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1、腫瘤細胞 學(xué)習(xí)內(nèi)容 腫瘤流行病學(xué)（了解）腫瘤的起因（了解）腫瘤的生理特征（熟悉）腫瘤發(fā)生的分子機制（掌握）腫瘤細胞起源（掌握）腫瘤干細胞（熟悉）腫瘤治療（了解）腫瘤流行病學(xué) Cancer is one of the most common diseases in the developed world Every year over 12 million people worldwide are diagnosed with cancer.Every year over 7 million people die from the disease thats 13%of the total of

2、 56 million deaths in the world from all causes each year At least 1 in 3 people will develop cancer in their lifetime.-1 in 4 men will die of cancer.-1 in 5 women will die cancer.Incidence of major cancers worldwide,2008.World cancer deaths,2008.我國部分地區(qū)居民前十位疾病死亡專率及死因構(gòu)成（2012年）良性腫瘤和惡性腫瘤 Benign tumours

3、 do not spread from their site of origin,but can crowd out(squash)surrounding cells，e.g.brain tumour,warts.Malignant tumours can spread from the original site and cause secondary tumours.This is called metastasis.They interfere with neighbouring cells and can block blood vessels,the gut,glands,lungs

4、 etc.良性腫瘤和惡性腫瘤的區(qū)別 Cancers are classified according to tissue and cell type from which they arise Carcinoma cancers arising from epithelial cell Sarcamas arise from connective tissue or muscle cells Leukemials and lymphomas derive from white blood cells or their precursors 腫瘤分類 The Hallmarks of Cance

5、r Summarized by Hanahan and Weinberg,Cell，2011 Basic properties of a cancer cell The differences between normal cells and cancer cells 生長失控（Loss of growth control）無限增殖能力（Limitless replicative capacity）基因組不穩(wěn)定性Genetic Instability 侵襲轉(zhuǎn)移（Invasiveness and metastasis）降低能量代謝（deregulating cellular energetics

6、)異質(zhì)性（Heterogeneity）Loss of growth control Loss of contact inhibition Normal cells show contact inhibition Cancer cells lack contact inhibition Normal cells growing in culture depend on growth factors,such as epidermal growth factor and insulin,that are present in serum Cancer cells can proliferate i

7、n the absence of stimulatory growth signals that are required by normal cells.Proliferate without stimulatory growth signal 無限增殖能力 Telomere maintain chromosome structure Telomere is a specified structure of chromosomes,consist of a repeated DNA sequence and proteins In human,The sequence of the repe

8、at unit is GGGTTA,and it is repeated roughly a thousand times at each telomere.Most human somatic cells lack telomerase.As a result,their telomeres shorten with each cell cycle.Complete loss of telomeres leads to end-to-end chromosome fusions and cell death Most tumor cells,despite their rapid proli

9、feration rate overcome this fate by expressing telomerase.Telomerase and the length of chromosomes 基因組不穩(wěn)定性 Aneuploidy in cancer cells Karyotype of a cell from a breast cancer line 降低能量代謝降低能量代謝 Warburg effect 癌細胞具有侵襲和轉(zhuǎn)移能力 Heterogeneity of Cancer Cells 腫瘤的誘發(fā)因素 The causes of cancer 遺傳因素（genetic factors

10、)-癌基因（Oncogene）-抑癌基因（Tumor suppressor gene）環(huán)境因素（Environmental factors）-Organic chemicals -Ionizing radiation,UV -Tumor viruses(SV40,SRV)-Other types of viruses(HPV,cervical Cancer)-Bacterium(H.Pylori,gastric cancer)-Smoking,diet 環(huán)境因素導(dǎo)致基因組的改變，最終導(dǎo)致腫瘤發(fā)生 化學(xué)致癌物導(dǎo)致基因突變 黃曲霉素引起基因突變 輻射引起DNA損傷 Formation of thy

11、mine-thymine dime,the most common type of DNA damage caused by UV irradiation Different carcinogens cause different cancer Vinyl chloride(氯乙烯）liver angiosarcoma Benzene acute leukemia Arsenic(砷）skin carcinoma,bladder cancer Asbestos(石棉）mesothelioma(間皮瘤)Radium osteosarcoma（骨肉瘤）腫瘤相關(guān)病毒 Virus associated

