腫瘤發(fā)生發(fā)展對(duì)非涉及器官代謝組的影響規(guī)律研究
發(fā)布時(shí)間：2019-01-26 22:06
【摘要】：近幾十年來,癌癥仍是全球死亡率最高的三大疾病之一,具有極高的發(fā)病率和死亡率,嚴(yán)重影響了人類的健康和生活。其中,肺癌和大腸癌是發(fā)生率和致死率都處于前三位的惡性腫瘤疾病。但目前癌癥的治療效果不盡理想,其治愈率很低,特別是在惡性腫瘤已經(jīng)發(fā)生轉(zhuǎn)移的中晚期階段,因此癌癥的預(yù)防和早期診斷對(duì)降低癌癥的發(fā)病率和死亡率具有重要的意義。認(rèn)識(shí)癌癥發(fā)病初期階段發(fā)生發(fā)展過程中機(jī)體的代謝應(yīng)答規(guī)律,為癌癥的早期診斷和癌癥初期的機(jī)制研究提供了重要的生物信息。在前人對(duì)癌癥的代謝組學(xué)的研究中主要集中在體液和腫瘤組織的代謝組變化,對(duì)腫瘤引起機(jī)體各器官組織的代謝組變化了解甚少,而腫瘤的生長則是對(duì)機(jī)體整個(gè)代謝系統(tǒng)產(chǎn)生影響,分析癌癥早期發(fā)生發(fā)展過程中機(jī)體器官組織的代謝組成和變化規(guī)律為癌癥的初期發(fā)生發(fā)展的機(jī)制研究提供了新的思路。在以上基礎(chǔ)上,本論文主要采用核磁共振技術(shù)結(jié)合多變量及多重單變量數(shù)據(jù)分析相結(jié)合的方法,以肺癌和大腸癌為研究對(duì)象,開展了肺癌腫瘤發(fā)生發(fā)展對(duì)小鼠代謝組的影響和二甲基肼誘導(dǎo)結(jié)腸早期損傷對(duì)大鼠部分器官組織的代謝組影響方面的研究工作。首先,本論文采用人肺腺癌A549細(xì)胞系移植到裸鼠皮下形成肺癌腫瘤體,觀察肺癌腫瘤的生長情況,動(dòng)態(tài)分析機(jī)體的體液(血清和尿液)以及器官組織(心臟、肝臟、脾臟、肺臟和腎臟)的代謝組變化。通過病理學(xué)觀察結(jié)果看出肺癌腫瘤到第39天均未轉(zhuǎn)移到以上器官組織,而由多變量數(shù)據(jù)模型分析結(jié)果發(fā)現(xiàn),腫瘤生長的不同階段對(duì)這些未發(fā)生腫瘤轉(zhuǎn)移的器官組織均產(chǎn)生了不同程度的代謝組影響。通過多變量統(tǒng)計(jì)分析模型發(fā)現(xiàn)肺癌腫瘤生長第6天(腫瘤直徑約2mm)的階段對(duì)機(jī)體多器官組織的代謝組影響較弱,腫瘤生長至第39天(腫瘤直徑約1Omm)對(duì)多器官組織的代謝影響明顯增強(qiáng)。為了進(jìn)一步獲得肺癌腫瘤生長過程的不同階段對(duì)機(jī)體體液和器官組織的代謝組影響,本工作進(jìn)一步通過統(tǒng)一采用多重單變量統(tǒng)計(jì)分析方法,得到在腫瘤生長的第6天和第39天的代謝物的變化,這也表明了代謝組分析手段成為癌癥早期診斷工具的可行性。本文還進(jìn)一步通過氣相色譜-質(zhì)譜聯(lián)用的檢測(cè)技術(shù)手段對(duì)血清和肝臟的脂肪酸進(jìn)行了檢測(cè)分析,對(duì)其脂類中具體脂肪酸的變化進(jìn)行了進(jìn)一步的挖掘分析。其次,本工作對(duì)肺癌腫瘤小鼠模型中腫瘤生長的兩個(gè)階段(第6天和第39天)的腫瘤組織的代謝組進(jìn)行了分析,由研究結(jié)果發(fā)現(xiàn),腫瘤組織不同的生長階段的代謝組有顯著的差異,主要表現(xiàn)在能量代謝(糖酵解的增強(qiáng))、脂類代謝、氨基酸代謝、核苷酸代謝、膜代謝等都發(fā)生了顯著的改變。另外,對(duì)腫瘤中膽堿類代謝進(jìn)一步分析發(fā)現(xiàn),磷酸膽堿和甘油磷酸膽堿含量的比值和肺癌腫瘤的生長呈正相關(guān)變化的線性關(guān)系。最后,本工作建立了二甲基肼誘導(dǎo)結(jié)腸早期損傷的大鼠大腸癌模型,采用中等劑量(90mg/kg,體重)的二甲基肼通過腹腔注射的方式誘導(dǎo)大鼠結(jié)腸組織中異常隱窩的產(chǎn)生,對(duì)注射二甲基肼后不同時(shí)間(第16天和第44天)里引起機(jī)體部分器官組織(心臟、脾臟和肝臟)代謝組的變化進(jìn)行了初步的研究分析。研究發(fā)現(xiàn),DMH誘導(dǎo)的結(jié)腸癌的發(fā)生發(fā)展過程中,經(jīng)過病理學(xué)觀察未引起器官組織(心臟、脾臟和肝臟)的損傷,但對(duì)以上組織均引起了不同程度的代謝紊亂,主要包括能量代謝、氨基酸代謝、脂代謝、核苷酸代謝和細(xì)胞膜代謝的改變。綜上所述,本論文研究了肺癌腫瘤發(fā)生發(fā)展和結(jié)腸早期損傷的大腸癌在兩個(gè)不同階段下機(jī)體的代謝應(yīng)答規(guī)律,特別是對(duì)未涉及器官組織的代謝組的影響改變,證明了基于核磁共振技術(shù)的代謝組學(xué)分析方法對(duì)癌癥的早期診斷具有很重要的應(yīng)用價(jià)值,為癌癥早期發(fā)生發(fā)展的機(jī)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.
【學(xué)位授予單位】：華中師范大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R730.2
本文編號(hào)：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.
【學(xué)位授予單位】：華中師范大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R730.2
【參考文獻(xiàn)】
相關(guān)期刊論文 前4條
1 H.Phillip Koeffler;;Mouse models of colorectal cancer[J];癌癥;2011年07期
2 唐惠儒;王玉蘭;;代謝組學(xué):一個(gè)迅速發(fā)展的新興學(xué)科(英文)[J];生物化學(xué)與生物物理進(jìn)展;2006年05期
3 ;Amino acid uptake in arterio-venous serum of normal and cancerous colon tissues[J];World Journal of Gastroenterology;2004年09期
4 張朝暉,陳鋒,譚佑銘,讓蔚清,張丹,羅招陽;烹調(diào)油煙致Balb/C小鼠肺癌的病理變化[J];中國公共衛(wèi)生;2003年12期
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