗中的潜在作用,并为其今后在食管癌治疗中与放、化疗方案联合使用提供了理论基础。
[Abstract]:The incidence of malignant tumor in China has been increasing, which has seriously affected the health of Chinese residents and caused a huge burden on medical treatment. Esophageal cancer is one of the most common malignant tumors of digestive tract. China is a country with a high incidence of esophageal cancer, in which more than 90% of the pathological types are esophageal squamous cell carcinoma, carcinomas. Therefore, the study of esophageal squamous cell carcinoma is of great significance to the health of Chinese residents. Esophageal cancer is a malignant tumor with poor prognosis. Because it is usually difficult to find early, patients in late treatment, so the rate of surgical resection is low. Esophageal cancer is insensitive to chemotherapy and has failed to make a breakthrough in recent years. The overall curative effect is poor. The 5-year survival rate is only 23%. The role of aspirin in the prevention of colorectal cancer has been unanimously acknowledged. More and more attention has been paid to its auxiliary effect in the treatment of malignant tumor. Clinical studies have shown that consistently taking aspirin in patients with colorectal cancer can reduce recurrence and metastasis and prolong survival, while other studies have shown that aspirin can reduce the risk of esophageal cancer. However, there is no clear evidence that aspirin can prevent the occurrence of esophageal cancer or improve the therapeutic effect of esophageal cancer, and there is no theoretical basis for aspirin to improve the therapeutic effect of malignant tumor. In this study, we confirmed that aspirin can inhibit the occurrence and growth of esophageal carcinoma by NMBA induced cancer model and xenograft tumor model in nude mice, and has a certain preventive effect on esophageal cancer. It was confirmed by in vitro experiments that aspirin could reduce the ability of cell clone formation and colonization of esophageal cancer cells, and decrease the characteristics of tumor stem cells. In addition, in combination with cisplatin, aspirin can significantly improve the efficacy of cisplatin in the treatment of esophageal cancer. Aspirin can reduce the drug resistance of esophageal cancer and promote the apoptosis induced by cisplatin: inhibition of ATM phosphorylation, inhibition of tumor cell efflux, and inhibition of ALDH1 activity in tumor cells. In a number of esophageal cancer cells, we detected the inhibitory effect of aspirin on PI3K/Akt signaling pathway. To sum up, our study shows that aspirin can inhibit the occurrence and development of esophageal cancer, reduce the chemotherapeutic resistance of esophageal cancer cells through a variety of mechanisms, and improve the efficacy of cisplatin and other chemotherapeutic drugs. Our experiments reveal the potential role of aspirin in the prevention and treatment of esophageal cancer, and provide a theoretical basis for the future use of aspirin in combination with radiotherapy and chemotherapy in the treatment of esophageal cancer.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.1

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