1、肿,瘤,肿,瘤,病理生理学教研室,良性,恶性,肿瘤(tumor),Carcinoma 癌,Sarcoma 肉瘤,Leukemia 白血病,癌症 (cancer),儿童肿瘤发病率在逐渐升高。在5-10岁儿童中，恶性肿瘤在造成死亡病种中排名第一位。,提高肿瘤防治水平和寻找治疗肿瘤的新方法已成为现代医学所面临的最大挑战。,恶性肿瘤: 人类死亡的元凶 现代医学面临的重要挑战之一,、多步骤,治疗,多因素,肿瘤发病学概论,1.肿瘤病因学,Pott P(1775):,Volkman and Bell (1870s):,Rehn (1880s):,Yamagiwa and Ichikawa (1915):,C
2、ook James (1933):,direct,indirect,Pro- carcinogen,童年时当过烟囱清扫工的男性患阴囊癌的比率增高,长期与石蜡油和焦油接触的工人易患皮肤癌,接触苯胺的工人发生泌尿道膀胱肿瘤,反复用煤焦油涂擦兔耳成功地诱发了皮肤癌,证明多种化学致癌物(Benzopyrene) 与动物肿瘤的关系,烷化剂、亚硝酰胺,巴豆油、糖精、 苯巴比妥,多环芳香烃、芳香胺类、亚硝胺、黄曲霉素,Indirect Carcinogen,precarcinigen,Proximate carcinigen,Ultimate carcinigen,carcinogen DNA adduct
3、s,潜,近,终,Polycyclic arimatic hydrocarbon, PAH,DNA damage,detoxication,DNA repair,malignant,Tobacco-specific nitrosamines,TSNA,Aromatic amines,Tobacco,Ellermann and Bang(1908,丹麦 ): chicken leukemia,Rous (1911，美国):,Shope (1933):,Burkitt (1962): viruslymphoma,Epstein and barr (1964): EB virus,DNA virus,
4、RNA virus,无细胞的滤液与恶性肿瘤有病因学上的关系,用滤液成功地诱发了鸡的肉瘤,将病毒所致的野兔乳头状瘤进行皮下移植实验， 发生浸润性鳞癌,发现病毒可以引起淋巴瘤,在Burkitt淋巴瘤细胞培养液中发现EB病毒,Rous sarcoma virus (RSV),DNA virus,与动物或人类肿瘤有关的致瘤性NDA病毒：,DNA病毒一般没有细胞内同源物,乳-多-空病毒类,腺病毒类,疱疹病毒类,乙型肝炎病毒类,痘病毒类,转化蛋白E1A、E1B,SV40 T抗原,HPV16、HPV18 E6、E7转化蛋白,Rb,p53,核蛋白,病毒的致癌作用发生在病毒进入细胞后复制的早期阶段，相关的瘤基因
5、多整合至宿主细胞DNA上。,共同特征：,某些NDA病毒在染色体上的定位具有倾向性，往往表现为累及多个染色体的位点，可能涉及到染色体的脆性部位和原瘤基因的位点.,DNA virus,permissive cell,DNA virus,DNA virus,DNA virus,DNA virus,DNA virus,DNA virus,DNA virus,DNA virus,DNA virus,lytic infection,DNA virus,DNA virus,abortive infection,Non-permissive cell,基因组整合到细胞的DNA中， 使细胞发生转化,retrov
6、irus,RNA virus,Non-defective virus,the Rous sarcoma virus (RSV): the RSV transforming gene (designated v-src) was homologous to a host cellular gene (c-src),defective virus,Retinoblastoma the most common intraocular cancer in children Incidence ： 1 of 13,500 - 25,000 live births Sites: unilateral (2
7、0% hereditary), bilateral (all hereditary) Onset time: Bilateral -12 m,unilateral- 18 m, Most (90%) : 3 y,种族分布差异,家族聚集现象,遗传缺陷,遗传因素,流行病学分析,家系分析,细胞遗传学研究,分子遗传学研究,染色体水平,分子/基因水平,?,chemical,physical,virus,Hugo De Vries and Boveri （1914） Mutational theory,Oswald Avery DNA-genetic carrier,James Watson and Fr
8、ancis Crick (1953),Mendal,Morgan,George Beadle/Edward Tatum(1940s),分子肿瘤学时代,the molecular pathogenesis of human cancer is due to structural and/or functional alterations of specific genes,Renato Dulbecco 1986 年发表于 Science杂志 231 卷 1055 1056页的短文 “ 肿瘤研究的转折点：人类基因组测序 ”中指出： “如果我们想更多地了解肿瘤，我们从现在起必须关注细胞的基因组 。
