医学精品课件:1-肿瘤与免疫-概述,癌变相关机制.pptx
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1、 上海交通大学医学院上海交通大学医学院免疫免疫与与微生物学微生物学系系 葛 海 良地址:医学院西院地址:医学院西院5 5号号楼楼8 8楼楼817817室室电话:电话:6384659063846590转分机转分机776792776792E-mail: 课程涉及主要内容课程涉及主要内容 参考书籍和引用文献参考书籍和引用文献 肿瘤与免疫肿瘤与免疫 肿瘤免疫学的发展简史肿瘤免疫学的发展简史 癌基因理论癌基因理论概概 述述一、细胞癌变的生物学特征和相关机制一、细胞癌变的生物学特征和相关机制二、肿瘤抗原二、肿瘤抗原三、机体抗肿瘤的免疫机制三、机体抗肿瘤的免疫机制四、肿瘤的免疫逃逸机制四、肿瘤的免疫逃逸机制
2、五、肿瘤标志物五、肿瘤标志物六、肿瘤的免疫治疗六、肿瘤的免疫治疗七、肿瘤的基因治疗七、肿瘤的基因治疗八、肿瘤免疫学常用实验技术八、肿瘤免疫学常用实验技术课程涉及主要内容课程涉及主要内容主要参考书和引用文献主要参考书和引用文献*参阅近期相关杂志参阅近期相关杂志 肿瘤是一群失去正常生长调控机制、肿瘤是一群失去正常生长调控机制、发生恶性转化、增殖的自身细胞。发生恶性转化、增殖的自身细胞。肿瘤免疫学肿瘤免疫学(tumor immunology)是是研究肿瘤的免疫原性、对肿瘤的免疫应研究肿瘤的免疫原性、对肿瘤的免疫应答和效应机制、机体的免疫功能与肿瘤答和效应机制、机体的免疫功能与肿瘤发生发展的相互关系,
3、以及肿瘤的免疫发生发展的相互关系,以及肿瘤的免疫诊断和免疫防治的科学诊断和免疫防治的科学。肿瘤与免疫肿瘤与免疫Lymphocytic inflammation associated with certain tumorsA.Medullary breast carcinoma.B.Malignant melanoma.Red arrows indicate malignant cells.Yellow arrows indicate lymphocyte-rich inflammatory infiltrates.肿瘤免疫学的发展简史肿瘤免疫学的发展简史18911891年年,William C
4、oleyWilliam Coley使用使用Robert KochRobert Koch提供提供的的脓性链球菌脓性链球菌培养物(培养物(ColeyColey毒素)来治疗毒素)来治疗恶性肉瘤恶性肉瘤,取得了取得了10%10%的治愈率。的治愈率。19091909年,年,EhrlichEhrlich首次提出侧链理论,免疫系统首次提出侧链理论,免疫系统防御微生物侵犯,从体内清除改变了的宿主成分。防御微生物侵犯,从体内清除改变了的宿主成分。19501950年,年,FoleyFoley在纯系小鼠诱发的肿瘤在同系小在纯系小鼠诱发的肿瘤在同系小鼠之间移植试验发现,肿瘤确能被宿主视为鼠之间移植试验发现,肿瘤确能被
5、宿主视为 非己非己 而产生特异的免疫排斥反应,这种排斥反应依赖于而产生特异的免疫排斥反应,这种排斥反应依赖于恶性转化细胞表面携带的肿瘤相关抗原(恶性转化细胞表面携带的肿瘤相关抗原(TAATAA)或)或肿瘤特异性移植抗原(肿瘤特异性移植抗原(TSTATSTA)。)。19601960年,年,BurnetBurnet和和ThomasThomas等人将等人将EhrlichEhrlich的观点的观点系统化,提出了系统化,提出了免疫监视学说免疫监视学说。免疫系统具有精确。免疫系统具有精确地分辨地分辨 自己自己 和和 非己非己 的成分;清除体内的转化细的成分;清除体内的转化细胞,阻止肿瘤的生长。胞,阻止肿瘤
6、的生长。u1970-19901970-1990年年,学科交叉、实验技术发展,人们相继发现一学科交叉、实验技术发展,人们相继发现一系列系列TAATAA和和TSATSA、肿瘤抗原刺激机体免疫应答以及单克隆技术、肿瘤抗原刺激机体免疫应答以及单克隆技术应用等实验证据,明确了机体肿瘤免疫监视存在的重要作用。应用等实验证据,明确了机体肿瘤免疫监视存在的重要作用。(1972年年Huebner和和Todaro提出提出 oncogene theory)。19951995年,陆续发现年,陆续发现DCDC能够递呈肿瘤抗原肽并诱发肿瘤特异能够递呈肿瘤抗原肽并诱发肿瘤特异性性T T细胞免疫。在免疫缺陷性基因敲除鼠(细胞
7、免疫。在免疫缺陷性基因敲除鼠(RAG-/-RAG-/-、STAT1-STAT1-/-/-、perforinperforin-/-/-、IFN-/-IFN-/-等)中,致癌物诱发的肿瘤比等)中,致癌物诱发的肿瘤比例明显增高。例明显增高。20002000年以来的研究结果明确显示,固有免疫系统(年以来的研究结果明确显示,固有免疫系统(M M、NKNK、NKTNKT、T T等)在肿瘤免疫监视中起着重要作用,以及与适应等)在肿瘤免疫监视中起着重要作用,以及与适应性免疫的相互关系。性免疫的相互关系。DCDC为平台的肿瘤疫苗、人源化抗体的肿为平台的肿瘤疫苗、人源化抗体的肿瘤治疗等取得很大进展。瘤治疗等取得很
8、大进展。20022002年年DunnDunn和和SchreiberSchreiber提出了提出了免疫编辑理论免疫编辑理论,对肿瘤免,对肿瘤免疫监视学说的完善和发展。疫监视学说的完善和发展。近近1010年来,免疫调节、肿瘤微环境对肿瘤发生、发展的影年来,免疫调节、肿瘤微环境对肿瘤发生、发展的影响作用越来越受到人们的重视。响作用越来越受到人们的重视。Cancer incidence increases with age.The incidence of cancer increases exponentially with age in a human population from the ag
