肿瘤发生发展对非涉及器官代谢组的影响规律研究
发布时间：2019-01-26 22:06
【摘要】：近几十年来,癌症仍是全球死亡率最高的三大疾病之一,具有极高的发病率和死亡率,严重影响了人类的健康和生活。其中,肺癌和大肠癌是发生率和致死率都处于前三位的恶性肿瘤疾病。但目前癌症的治疗效果不尽理想,其治愈率很低,特别是在恶性肿瘤已经发生转移的中晚期阶段,因此癌症的预防和早期诊断对降低癌症的发病率和死亡率具有重要的意义。认识癌症发病初期阶段发生发展过程中机体的代谢应答规律,为癌症的早期诊断和癌症初期的机制研究提供了重要的生物信息。在前人对癌症的代谢组学的研究中主要集中在体液和肿瘤组织的代谢组变化,对肿瘤引起机体各器官组织的代谢组变化了解甚少,而肿瘤的生长则是对机体整个代谢系统产生影响,分析癌症早期发生发展过程中机体器官组织的代谢组成和变化规律为癌症的初期发生发展的机制研究提供了新的思路。在以上基础上,本论文主要采用核磁共振技术结合多变量及多重单变量数据分析相结合的方法,以肺癌和大肠癌为研究对象,开展了肺癌肿瘤发生发展对小鼠代谢组的影响和二甲基肼诱导结肠早期损伤对大鼠部分器官组织的代谢组影响方面的研究工作。首先,本论文采用人肺腺癌A549细胞系移植到裸鼠皮下形成肺癌肿瘤体,观察肺癌肿瘤的生长情况,动态分析机体的体液(血清和尿液)以及器官组织(心脏、肝脏、脾脏、肺脏和肾脏)的代谢组变化。通过病理学观察结果看出肺癌肿瘤到第39天均未转移到以上器官组织,而由多变量数据模型分析结果发现,肿瘤生长的不同阶段对这些未发生肿瘤转移的器官组织均产生了不同程度的代谢组影响。通过多变量统计分析模型发现肺癌肿瘤生长第6天(肿瘤直径约2mm)的阶段对机体多器官组织的代谢组影响较弱,肿瘤生长至第39天(肿瘤直径约1Omm)对多器官组织的代谢影响明显增强。为了进一步获得肺癌肿瘤生长过程的不同阶段对机体体液和器官组织的代谢组影响,本工作进一步通过统一采用多重单变量统计分析方法,得到在肿瘤生长的第6天和第39天的代谢物的变化,这也表明了代谢组分析手段成为癌症早期诊断工具的可行性。本文还进一步通过气相色谱-质谱联用的检测技术手段对血清和肝脏的脂肪酸进行了检测分析,对其脂类中具体脂肪酸的变化进行了进一步的挖掘分析。其次,本工作对肺癌肿瘤小鼠模型中肿瘤生长的两个阶段(第6天和第39天)的肿瘤组织的代谢组进行了分析,由研究结果发现,肿瘤组织不同的生长阶段的代谢组有显著的差异,主要表现在能量代谢(糖酵解的增强)、脂类代谢、氨基酸代谢、核苷酸代谢、膜代谢等都发生了显著的改变。另外,对肿瘤中胆碱类代谢进一步分析发现,磷酸胆碱和甘油磷酸胆碱含量的比值和肺癌肿瘤的生长呈正相关变化的线性关系。最后,本工作建立了二甲基肼诱导结肠早期损伤的大鼠大肠癌模型,采用中等剂量(90mg/kg,体重)的二甲基肼通过腹腔注射的方式诱导大鼠结肠组织中异常隐窝的产生,对注射二甲基肼后不同时间(第16天和第44天)里引起机体部分器官组织(心脏、脾脏和肝脏)代谢组的变化进行了初步的研究分析。研究发现,DMH诱导的结肠癌的发生发展过程中,经过病理学观察未引起器官组织(心脏、脾脏和肝脏)的损伤,但对以上组织均引起了不同程度的代谢紊乱,主要包括能量代谢、氨基酸代谢、脂代谢、核苷酸代谢和细胞膜代谢的改变。综上所述,本论文研究了肺癌肿瘤发生发展和结肠早期损伤的大肠癌在两个不同阶段下机体的代谢应答规律,特别是对未涉及器官组织的代谢组的影响改变,证明了基于核磁共振技术的代谢组学分析方法对癌症的早期诊断具有很重要的应用价值,为癌症早期发生发展的机制研究提供了重要的信息和思路。
[Abstract]:In recent decades, cancer remains one of the highest in the world's highest mortality rate, with very high morbidity and mortality, which seriously affects human health and life. Among them, lung cancer and large intestine cancer are the first three-position malignant tumor disease. but at present, the treatment effect of the cancer is not ideal, the cure rate is low, especially in the middle and late stage of the malignant tumor, so the prevention and the early diagnosis of the cancer are of great significance to the reduction of the morbidity and the mortality of the cancer. The study of the metabolic response of the body during the early stage of the development of cancer has provided important biological information for the early diagnosis of cancer and the mechanism of the early stage of cancer. In the study of the study of the metabolic group of cancer, the change of the metabolic group of body fluid and tumor tissue is mainly concentrated, and the change of the metabolic group of the organ tissues of the body caused by the tumor is very small, and the growth of the tumor is an effect on the whole metabolism system of the body, In the early stage of the development of cancer, the metabolic composition and the rule of the body organ tissues provide a new thought for the mechanism of the early development of the cancer. on the basis of the above, the present thesis mainly uses nuclear magnetic resonance technology to combine the multi-variable and multiple single-variable data analysis method to study the lung cancer and the large intestine cancer as the research object, The effects of the development of the tumorigenesis of lung cancer on the metabolism of mice and the effect of dimethylbenzene on the metabolism of some organ tissues in rats were studied. First, a human lung adenocarcinoma A549 cell line was transplanted to a nude mouse to form a lung cancer tumor, and the growth of the lung cancer tumor was observed, and the body fluid (serum and urine) of the body and the metabolic