Presentation is loading. Please wait.

Presentation is loading. Please wait.

Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition.

Similar presentations

Presentation on theme: "Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition."— Presentation transcript:

1 Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition 邵吉民,教授,病理学与病理生理学系

2 Introduction Tumor Benign tumor Malignant tumor

3 Cancer Incidence and Mortality
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10-29. 1,638,910 new cancer cases and 577,190 deaths from cancer are projected to occur in USA in 2012. One in 4 deaths in USA is due to cancer. 2010年国际抗癌联盟(UICC): 2008年全世界1270万新增癌症患者,死亡人数760万。 全国肿瘤登记中心《2012中国肿瘤登记年报》 每年新发肿瘤病例约312万例,每天约8550人; 每年因癌死亡270万例,居民因癌死亡率13%,即每7-8人中有1人因癌死亡。 恶性肿瘤发病:第一位肺癌,其次胃癌、结直肠癌、肝癌和食管癌; 恶性肿瘤死亡:第一位肺癌,其次肝癌、胃癌、食管癌和结直肠癌; 中国近20年来癌症呈现年轻化及发病率和死亡率“三线”走高的趋势。癌症种类呈现地域化特点。

4 History of Cancer Research
Kiberstis P, Marshall E. Cancer crusade at 40. Celebrating an anniversary. Introduction. Science. 2011;331(6024):1539.

5 Chemical Carcinogenesis
Multi-stage Theory of Chemical Carcinogenesis Classification of chemical carcinogens Mechanisms of Chemical Carcinogenesis DNA Damage Induced by Ultimate Carcinogens DNA Repair

6 Multi-stage Theory of Chemical Carcinogenesis
Initiation Genetic events Chemical Carcinogens (Direct and Indirect Carcinogens) Promotion Epigenetic events Tumor promoters Murine skin carcinogenesis model: A single dose of polycyclic aromatic hydrocarbon (PAH, initiator) Repeated doses of croton oil (promoter) Malignant conversion Progression Genetic and epigenetic events 6

7 7

8 Initiation Irreversible genetic damage:
A necessary, but insufficient prerequisite for tumor initiation Activation of proto-oncogene, inactivation of a tumor suppressor gene, and etc 8

9 Promotion Promotion: Selective expansion of initiated cells, which are at risk of further genetic changes and malignant conversion Promoters are usually nonmutagenic, not carcinogenic alone, often do not need metabolic activation, can induce tumor in conjuction with a dose of an initiator that is too low to be carcinogenic alone Chemicals capable of both initiation and promotion are called complete carcinogens: benzo[a]pyrene and 4-aminobiphenyl 9

10 Malignant conversion The transformation of a preneoplastic cell into that expresses the malignant phenotype Further genetic changes Reversible The further genetic changes may result from infidelity of DNA synthesis May be mediated through the activation of proto-oncogene and inactivation of tumor-suppressor gene 10

11 Progression The expression of malignant phenotype, the tendency to acquire more aggressive characteristics, Metastasis Propensity for genomic instability and uncontrolled growth Further genetic changes: the activation of proto-oncogenes and the inactivation of tumor-suppressor genes 11

12 Activation of proto-oncogenes:
Point mutations: ras gene family, hotspots Overexpression: Amplification Translocation Loss of function of tumor-suppressor genes: usually a bimodal fashion Point mutation in one allele Loss of second allele by deletion, recombinational event, or chromosomal nondisjunction 12

13 Gene-environmental interactions
The metabolism of xenobiotics by biologic systems Individual variation The competition between activation and detoxication The alteration of genes by xenobiotics 13

14 Classification of chemical carcinogens
1. Based on mechanisms Genotoxic carcinogen (DNA-reactive) Direct-acting: intrinsically reactive N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS), N-ethyl-N-nitrosourea (ENU), nitrogen and sulfur mustards Indirect-acting: require metabolic activation by cellular enzyme to form the DNA-reactive metabolite (members of the cytochrome P450 family) benzo[a]pyrene, 2-acetylaminofluorene, benzidine, Aflatoxin B1, B2. 14

