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Jimin Shao shaojimin@zju

Cancer Etiology 1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis 4. Viral Oncogenesis 5. Genetic Predisposition. Jimin Shao shaojimin@zju.edu.cn. Introduction. Cancer Incidence and Mortality History of Cancer Research What Is Cancer.

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Jimin Shao shaojimin@zju

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  1. Cancer Etiology1. Introduction 2. Chemical Factors in Carcinogenesis 3. Physical Factors in Carcinogenesis4. Viral Oncogenesis5. Genetic Predisposition Jimin Shao shaojimin@zju.edu.cn

  2. Introduction • Cancer Incidenceand Mortality • History of Cancer Research • What Is Cancer

  3. Cancer Incidence and Mortality Cancer is a leading disease, cause of death, and source of morbidity in the world. • WHO国际癌症研究机构IARC《2014年世界癌症报告》: • 全球癌症发病率与死亡率持续上升： • 2012年当年1400万人被诊断患癌、800万死于癌症； • 预测2035年癌症新患者将增至2400万、1460万人死于癌症。 • 2012年发病率前三名癌症: 肺癌(180万)、乳癌(170万)、大肠癌(140万)。 死亡率前三名癌症：肺癌、肝癌、胃癌。 • 2012年，全球约180万肺癌新增病例，肺癌死亡病例超过160万。 • 在发展中国家，超过22%死亡由传染性病原体相关癌症造成，例如由乙型和丙型病毒性肝炎引起的肝癌、由人乳头状瘤病毒感染导致的宫颈癌，以及由幽门螺旋菌导致的胃癌等。 • 2012年，全球新病例有一半发生在亚洲，其中大部分发生在中国。 Ferlay J SI, Ervik M, Dikshit R, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. [cited 2014 Jul 31]. Available from: http://globocan.iarc.fr.

  4. 中国肿瘤登记中心《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”走高趋势。

  5. Tumor: • Benign tumor • Malignant tumor Developing Cancer • TNM: staging describes the severity of a person’s cancer. （Most solid tumors except for brain and spinal tumors are staged using the TNM system; gynecological tumors use a variant of the TNM system）.

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

  7. Chemical Carcinogenesis • Multi-stage Theory of Chemical Carcinogenesis • Classification of chemical carcinogens • Mechanisms of Chemical Carcinogenesis • Types of DNA Damage • DNA Repair

  8. 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 15

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  10. Initiation • Irreversible genetic damage: A necessary, but insufficient prerequisite for tumor initiation • Activation of proto-oncogene, inactivation of a tumor suppressor gene, and etc 18

  11. 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 19

  12. 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 20

  13. 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 21

  14. 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 22

  15. 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. 23

  16. 直接致癌物 • 间接致癌物 代谢激活 终致癌物 （ultimate carcinogen） 前致癌物 （procarcinogen） 水解，氧化，还原 混合功能氧化酶系统 （CYP450和P448 等）

  17. (2) Epigenetic carcinogens • Promotes cancer in ways other than direct DNA damage/ do not change the primary sequence of DNA • Alter the expression of certain genes and cellular events related to proliferation and differentiation • Promoters, hormone modifying agents, peroxisome proliferators, cytotoxic agents, and immunosuppressors • Organochlorine pesticides, estrogen, cyclosporine A, azathioprine 25

  18. 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 26

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  20. 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, etc 28

  21. 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. 2012 Jan 12;12(2):104-20. doi: 10.1038/nrc3185.] • (2) These agents can be either monofunctional or bifunctional. • ---Monofunctional alkylating agentshave a single reactive group and thus interact covalently with single nucleophilic centers in DNA (although varied). • such as MNNG • ---Bifunctional alkylating agentshave 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 29

  22. ---Monofunctional alkylating agents Numerous potential reaction sites for alkylation have been identified in all four bases of DNA (not all of them have equal reactivity): 30