9、e of 40 to-80,when it plateaus.Immediately this suggests that cancer is the result of the occurrence of a series of independent events.Cancers proliferate by clonal selection.When a mutation occurs to confer a growth advantage,the descendent cells will dominate the population.A cancer advances by cl
10、onal selection for more malignant cells at each stage.The two major types of change in the genome are the accumulation of somatic mutations and the development of genetic instability.癌基因理论癌基因理论By comparing cancer cells with normal cells,we can identify genes that have been changed by mutation.Those
11、that have direct effects on the generation of a cancer can be divided into oncogenes(where a mutation has activated a gene whose function contributes to the tumorigenic state)and tumor suppressors(where a mutation has inactivated a gene whose function antagonizes the tumorigenic state).In most cases
12、,a cancer arises because a series of mutations have accumulated in a somatic cell,activating oncogenes and/or inactivating tumor suppressors.Genetic diversity in the population means that each individual may have a different set of alleles at these loci.Natural selection acts to eliminate alleles in
13、 the germline that contribute to cancer formation.However,there are some rare hereditary diseases that are caused by such alleles.In these cases,the affected individuals have a high probability of suffering from a cancer.In addition,susceptibility to cancer is influenced by many other loci,generally
14、 known as tumor modifiers.The products of these loci affect the functions of oncogenes or tumor suppressors,either directly or indirectly,but do not themselves have any direct effects.Oncogenes were initially identified as genes carried by viruses that cause transformation of their target cells.A ma
15、jor class of the viral oncogenes have cellular counterparts that are involved in normal cell functions.The cellular genes are called proto-oncogenes,and in certain cases their mutation or aberrant activation in the cell to form an oncogene is associated with tumor formation.About 100 oncogenes have
16、been identified.Viral class Type of virus Genome size Oncogenes Origin of oncogene Action of oncogenePolyoma dsDNA 5-6kb T antigens Early viral gene Inactivates tumor suppressorHPV dsDNA 8kb E6&E7 Early viral gene Inactivates tumor suppressorAdeno dsDNA 37kb E1A&E1B Early viral gene Inactivates tumo
17、r suppressorRetrovirus ssRNA 6-9kb Individual Cellular Activates oncogenic pathway(acute)Transforming viruses may carry oncogenes The oncogenes of DNA transforming viruses are early viral functions.The oncogene becomes integrated into the host cell genome and is expressed constitutively.The oncogene