15 15

16 (2) Epigenetic carcinogens
Promotes cancer in ways other than direct DNA damage/ do not change the primary sequence of DNA Alter the expression or repression of certain genes and cellular events related to proliferation and differentiation Promoters, hormone modifying agents, peroxisome proliferators, cytotoxic agents, and immunosuppressors Organochlorine pesticides, [saccharin], estrogen, cyclosporine A, azathioprine 16

17 2. Based on sturcture (1) Nitrosamines (NA)
MNNG, MMS (direct carcinogen) (2) Polycyclic aromatic hydrocarbons (PAH) Benzo(a)pyrene (indirect carcinogen) (3) Aromatic amines (AA) 2-acetylaminofluorene, benzidine (indirect carcinogen) (4) Aflatoxin (AF) (5) Inorganic elements and their compounds: arsenic, chromium, and nickel are also considered genotoxic agents 17

18 18

19 Mechanisms of Initiation in Chemical Carcinogenesis
(1) DNA damages: Pro-carcinogen metabolic activation (Phase I and II) Ultimate carcinogen (electrophiles) Interaction with macromolecules (nucleophiles) DNA damage, mutations, chromosomal aberrations, or cell death (2) Epigenetic changes (3)Activation of oncogenes; inactivation of tumor suppressor genes 19

20 Direct Chemical Carcinogens
(1) Alkylating agents are electrophilic compounds with affinity for nucleophilic centers in organic macromolecules. [Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer Jan 12;12(2): doi: /nrc3185.] (2) These agents can be either monofunctional or bifunctional. ---Monofunctional alkylating agents have a single reactive group and thus interact covalently with single nucleophilic centers in DNA (although varied). such as MNNG ---Bifunctional alkylating agents have two reactive groups, and each molecule is potentially able to react with two sites in DNA. Interstrand DNA cross-link: the two sites are on opposite polynucleotide strands; Intrastrand cross-link: on the same polynucleotide chain of a DNA duplex. such as Nitrogen and sulfur mustard, mitomycin, cis-platinum 20

21 ---Monofunctional alkylating agents
MNNG N-Methyl-N-nitroso-N'-nitroguanidine Numerous potential reaction sites for alkylation have been identified in all four bases of DNA (not all of them have equal reactivity: 21

22 ---Bifunctional alkylating agents

23 Indirect Chemical Carcinogens and Their Phase I Metabolic derivatives

24 BPDE binds DNA covalently, resulting in bulky adduct damage
BPDE intercalates into dsDNA non-covalently, leading to conformational abnormalities

25 Types of DNA Damage Induced by Ultimate Carcinogens
DNA Adduct Formation DNA Break Single Strand Break Double Strand Break DNA Linkage DNA-DNA linkage DNA-protein Linkage Intercalation Bulky aromatic-type adducts, Alkylation (small adducts), Oxidation, Dimerization, Deamination 25

26 DNA Repair Repair systems Direct DNA repair/ Direct reversal :
DNA alkyltransferase (O6-alkylguanine-DNA alkyl transferase) One enzyme per lesion Base excision repair (BER) small adducts, overlap with direct repair glycosylase to remove the adducted base 26

27 Nucleotide excision repair (NER):
involves recognition, preincision, incision, gap-filling, and ligation, large distortions strand specific, the transcribed strand is preferentially repaired xeroderma pigmentosum (XP): NER deficiency Mismatch repair (MMR) transition mispairs are more efficiently repaired (G-T or A-C) than transversion mispairs microenvironment influences efficiency similar to NER involves the excision of large pieces of the DNA XP:着色性干皮病患者的皮肤部位缺乏核酸内切酶,不能修复被紫外线损伤的皮肤的DNA,因此在日光照射后皮肤容易被紫外线损伤,先是出现皮肤炎症,继而可发生皮肤癌... 27

