1. CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS Salvador J. Diaz-Cano s.j.diaz-cano@qmul.ac.uk

2. CANCER BIOLOGY Causes of Cancer: General Etiology

3. Cancer: General Etiology and Pathogenesis

4. Environmental vs. Hereditary Cancer

7. Environmental Carcinogens A cancer-causing agent Three main types: –Chemical –Physical (radiation) –Biological (especially virus)

8. Chemical Carcinogenesis Firstly described by Sir Percival Pott in 1775 –Chimney sweeps and scrotal cancer –Relationship between occupational exposure to chimney soot and scrotal carcinoma was established

9. Chemical Carcinogens Direct-acting Indirect-acting (must be metabolized to activated metabolic forms)

10. Electrophiles Direct-acting carcinogens are already electrophilic Indirect-acting carcinogens are metabolically activated into electrophilic species

11. Electrophilic Theory of Chemical Carcinogenesis Electrophilic (electron-seeking) molecules will bind to nucleophilic (electron-rich) macromolecules in the cell –DNA –RNA –Proteins

12. Direct-acting Carcinogens Nitrogen mustard Nitrosomethylurea Benzyl chloride

13. Indirect-acting Carcinogens Polycyclic aromatic hydrocarbons (PAH) Produced by incomplete combustion of organic materials Present in chimney soot, charcoal- grilled meats, auto exhaust, cigarette smoke

14. Ames Test Many synthetic and natural compunds in our environment have been screened by the Ames test Test is based upon correlation between carcinogenicity and mutagenicity

15. Human carcinogens - environmental Aflatoxins Asbestos Benzene Cadmium Coal tar Creosote DDT Polycyclic aromatic hydrocarbons Radon Solar radiation

16. Human carcinogens - drugs/therapeutic agents Adriamycin (doxorubicin) Androgenic steroids Chlorambucil Cisplatin Cyclophosphamide Cyclosporin A Diethylstilbestrol Ethylene oxide Melphalan Tamoxifen

17. Physical Carcinogens Ultraviolet light Ionizing radiation (X-rays) Asbestos

19. Skin cancer is one of the most common human cancer and one of the most preventable ~10 6 cases of BCC and SCC are diagnosed per year This is more than all other types of cancer combined Most of these will be caused by exposure to ultraviolet (UV) irradiation

21. Asbestos Widely used in construction, insulation, and manufacturing Family of related fibrous silicates Chrysotile Crocidolite

23. Malignant Mesothelioma Mainly occurs in pleural and peritoneal cavities Rare in general population Latent period of ≥20 years

24. Ionizing Radiation Death of pioneer radiation researchers from neoplasms High incidence of leukemia among radiologists recognized in 1940s Osteosarcoma incidence in radium dial painters

25. Viral Carcinogenesis Viral infections account for an estimated one in seven human cancers worldwide Majority of these are due to infection with two DNA viruses –HBV - linked to hepatocellular carcinoma –HPV - linked to cervical carcinoma

26. Oncogenic Viruses Human papillomaviruses - HPV Epstein-Barr Virus (EBV) Human herpesvirus 8 (HHV8) Hepatitis B virus - HBV Hepatitis C virus - HCV HTLV-I, HTLV-II

27. Human papilloma virus (HPV) Over 70 subtypes DNA virus with small double- stranded circular genome Subtypes possess varying degrees of low risk and high risk

28. Low and High Risk HPV HPV subtypes classified as low risk or high risk based on whether the genital tract lesions with which these HPVs are associated are at significant risk for malignant progression

31. EBV - Involvement in Human Tumors African Burkitt lymphoma B-cell lymphomas of immunosuppressed patients Some cases of Hodgkin lymphoma Nasopharyngeal carcinomas

32. How Do Viruses like HPV and HBV Cause Cancer? Very small viruses Can integrate their viral DNA into host genome They code for viral proteins which block tumor suppressor proteins in cells

33. Helicobacter pylori Gastric infection linked to gastric lymphomas and adenocarcinomas Detection of H pylori in majority of cases of gastric lymphomas Antibiotic treatment results in gastric lymphoma regression in most cases