9、 从哪个物种着手努力 ？如果我们想理解人类肿瘤，那就应从人类开始 。 人类肿瘤研究将因对 DNA 的详细知识而得到巨大推动。”,RNA,Proteins,DNA,Biological Function,Genome,Transcriptome,Proteome,x 5 to 50 functional links per protein,2.肿瘤相关基因,DNA recombinant techniques,DNA transfection,Oncogene,Karyotypic analysis,Molecular clone,Oncogene,homogeneously staining
10、regions HSR,Tumor suppressor,hereditary nonpolyposis colorectal cancer (HNPCC) syndromes,mutator / DNA-mismatch repair -involved genes,Oncogene,Oncogene,retrovirus,RNA virus,Rous (1911，美国):,1950s:电镜的应用,RNA virus,用滤液成功地诱发了鸡的肉瘤,Rous sarcoma virus (RSV),1966:Nobel奖,the RSV transforming gene (designated
11、 v-src),homologous to a host cellular gene (c-src),1989:Bishop and Varmas, Nobel奖,Oncogenes are essential for human life activity, whose normal function is to control cellular growth and differentiation /apoptosis or, in different terms, cell birth and cell death. Correspondingly, their structural a
12、nd/or functional alterations lead uncontrolled cellular growth and abnormal differentiation/apoptosis,Mechanisms of Oncogene Activation,ORF,RS,Proto-oncogene,ORF,RS,ORF,RS,mutation,amplification,Re-arrangement,insersion,Partial karyotypes of trypsin-Giemsa-banded metaphase cells depicting nonrandom
13、chromosomal rearrangements observed in lymphoid malignant diseases.,8q24 :MYC gene,18q21: BCL2,14q32 : IGH,慢性粒细胞性白血病（CML）,3T3 cells,Tumor suppressor,Tumor suppressor,Tumor suppressor,Knudson： two hit hypothesis,Retinoblastoma the most common intraocular cancer in children Incidence ： 1 of 13,500 - 2
14、5,000 live births Sites: unilateral (20% hereditary), bilateral (all hereditary) Onset time: Bilateral -12 m,unilateral- 18 m, Most (90%) : 3 y,1978年 Francke 13q14,1983年Cavenee等 loss of heterozygosity，LOH 染色体 13q14处的DNA标志。,1986年，美国三个实验室分别独立克隆了该基因,Rb,Cell cycle,Quiescence (G0),cyclins,DP,E2F,DNA synt
15、hesis-related genes,E2F,E2F,P,P,P,P,等位基因缺失:视网膜母细胞瘤、骨肉瘤、小细胞肺癌、非小细胞肺癌、膀胱癌、乳腺癌、软组织肉瘤、肝癌等肿瘤,Rb基因的异常,基因突变：以肺癌、乳腺癌、骨肉瘤、软组织肉瘤出现率高，从 1550不等，主要集中于外显子 1317上。在小细胞肺癌中 Rb基因异常可达47，骨肉瘤可达43，乳腺癌可达32。在原发性肝癌可达18。,tumor suppressor gene,Oncogene,该恶性肿瘤的相应正常组织中该基因必须正常表达；,该恶性肿瘤中这种基因应有功能失活或结构改变或表达缺陷；,导人基因异常的肿瘤细胞内可部分或全部改变其恶性表型,Genes,？,growth,differentiation,death,growth,differentiation,death,谢 谢,