28 Double-strand breaks (DSBs)
homologous recombination non-homologous end joining (NHEJ): DNA-PK Postreplication repair a damage tolerance mechanism occurs in response to replication of DNA on a damaged template the gap either filled through homologous recombination with parental strand or insert an A residue at the single nucleotide gap 28

29 Translesion DNA synthesis

30 Hormones and the etiology of cancer
Major carcinogenic consequence of hormone exposure: cell proliferation The emergence of a malignant phenotype depends on a series of somatic mutation Germline mutations may also occur How to get exposure: contraceptives, hormone replacement therapy, or during prevention of miscarriage Epidemiological studies

31 Hormone-related cancer
Breast cancer and estrogen Endometrial cancer: Estrogen replacement therapy Ovarian cancer: follicle stimulating hormone Prostate cancer and androgen Vaginal adenocarcinoma: in utero diethylstilbestrol (DES) exposure

32 Other hormone-related cancers
Cervical cancer: OC use might increase the risk, still a lot complicating factors Thyroid cancer: the pituitary hormone thyroid stimulating hormone (TSH) Osteosarcoma: incidence associates with the pattern of childhood skeleton growth; and hormonal activity is a primary stimulus for skeleton growth

33 Physical factors in carcinogenesis

34 Physical carcinogens Corpuscular radiations
Electromagnetic radiations (EMF) Ultraviolet lights (UV) Low and high temperatures Mechanical traumas Solid and gel materials


36 Viral Oncogenesis RNA Oncovirus (Retrovirus) DNA Oncovirus 36

37 RNA Oncovirus Retroviruses: Rous sarcoma in chickens (RSV): in 1911
ssRNA viruses Reverse transcriptase Oncogenes Rous sarcoma in chickens (RSV): in 1911 Human T-cell lymphotropic virus (HTLV-I,II) Human immunodeficiency virus (HIV)

38 Classification of retrovirus

39 Structure of RNA Oncovirus

40 Genome of RNA Oncovirus and Gene Products
Genome of Human T-cell Leukemia virus (HTLV) 40

41 Life cycle Receptor binding and membrane fusion
Internalization and uncoating Reverse transcription of the RNA genome to form double-stranded linear DNA Nuclear entry of the DNA Integration of the linear DNA into host chromosomal DNA to form the provirus Transcription of the provirus to form viral RNAs Splicing and nuclear export of the RNAs Translation of the RNAs to form precursor proteins Assembly of the virion and packaging of the viral RNA genome Budding and release of the virions Proteolytic processing of the precursors and maturation of the virions 41

42 Replication of RNA Oncovirus

43 Mechanisms of Oncogenesis Induced by RNA Oncovirus
Transducing Retrovirus v-onc cis-Activating Retrovirus c-onc trans-Activating Retrovirus tax trans-acting x p40tax rex repressive expression x p27rex, p21rex 43

44 Oncogene transduction
Acutely transforming in vivo and in vitro Transform cells by the delivery (transduction) of an oncogene from the host cell (v-onc) to a target cell Cause the formation of polyclonal tumors Most of this group of viruses are replication defective (the requirement of a helper virus) Examples: RSV (v-src); Abelson murine leukemia virus (v-Abl) 44

45 Insertional activation
Long latent periods, Less efficient Do not induce transformation of cells in vitro Usually are replication competent No oncogenes Tumors are usually monoclonal Provirus (LTR) is found within the vincity of a proto-oncogene (c-myc) Examples: lymphoid leukosis virus; 45

46 Grow stimulation and two-step oncogenesis
The defective spleen focus-forming virus (SFFV) and its helper, the Friend murine leukemia virus (Fr-MuLV) Induce a polyclonal erythrocytosis in mice Require the continued viral replication A mutant env protein gp55 of SFFV binds and stimulated the erythropoietin receptor, thus inducing erythroid hyperplasia Fr-MuLV or SFFV integration inactivates p53 46

