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CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS

CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS. Salvador J. Diaz-Cano s.j.diaz-cano@qmul.ac.uk. CANCER BIOLOGY. Causes of Cancer: General Etiology. Cancer: General Etiology and Pathogenesis. Environmental vs . Hereditary Cancer. Environmental Carcinogens. A cancer-causing agent

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CANCER: ETIOLOGIC AGENTS AND GENERAL MECHANISMS

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  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

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

  6. 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

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

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

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

  10. Direct-acting Carcinogens • Nitrogen mustard • Nitrosomethylurea • Benzyl chloride

  11. 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

  12. 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

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

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

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

  16. Skin cancer is one of the most common human cancer and one of the most preventable • ~106 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

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

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

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

  20. 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

  21. 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

  22. 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

  23. 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

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

  25. 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

  26. 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

  27. CANCER BIOLOGY Basic Mechanisms: General Pathogenesis

  28. Cancer: General Pathways

  29. Basic Mechanisms in Neoplasms • Genetic bases • Basic aspects of tumorigenesis • Correlation between genetics and kinetics

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

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

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

  33. Gene Inactivation • Genetic Changes • Inactivating mutation • Interstitial DNA deletion • Epigenetic Changes • Promoter hypermethylation

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

  35. Telomeres and Cell Senescence

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

  37. Telomeres and Chromosomal Anomalies Invasive carcinoma

  38. Mismatch Repair and Microsatellites

  39. Basic Mechanisms in Neoplasms • Genetic bases • Basic aspects of tumorigenesis • Correlation between genetics and kinetics

  40. Alterations of Specific Cellular Functions in Cancer DNA Repair Tumor Suppressor Genes Inactivation Oncogenes Activation Differentiation Apoptosis/Proliferation CANCER

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

  42. Progressive Acquisition of Neoplastic Features

  43. 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 Hallmarks of Cancer Cells

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