RAGE在肿瘤微环境中血管生成作用机制的研究

发布时间：2018-06-07 19:14

本文选题：晚期糖基化终产物受体（RAGE） + 肿瘤相关巨噬细胞（TAMs）　；参考：《吉林大学》2014年博士论文

【摘要】：随着对神经胶质瘤的靶向治疗的发展，肿瘤微环境对于治疗反应的贡献也越来越明显。包括星形胶质细胞，内皮细胞，间质细胞和炎性浸润细胞在内的神经胶质瘤相关的基质细胞在肿瘤发生，，血管生成，浸润和免疫逃避过程中均发挥了重要作用。在这些细胞中，浸润性小神经胶质细胞和巨噬细胞（这里指肿瘤相关的巨噬细胞），由于其能够使神经胶质瘤免受抗血管生成影响而备受关注。作为先天性免疫系统中的一员，肿瘤相关巨噬细胞和那些起源于大脑及脊髓的能够在体温检测系统中表现出不同识别受体的细胞不同。在这些受体其中之一便是晚期糖化终产物受体，这种受体最早被发现是连接糖基化大分子产物的表面蛋白分子。晚期糖化终产物受体是涉及到多种人类疾病过程的多配体受体免疫球蛋白大家族中的一员[1]。在正常的生理学条件下，晚期糖化终产物受体在肺组织中表达很高，在其他类型细胞如免疫细胞，神经元细胞，激活的内皮细胞，血管平滑肌细胞和成骨细胞中表达相对较低。然而在病理情况下，比如糖尿病，慢性炎症或者神经退行性疾病中，晚期糖化终产物受体会在其他组织，如脉管系统，造血细胞及中枢神经系统组织中剧烈增加。晚期糖化终产物受体连接多种分子，如糖化产物和S100蛋白分子，而且作为识别受体中的一员，晚期糖基化产物受体可以连接类似于高迁移率蛋白样的分子[1]。高迁移率蛋白起源于受损细胞分子和激活的免疫系统。晚期糖化终产物受体通过连接配体导致激活多种信号通路的下调，最终导致NF-κB,AP-1, CREB, STAT3, and NFAT等细胞因子，趋化因子，粘附分子和能够调节细胞增生，存活，分化，迁移，吞噬，自噬的通路的激活[2]。因此晚期糖化终产物受体与致癌作用相关丝毫不让人感到惊讶。上调RAGE和它的配体水平，不但能够维持慢性炎症状态，而且已经被证实与许多种肿瘤例如胃癌[3]、结肠癌[4]、前列腺癌[5]等的发生与发展有关。而且，一个比较早的报道表述了通过阻断RAGE与HMGB1之间的相互作用可以通过抑制p42/p44，p38和SAP/JNK激酶，有效抑制肿瘤的生长[6]。多数的研究在评价晚期糖化终产物受体时更关注于他和配体之间相互作用在肿瘤生成过程中的作用，而它在肿瘤微环境（TME）到肿瘤生成过程中的表达却没有被详细描述。本实验首先通过引进RAGE基因敲除小鼠模型，选取GL261和K-Luc两种神经胶质瘤细胞株，通过颅内注射原位种植的方式建立神经胶质瘤小鼠模型，以野生型小鼠为对照，对RAGE基因敲除的神经胶质瘤小鼠的生存期、肿瘤炎症反应、肿瘤血管生成作用以及肿瘤微环境中肿瘤相关巨噬细胞通过RAGE活化参与血管生成的作用进行了细致深入的研究，结果显示RAGE敲除可显著延长神经胶质瘤小鼠的生存期，可能的机制在于RAGE的敲除降低了肿瘤的炎症反应以及在肿瘤增大后对肿瘤血管生成的损伤。本文还进一步证实了肿瘤相关的巨噬细胞TAMs中巨噬细胞MP和小胶质细胞MG分别在肿瘤的微环境中通过活化RAGE参与肿瘤炎症反应和血管的生成。并且由于GL261和K-Luc两种细胞株的表现不同，体现出肿瘤的异质性，提示针对RAGE的靶向治疗应更为具体化。
[Abstract]:As a member of the innate immune system , tumor - related macrophages and macrophages ( herein referred to as tumor - related macrophages ) have different recognition receptors in body temperature detection systems , including astrocytes , endothelial cells , interstitial cells and inflammatory infiltrate cells . One of these receptors is advanced glycated end - product receptors , one of which is first found to be a surface protein molecule linked to a glycosylated macromolecular product .

Advanced glycated end product receptors are one of the multiple ligand receptor immunoglobulin families involved in a variety of human disease processes . In normal physiological conditions , advanced glycated end - product receptors are highly expressed in lung tissues and are relatively low in other types of cells such as immune cells , neuronal cells , activated endothelial cells , vascular smooth muscle cells , and osteoblasts . However , in pathological conditions , such as diabetes , chronic inflammation , or neurodegenerative diseases , advanced glycated end product receptors may be strongly increased in other tissues , such as vasculature , hematopoietic cells and central nervous system tissues .

Advanced glycated end product receptors are linked to a variety of molecules , such as glycated products and S100 protein molecules , and as a member of the recognition receptor , advanced glycosylation product receptors may be linked to molecules like high mobility protein - like molecules .

High mobility proteins are derived from damaged cell molecules and activated immune systems . The late glycated end product receptors activate downregulation of multiple signal pathways by linking ligands , eventually leading to activation of cytokines , chemokine , adhesion molecules , and the like of NF - & kappa . B , AP - 1 , CREB , STAT, and NFAT , as well as activation of the pathways that regulate cell proliferation , survival , differentiation , migration , phagocytosis , autophagy . Therefore , the advanced glycosylation end product receptor is not surprisingly related to carcinogenesis .

Up - regulation of RAGE and its ligand levels can not only maintain chronic inflammatory conditions but also have been demonstrated to be associated with the development of many types of tumors such as gastric cancer , stomach cancer , colon cancer , prostate cancer , and prostate cancer . Most studies focus more on the role of the interaction between him and the ligand in the course of tumor formation during the evaluation of advanced glycated end - product receptors , which have not been described in detail in the course of tumor microenvironment ( tme ) to tumor formation .

In this experiment , we studied the effects of RAGE activation on tumor angiogenesis by introducing RAGE gene knockout mice model , selecting GL261 and K - Luc glioma cell lines , and by means of intracranial injection in - situ implantation . The results showed that RAGE - knockout could prolong the survival time of glioma mice .
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R739.4

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