group of the organ tissue (heart, liver, spleen, lung and kidney) were analyzed. The results of the pathology observation show that the tumor of the lung cancer is not transferred to the above organ tissue at the 39 th day, and the results of the multi-variable data model show that the different stages of the tumor growth have a different degree of the effect of the metabolism group on these organ tissues which do not have the tumor metastasis. The effect of tumor growth on the metabolism of multi-organ tissues was found to be weaker in the stage 6 (the diameter of the tumor was about 2 mm) by the multi-variable statistical analysis model, and the effect of tumor growth on the metabolism of the multi-organ tissues was significantly increased on the day 39 (the diameter of the tumor was about 1Omm). In order to further obtain the effect of different stages of the growth process of the lung cancer tumor on the body fluid and the metabolism group of the organ tissue, the work is further adopted to obtain the change of the metabolites in the 6th and 39th days of the tumor growth by uniformly adopting the multiple single-variable statistical analysis method, This also shows the feasibility of metabolic group analysis as a tool for early diagnosis of cancer. In this paper, the fatty acid in serum and liver was analyzed and analyzed by gas chromatography-mass spectrometry (GC-MS). Second, this work performed an analysis of the metabolic groups of tumor tissues in two stages of tumor growth in the lung cancer mouse model (Day 6 and Day 39), and the results of the study found that there was a significant difference in the metabolic groups at different growth stages of the tumor tissue, The main manifestations are energy metabolism (the enhancement of glycolysis), lipid metabolism, amino acid metabolism, metabolism of the core and acid, membrane metabolism, and so on. In addition, the further analysis of the choline metabolism in the tumor found that the ratio of the content of the choline and the phosphocholine in the tumor and the growth of the lung cancer tumor were in a linear relationship with the positive correlation. In the end, this work established a rat colon cancer model induced by dimethylbenzene to induce the early injury of the colon, and a medium-dose (90mg/ kg, body weight) dimethyl ether was used to induce the generation of abnormal crypt in the colon tissue of the rat. A preliminary study of the changes in the metabolism of some organ tissues (heart, spleen, and liver) was carried out in different time after injection of dimethyl ether (day 16 and day 44). The study found that in the course of the development of the colon cancer induced by DMH, the pathological observation did not cause the damage of organ tissue (heart, spleen and liver), but the above-mentioned tissues caused different degree of metabolic disorder, mainly including energy metabolism, amino acid metabolism and lipid metabolism. changes in the metabolism of the core and the metabolism of the cell membrane. To sum up, this paper studies the metabolic response of the body in two different stages of the development of lung cancer and the early injury of the colon, in particular the change of the effect of the metabolic group not involved in the organ tissue, It is proved that the method of metabolic group study based on nuclear magnetic resonance (MRI) has important application value to the early diagnosis of cancer, and provides important information and thought for the mechanism of early development of cancer.