12、 with human cancers Lifestyle,diet and cancer incidence 腫瘤細胞發(fā)生的分子機制 腫瘤細胞產(chǎn)生的根本原因是在體內(nèi)外因素的作用下，細胞內(nèi)遺傳物質(zhì)改變，最終導(dǎo)致細胞增殖失去控制。癌基因（oncogenes)抑癌基因(Tumor-suppressor genes）癌基因(oncogene)原癌基因（原癌基因（proto-oncogene）：是細胞內(nèi)與細胞增殖相關(guān)的基因，是維持機體正常生命活動所必須的，在進化上高等保守。當(dāng)原癌基因的結(jié)構(gòu)或調(diào)控區(qū)發(fā)生變異，基因產(chǎn)物增多或活性增強時，使細胞過度增殖，從而形成腫瘤。癌基因（癌基因（Oncogenes）:癌

13、基因是一類能夠引起細胞癌變的基因。癌基因可以分成兩大類：一類是病毒癌基因，指病毒基因組里帶有的可使受病毒感染的宿主細胞發(fā)生癌變的基因，簡寫成V-OnC；另一類是細胞癌基因，簡寫成c-onc，又稱原癌基因（proto-oncogene），這是指正常細胞基因組中，一旦發(fā)生突變或被異常激活后可使細胞發(fā)生惡性轉(zhuǎn)化的基因。原癌基因編碼7類蛋白質(zhì) Seven types of proteins that participate in controlling cell growth and proliferation 1.Signaling molecules 2.Signal receptors 3.In

14、tracellular transducers 4.Transcription factors 5.Apoptotic proteins 6.Cell cycle proteins 7.DNA repair proteins 病毒癌基因和細胞癌基因病毒癌基因和細胞癌基因 細胞癌基因c-src 受C-末端527位酪氨酸磷酸化的調(diào)節(jié)；病毒癌基因缺少c-src 的C-末端，因而是組成型活化的 原癌基因激活的方式 原癌基因激活的4種方式 Ligand binding leads to dimerization and autophosphorylation Example of proto-oncog

15、ene activation(I)Mutation Example of proto-oncogene activation(II)Amplification Example of proto-oncogene activation(III)Translocation,overexpression Proto-oncogene to oncogene Translocation,fusion protein chronic myelocytic leukemia,CML bcr，breakpoint cluster region,22q11 Abl,9q34 Philadelphia chro

16、mosome Translocation-fusion protein 抑癌基因抑癌基因 Tumor-Suppressor gene 抑癌基因（Tumor-suppressor genes）:抑癌基因也稱為抗癌基因。是正常細胞中存在的基因，在被激活情況下它們具有抑制細胞增殖作用，但在一定情況下被抑制或丟失后可減弱甚至消除抑癌作用的基因。正常情況下它們對細胞的發(fā)育、生長和分化的調(diào)節(jié)起重要作用。常見的抑癌基因常見的抑癌基因 抑癌基因突變引發(fā)腫瘤抑癌基因突變引發(fā)腫瘤 二次打擊學(xué)說(two hit theory)1971年，Knudson通過對兒童視網(wǎng)膜母細胞瘤發(fā)病率的分析，認為此病的發(fā)生是兩次突變的結(jié)果。二次打擊學(xué)說的實質(zhì)是：在遺傳學(xué)上抑癌基因為隱性基因，抑癌基因的編碼產(chǎn)物抑制細胞增殖，抑癌基因一個拷貝突變，不足以致病，只有兩個等位基因全部突變才可能致病。Tumor suppressor gene-Rb Rb control G1/S transition Rb基因突變導(dǎo)致視網(wǎng)膜母細胞瘤基因突變導(dǎo)致視網(wǎng)膜母細胞瘤 遺產(chǎn)性視網(wǎng)膜母細胞瘤和散發(fā)性視網(wǎng)膜母細胞瘤 發(fā)病早，雙側(cè)發(fā)病 發(fā)病晚，單側(cè)發(fā)病