47 Transactivation HTLV-1 and 2
Like cis-activation group: replication competent, carries no oncogene, induces monoclonal leukemia, and latent Like transducing group: can immortalize cells in vitro, has no specific integration site Unique 3’ genomic structure: the X region; Encodes at least three proteins: Tax (p40), Rex (p27, p21) Tax is the focus Transactivate the viral LTR, results in a 100- to 200-fold increase in the rate of proviral transcription Transactivate cellular enhancers and promoters, including genes for IL-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), c-fos, and others. 47

48 DNA Oncovirus Papilloma virus Polyoma virus Adenovirus
Herpes virus: EB virus Hepatitis B virus 48

49 Mechanism of Oncogenesis Induced by DNA Oncovirus
Transforming proteins 1. HPV E6 interact with P53 E7 interact with RB 2. Adenovirus E1a interact with RB E1b 3. Polyoma virus SV Large T interact with RB Py virus Large and Middle T Transcription activators 1. EB virus EBNA-2 and LMP 2. HBV p28 X protein 49

50 Gene Map and Function of HPV
ORF Function E Virus proliferation E Regulation of transcription E5、E6、E Cell transformation L1、L Encoding capsid protein E Encoding late cytosolic protein E3、E Unkown E5: activates growth factor receptor E6: ubiquitin-mediated degradation of p53 E7: binds and inactivates unphosphorylated pRb 50

51 Genome and Products of HBV
李文辉博士,北京生命科学研究所研究员.本实验室的主要研究兴趣为囊膜病毒侵入及相关过程的分子机制。病毒侵入细胞起始于与细胞表面受体的结合,围绕这一过程,我们希望探索:病毒细胞受体分子的识别;病毒受体是如何介导膜融合的;其它胞内因子是如何参与病毒侵入的;病毒蛋白是如何进行免疫逃逸的;病毒跨物种感染与传播;如何有效地抑制病毒的侵入,等。我们将以几种重要的病毒如新型冠状病毒,出血热病毒,乙脑病毒,乙肝病毒等为研究对象,综合运用以生物化学为主,无生物安全隐忧的多学科方法,以回答上述问题。这些研究将有利于深化对于这些病毒基本生物学及病毒与感染宿主相互作用的认识与理解,并且有助于开发有效的抗病毒制剂及新型疫苗。 乙型肝炎病毒(HBV)及其卫星病毒丁型肝炎病毒(HDV)必须通过结合细胞表面受体分子来实现对宿主细胞的感染。因此,发现该受体,以深入理解乙肝感染过程并为乙肝及其相关疾病提供有效的治疗靶点 在这篇文章中,研究人员从树鼩这种动物入手,开始了他们的探索之旅。树鼩是一种与灵长类动物类似的小动物,也是除人类和黑猩猩以外,唯一能被乙肝病毒感染的物种。生物通 李文辉博士的团队首先绘制了一幅高质量的树鼩肝细胞基因表达图谱,为后续的研究奠定了坚实的基础。有了这个数据库,再结合先进的纯化技术和高分辨质谱分析手段,他们发现,肝脏胆酸转运蛋白(NTCP,钠离子-牛磺胆酸钠共转运多肽)会与乙肝病毒表面包膜大蛋白的关键受体结合区发生特异性相互作用。 随后,他们在HBV/HDV易感的肝细胞中进行的一系列基因敲除实验,证明NTCP的确是病毒感染所需的细胞受体。人肝癌细胞株HepG2细胞通常情况下不表达NTCP,也不能被HBV感染, 他们深入研究发现,如果在该细胞株中外源性表达人或树鼩的 NTCP后,则该细胞可以被HBV及HDV感染。他们还鉴定出NTCP上关键的病毒结合区域。比如猴子的NTCP通常不能结合乙肝病毒,但只要突变其NTCP上一段极小的区域,就能使之变成有效的HBV受体。 Transforming gene: X gene X protein activates gene transcription via XRE 51

52 Genetic Predisposition
Hereditary Cancer Tumor Genetic Susceptibility ---Tumor susceptibility genes (Cytochrome P450 family, DNA repair genes, Tumor suppressor genes, etc) Immunity Hormones and metabolism Psychological factors others 52

Download ppt "Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition."

Similar presentations

Ads by Google