【学位授予单位】：华中师范大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.2
本文编号：2415958
[Abstract]:In recent decades, cancer remains one of the highest in the world's highest mortality rate, with very high morbidity and mortality, which seriously affects human health and life. Among them, lung cancer and large intestine cancer are the first three-position malignant tumor disease. but at present, the treatment effect of the cancer is not ideal, the cure rate is low, especially in the middle and late stage of the malignant tumor, so the prevention and the early diagnosis of the cancer are of great significance to the reduction of the morbidity and the mortality of the cancer. The study of the metabolic response of the body during the early stage of the development of cancer has provided important biological information for the early diagnosis of cancer and the mechanism of the early stage of cancer. In the study of the study of the metabolic group of cancer, the change of the metabolic group of body fluid and tumor tissue is mainly concentrated, and the change of the metabolic group of the organ tissues of the body caused by the tumor is very small, and the growth of the tumor is an effect on the whole metabolism system of the body, In the early stage of the development of cancer, the metabolic composition and the rule of the body organ tissues provide a new thought for the mechanism of the early development of the cancer. on the basis of the above, the present thesis mainly uses nuclear magnetic resonance technology to combine the multi-variable and multiple single-variable data analysis method to study the lung cancer and the large intestine cancer as the research object, The effects of the development of the tumorigenesis of lung cancer on the metabolism of mice and the effect of dimethylbenzene on the metabolism of some organ tissues in rats were studied. First, a human lung adenocarcinoma A549 cell line was transplanted to a nude mouse to form a lung cancer tumor, and the growth of the lung cancer tumor was observed, and the body fluid (serum and urine) of the body and the metabolic group of the organ tissue (heart, liver, spleen, lung and kidney) were analyzed. The results of the pathology observation show that the tumor of the lung cancer is not transferred to the above organ tissue at the 39 th day, and the results of the multi-variable data model show that the different stages of the tumor growth have a different degree of the effect of the metabolism group on these organ tissues which do not have the tumor metastasis. The effect of tumor growth on the metabolism of multi-organ tissues was found to be weaker in the stage 6 (the diameter of the tumor was about 2 mm) by the multi-variable statistical analysis model, and the effect of tumor growth on the metabolism of the multi-organ tissues was significantly increased on the day 39 (the diameter of the tumor was about 1Omm). In order to further obtain the effect of different stages of the growth process of the lung cancer tumor on the body fluid and the metabolism group of the organ tissue, the work is further adopted to obtain the change of the metabolites in the 6th and 39th days of the tumor growth by uniformly adopting the multiple single-variable statistical analysis method, This also shows the feasibility of metabolic group analysis as a tool for early diagnosis of cancer. In this paper, the fatty acid in serum and liver was analyzed and analyzed by gas chromatography-mass spectrometry (GC-MS). Second, this work performed an analysis of the metabolic groups of tumor tissues in two stages of tumor growth in the lung cancer mouse model (Day 6 and Day 39), and the results of the study found that there was a significant difference in the metabolic groups at different growth stages of the tumor tissue, The main manifestations are energy metabolism (the enhancement of glycolysis), lipid metabolism, amino acid metabolism, metabolism of the core and acid, membrane metabolism, and so on. In addition, the further analysis of the choline metabolism in the tumor found that the ratio of the content of the choline and the phosphocholine in the tumor and the growth of the lung cancer tumor were in a linear relationship with the positive correlation. In the end, this work established a rat colon cancer model induced by dimethylbenzene to induce the early injury of the colon, and a medium-dose (90mg/ kg, body weight) dimethyl ether was used to induce the generation of abnormal crypt in the colon tissue of the rat. A preliminary study of the changes in the metabolism of some organ tissues (heart, spleen, and liver) was carried out in different time after injection of dimethyl ether (day 16 and day 44). The study found that in the course of the development of the colon cancer induced by DMH, the pathological observation did not cause the damage of organ tissue (heart, spleen and liver), but the above-mentioned tissues caused different degree of metabolic disorder, mainly including energy metabolism, amino acid metabolism and lipid metabolism. changes in the metabolism of the core and the metabolism of the cell membrane. To sum up, this paper studies the metabolic response of the body in two different stages of the development of lung cancer and the early injury of the colon, in particular the change of the effect of the metabolic group not involved in the organ tissue, It is proved that the method of metabolic group study based on nuclear magnetic resonance (MRI) has important application value to the early diagnosis of cancer, and provides important information and thought for the mechanism of early development of cancer.
【学位授予单位】：华中师范大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.2
【参考文献】
相关期刊论文 前4条
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4 张朝晖,陈锋,谭佑铭,让蔚清,张丹,罗招阳;烹调油烟致Balb/C小鼠肺癌的病理变化[J];中国公共卫生;2003年12期
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