肿瘤病因_发病机理.ppt

肿 瘤 学,王彩莲,肿瘤的基本概念,肿瘤 机体在致瘤因子作用下，细胞遗传物质改变导致基因表达异常，细胞异常增殖而形成的新生物,肿瘤的基本概念,Cancer (medical term: malignant neoplasm) is a large, heterogeneous class of diseases in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and often metastasizes, wherein the tumor cells spread to other locations in the body via the lymphatic system or through the bloodstream,肿瘤的基本概念,These three malignant properties of cancer differentiate malignant tumors from benign tumors, which do not grow uncontrollably, directly invade locally, or metastasize to regional lymph nodes or distant body sites like brain, bone, liver, or other organs,肿瘤发生原因,1、肿瘤发生的环境因素 化学致癌 化学致癌物 物理致癌 辐射致癌 生物致癌 病毒致癌 2、遗传因素 3、肿瘤发生的学说,化学致癌,物理、生物致癌,遗传性肿瘤与遗传性肿瘤综合征,遗传性肿瘤与遗传性肿瘤综合征,遗传性肿瘤与遗传性肿瘤综合征,肿瘤发生学说,三阶段学说 两次突变学说（克隆起源学说） 生殖细胞突变 体细胞突变 多阶段学说 干细胞起源学说,肿瘤发生学说,变异细胞,癌前病变,恶性肿瘤,三阶段学说,启动阶段,促进阶段,发展阶段,癌基因,Ras H-ras，K-ras, N-ras 编码产物：鸟苷酸结合蛋白，具有GTP酶活性， 定位于细胞膜的内侧面，为细胞的第二信使 K-ras突变：50%结肠癌、70%-90%胰腺癌、30%肺腺癌,癌基因,myc 编码产物：P62蛋白，使细胞从G0期进入G1期，细胞分裂效应蛋白 myc 扩增：30%-40%小细胞肺癌、神经母细胞瘤、胶质细胞瘤,癌基因,1、HER-2 过表达：乳腺癌、卵巢癌、胃癌，Prognostic Marker 2、C-met 基因扩增、重排、过量表达 3、Bcl-2 基因：NHL 中有易位活化的该基因的表达，与凋亡相关 4、细胞周期蛋白：cyclin蛋白，淋巴瘤、乳腺癌、胃癌、食管癌有蛋白的过度表达 5、端粒酶：染色体末端由端粒DNA和端粒蛋白质构成,H-Ras structure PDB 121p, ribbon showing strands in purple, helices in aqua, loops in gray. Also shown are the bound GTP analog and magnesium ion.,抑癌基因,Rb P53 INK4基因家族 CIP-KIP基因家族 PTEN FHIT BRCA APC DCC WT-1,抑癌基因,Rb： 视网膜母细胞瘤基因 基因缺失或突变 骨肉瘤 肺癌 软组织肉瘤,抑癌基因,p53： 基因缺失或基因突变 抑制细胞生长，诱导细胞凋亡 结肠癌、胃癌、乳腺癌、膀胱癌、 肺癌、肝癌,抑癌基因,INK4基因家族： inhibitors of cyclin-dendent kinases-4 p15,p15,p18,p19 抑制细胞周期蛋白依赖性激酶（CDKs）的活性,抑癌基因,CIP-KIP基因家族： p21, p27, p57 抑制细胞周期蛋白依赖性激酶（CDKs） 的活性 参与细胞分化、细胞周期及调控,抑癌基因,PTEN,Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers,Stucture of human PTEN,抑癌基因,PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. It is one of the targets of an oncomiR, MIRN21.,抑癌基因,This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase,抑癌基因,It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating Akt/PKB signaling pathway,抑癌基因,PTEN is one of the most commonly lost tumor suppressors in human cancer Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, and prostate cancer reduced expression is found in many other tumor types such as lung and breast cancer,抑癌基因,BRCA,Both BRCA genes are tumor suppressor genes that produce proteins that are used by the cell in an enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have double-stranded breaks. The pathway requires proteins produced by several other genes, including CHEK2, FANCD2 and ATM,Harmful mutations in any of these genes disable the gene or the protein that it produces,抑癌基因,The cancer risk caused by BRCA1 and BRCA2 mutations are inherited in an dominant fashion A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations rather than acquired or somatic mutations Cancer caused by a mutated gene is a hereditary cancer rather than a sporadic cancer,抑癌基因,Mutations have been associated with increased risk of developing any kind of invasive cancer stomach cancer pancreatic c