  23. ---Bifunctional alkylating agents 31

  24. Indirect Chemical Carcinogensand Their Phase I Metabolic derivatives 32

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

  26. 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 34

  27. 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 35

  28. 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 36

  29. 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 37

  30. Extended ReadingTranslesion DNA synthesis 38

  31. 1.DNA damage blocks the progression of the replication fork. 2.PCNA plays a central role in recruiting the TLS polymerases (translesion DNA synthesis) and effecting the polymerase switch from replicative to TLS polymerase (low stringency DNA polymerases). 3. TLS polymerases carry out TLS, either singly or in combination, past different types of DNA damage. 4.Such regulation must ensure that (1) the specialized polymerases act only when needed, and (2) that polymerases act only at the right location in DNA. 5.TLS evolved in mammals as a system that balances gain in survival with a tolerable mutational cost, and that disturbing this balance causes a potentially harmful increase in mutations, which might play a role in carcinogenesis. 39

  32. Classification of TLS polymerases 40

  33. Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4):Y-family of DNA polymerases.

  34. Characteristics of TLS polymerases • They operate at low speed, low processivity and with low fidelity. • Their active sites adopt a much more open structure than replicative polymerases, they are less stringent and can accommodate altered bases in their active sites. • Y-family polymerases lack a 3’-5’ exonuclease activity, which is an integral part of all replicative polymerases and performs a proofreading function. • Each Y family polymerase differs in substrate specificity. • All the Y-family polymerases are localized in the nucleus, and during S phase, • polη, ι, and Rev1 relocate to replication factories with the polymerase sliding • clamp PCNA, and other proteins associated with DNA replication. • There are three examples of TLS reactions in which a specialized DNA • polymerase bypasses its cognate DNA lesion with higher efficiency and higher • fidelity than any other polymerase in the cell: • ---Polh and the UV light-induced CPD (cyclobutane pyrimidine dimers); • ---Polk and benzo[a]pyrene-guanine (major tobacco smoke-induced DNA lesion); • ---Polh and cisplatin-GG (an adduct produced by a drug used in cancer chemotherapy). 42

  35. 1. Polη • Polη was discovered as the protein deficient in the variant form of the skin cancer-prone genetic disorder xeroderma pigmentosum (XP). • Most XP patients are deficient in the ability to remove UV photoproducts from their DNA by nucleotide excision repair (NER), but about 20% have problems in replicating their DNA after UV irradiation because of defectiveness of polη gene. • Polη carrys out TLS past CPD (cyclobutane pyrimidine dimers) photoproducts generated by exposure to sunlight. XP variant cells have an elevated UV-induced mutation frequency. 2. Polκ Polκcan carry out TLS past DNA containing benzo[a] pyrene-guanine adducts. 3. Rev1 Rev1 has a restricted DNA polymerase activity that is confined to the incorporation of one or two molecules of dCMP regardless of the nature of the template nucleotide. • Rev1 interacts with multiple TLS polymerases, notably Polη, Polκ, Polι, Polλ, and the REV7 (subunit of Polζ). • Rev1 protein may be specifically involved in polymerase switching during TLS. 4. Polι 5. Polζ is a heterodimer containing the Rev3 catalytic subunit and the Rev7 regulatory subunit. 43

  36. Cellular responses evoked by DNA damaging agents are very complex events • Responses may triggered by the signals originated from: genomic and mitochondrial DNA damages, malfunction of signaling molecules, endoplasmic reticulum stress, others • Networks between different signaling pathways; • Cellular responses are the comprehensive and integrated consequences. 44

  37. Gene-environmental interactions The metabolism of xenobiotics by biologic systems Individual variation The competition between activation and detoxication The alteration of genes and epigenetics by xenobiotics 45

  38. Physical factors in carcinogenesis

  39. Physical carcinogens • Corpuscular radiations • Electromagnetic radiations • Ultraviolet lights (UV) • Low and high temperatures • Mechanical traumas • Solid and gel materials

  40. Ionizing radiation (IR) • Penetrate cells, unaffected by the usual cellular barriers to chemical agents • IR: a relatively weak carcinogen and mutagen • The initial critical biologic change is damages to DNA • It takes place in a matter of the order of a microsecond or less

  41. Electromagnetic fields (EMF) Remains controversial: • Minimal increase in relative risk of brain tumor and leukemia in electric utility workers • Also relatively increased risk for acute lymphoblastic leukemia by EMF exposure during pregnancy or postnatally • However, some studies lend no support for this proposition

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