34. Basic Mechanisms: General Pathogenesis CANCER BIOLOGY

35. Cancer: General Pathways

36. Basic Mechanisms in Neoplasms Genetic basesGenetic bases Basic aspects of tumorigenesisBasic aspects of tumorigenesis –Correlation between genetics and kinetics

37. Cancer General Mechanisms Single “gross” genetic abnormalities –Translocations Multiple “punctual” genetic alterations –Mutations –LOH Malignant lymphomas Sarcomas Carcinomas Malignant melanomas Activating Mechanisms Activating/Inactivating Mechanisms

38. Genetic Lesions in Tumors Activating or inactivating Dominant / Recessive / Dominant negative Somatic or germline Genetic targets (oncogenes, tumor suppressor genes, mismatch repair genes)

39. Genetic Mechanisms of Tumors Gene deletions / amplifications Mutations Insertional Point Mutations Genetic Instability Microsatellite Instability (MSI) Chromosomal Instability (CIN)

40. Gene Inactivation Genetic Changes –Inactivating mutation –Interstitial DNA deletion Epigenetic Changes –Promoter hypermethylation

41. Genetic Instability in Tumors (+) Oncogenes (-) Tumor suppressor genes Telomere shortening Mismatch repair (MMR) genes Chromosomal Instability Microsatellite Instability ? Cause or tumor progression byproduct

42. Telomeres and Cell Senescence

43. Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603 Telomeres, Telomerase, and Cancer

44. Invasive carcinoma Telomeres and Chromosomal Anomalies

45. Mismatch Repair and Microsatellites

46. Basic Mechanisms in Neoplasms Genetic basesGenetic bases Basic aspects of tumorigenesisBasic aspects of tumorigenesis –Correlation between genetics and kinetics

47. DNA Repair Oncogenes Activation Tumor Suppressor Genes Inactivation DifferentiationApoptosis/Proliferation CANCER Alterations of Specific Cellular Functions in Cancer

48. DNA Repair Tumor Suppressor Genes Oncogenes Interstitial Deletion Inactivating Mutation Hypermethylation Gene Amplification Gene Overexpression Activating Mutation Genetic Instability: RER Phenotype CANCER Specific Cellular Functions in Cancer: Genetic Alterations

49. Progressive Acquisition of Neoplastic Features

50. Hallmarks of Cancer Cells Self-maintained replication Longer survival Genetic instability Capable of inducing neoangiogenesis Capable of invasion and metastasis –Apoptosis down- regulation –Lack of response to inhibitory factors –Self-sustained proliferation

51. Hallmarks of Cancer Cells Self-maintained replication Longer survival Genetic instability Capable of inducing neoangiogenesis Capable of invasion and metastasis –Apoptosis down- regulation –Telomerase reactivation

52. Hallmarks of Cancer Cells Self-maintained replication Longer survival Genetic instability Capable of inducing neoangiogenesis Capable of invasion and metastasis –Cooperative genetic damage –Mutagenic agents –Defective repair systems

53. Hallmarks of Cancer Cells Self-maintained replication Longer survival Genetic instability Capable of inducing neoangiogenesis Capable of invasion and metastasis

54. Basic Biologic Features of Neoplasms Oncogenic Lesion (e.g. RAS, MYC, E2F Activation) Oncogenic Lesion (e.g. RAS, MYC, E2F Activation) Differentiation Abnormal Proliferation AngiogenesisInvasion SenescenceApoptosis

55. Multistep Tumorigenesis

56. Hahn, W. C. et. al. N Engl J Med 2002;347:1593-1603 Acquired Capabilities, Molecular Pathways, and the Transformation of Human Cells: Emerging Rules That Govern Cancer Formation

57. Cancer Molecular Pathways

59. Molecular Progression Mutation Accumulation

60. Cancer: General Etiology and Pathogenesis Etiologic agents:Etiologic agents: –Environmental (chemical, physical, and biological) –Hereditary (familial cancer syndromes) General mechanisms:General mechanisms: –Acquired capabilities (Self-maintained replication, longer survival, genetic instability, neoangiogenesis, invasion and metastasis) –Activation of oncogenes, inactivation of TSG, non-effective DNA repair –Caretaker and gatekeeper pathways