18、s of polyoma viruses are T antigens,which are expressed by alternative splicing from a single locus.Adenoviruses express several E1A and E1B proteins from two genes.The oncogenes of DNA transforming viruses are early viral functions,whereas the oncogenes of retroviruses are modified from cellular ge
19、nes.Transformation may occur spontaneously,may be caused by certain chemical agents,and,most notably,may result from infection with tumor viruses.There are many classes of tumor viruses,including both DNA and RNA viruses,and they occur widely in the avian and animal kingdoms.The transforming activit
20、y of a tumor virus resides in a particular gene or genes carried in the viral genome.Oncogenes were given their name by virtue of their ability to convert cells to a tumorigenic(or oncogenic)state.An oncogene initiates a series of events that is executed by cellular proteins.In effect,the virus thro
21、ws a regulatory switch that changes the growth properties of its target cell.一、一、恶性肿瘤生物学特征恶性肿瘤生物学特征二、二、细胞癌变的相关机制细胞癌变的相关机制细胞癌变的生物学特征细胞癌变的生物学特征和相关机制和相关机制一、恶性肿瘤生物学特征一、恶性肿瘤生物学特征 肿瘤肿瘤细胞的基因突变和遗传细胞的基因突变和遗传不稳定性,出现不稳定性,出现新新的的 或异常表达或异常表达的的蛋白,干扰或发挥特定的生物学功能。蛋白,干扰或发挥特定的生物学功能。肿瘤细胞具有自主肿瘤细胞具有自主生成、不受宿主调控生成、不受宿主调控、无限
22、增殖、无限增殖 行为行为。细胞细胞与细胞及与周围组织之间正常与细胞及与周围组织之间正常相互作用改变,相互作用改变,并具有并具有周围组织侵袭和周围组织侵袭和转移能力。转移能力。肿瘤肿瘤组织中有新血管的形成。组织中有新血管的形成。某些某些肿瘤细胞可表达或分泌相关分子肿瘤细胞可表达或分泌相关分子,营造免疫抑营造免疫抑 制、促进肿瘤生长的微环境制、促进肿瘤生长的微环境。1.1.体外细胞培养体外细胞培养2.2.荷瘤动物模型荷瘤动物模型3.3.体内生长特征体内生长特征Normal fibroblasts grow as a layer of flat,spread-out cells,whereas tr
23、ansformed fibroblasts are rounded up and grow in cell masses.The cultures on the left contain normal cells.Those on the right contain transformed cells.The top views are by conventional microscopy,the bottom by scanning electron microscopy.u Anchorage dependence a solid or firm surface is needed for
24、 the cells to attach to.u Serum dependence(also known as growth factor dependence)serum is needed to provide essential growth factors.u Density-dependent inhibition cells grow only to a limited density,because growth is inhibited,perhaps by processes involving cell-cell contacts.体外细胞培养体外细胞培养Rao W,Xi
25、e G,Zhang Y,Ge H,et al.PLoS One.2014;9(3):e85705Three types of properties distinguish a cancer cell from a normal cell.Sequential changes in cultured cells can be correlated with changes in tumorigenicity.荷瘤动物模型荷瘤动物模型Renfeng Zhang,Cancer Letters 2015,357,141-151形态观察:形态观察:细胞外形改变;细胞外形改变;细胞骨架结构紊乱;细胞骨架结
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