Neoplasia Neoplasia Nomenclature Benign vs. Malignant tumors

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Neoplasia
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• Carcinogens
• How ? cause genetic ( DNA ) damage and induce
  cancers
• Types chemical, radiation, Oncogenic viruses
  microbes
• Historical
• John Hill? Snuff use? Polyps
• Sir. Pott ? Chimney Sweeps ( Exposure to soot) ?
  Scrotal cancer
• Chemical carcinogens
• Categorized to initiators Promoters
• Initiators ? Natural and Synthetic
• Two Categories Direct acting Indirect acting

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Initiators Promoters

• Initiator
• carcinogenic agent
• not sufficient for tumor formation by themselves
• permanent DNA damage (Mutations)
• rapid and irreversible

• Promoters
• ? Changes are reversible
• non- tumorigenic by themselves
• not affect DNA directly
• induce tumors in initiated cells reversible

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• Carcinogens
• Initiators
• Natural and Synthetic
• Two Categories Direct acting Indirect acting
• Direct acting not need metabolic conversion
• highly reactive electrophiles (have
  electron-deficient atoms)
• react with nucleophilic (electron-rich) sites in
  the cell (DNA, RNA, and proteins)
• DNA primary target
• Reactions nonenzymatic
• interaction nonlethal
• Indirect acting - requires metabolic conversion
• Carcinogens use cytochrome P-450 gene
• CYP1A1?polymorphic form of P-450 (10 of whites)
• Metabolizes BENZ(O)PYRENE (of tobacco smoke)?
  carcinogen
• 2. Glutathione s-transferase
• detoxification of polycyclic aromatic
  hydrocarbons (PAH)
• 50 of whites ? enzyme polymorphism
• ?risk of Bladder Lung cancers in smokers

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• Molecular Targets
• DNA damage ?primary target for chemical
  carcinogens
• AMES TEST
• ability of chemical to induce mutations in the
  bacterium S. typhimurium ? if MUTATION present
  positive score
• Environmentally induced insults to DNA defect
  in DNA repair (inherited) ??risk of cancers
• Molecular fingerprinting of tumors
• Example Hepatocellular carcinoma (HCC) p53
  (at 249 GCTA) )mutations
• HCC Africa and China ? linked to Aflatoxin B1
  p53 mutations are frequent
• HCC in other parts ? follows chronic HBV
  infection p53 mutations are much less frequent
• Initiated Cell
• carcinogen-altered cells
• must undergo at least one cycle
• Then change in DNA becomes fixed or permanent
• Promotion of Chemical Carcinogenesis
• promoters (such as phorbol esters, hormones,
  phenols, and drugs)
• proliferation and Clonal expansion of initiated
  (mutated) cells
• Promoters Tumorogenesis
• Phenobarbital ?blockage of the TGF-ß pathway
• phorbol ester (activator of protein kinase C) ?
  signal transduction pathways

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• Chemical carcinogens Initiators
• Alkylating Agents Weak carcinogens, direct
  acting
• Anti Cancer Drugs (cyclophosphamide,
  chlorambucil, busulfan)
• damage DNA (anticancer effect) but also render it
  carcinogenic
• Polycyclic Aromatic Hydrocarbons Most potent
  carcinogens known, indirect
• Smoking Tobacco
• animal fats ? broiling meats
• smoked meats and fish.
• Aromatic Amines ?ß-naphthylamine aniline (dye and
  rubber industries) ?Cause TCC of Urinary bladder
  (glucoronidase)
• Azo Dyes? found in food coloring (butter yellow
  scarlet red)
• Naturally Occurring Carcinogens Aflatoxin B1
  (Africa and China)
• Potent hepatic carcinogen
• Produced by Aspergillus flavus (improperly stored
  corn, rice, and peanuts)
• Nitrosamines and Amides
• Nitirostable amines and nitrite ?nitrates (by
  bacteria)
• Miscellaneous Agents
• Asbestos? bronchogenic ca., Mesotheliomas, and
  GIT cancers
• Vinyl Chloride? Hemangiosarcoma of the liver
• Insecticides ?carcinogenic in animals (aldrin,
  dieldrin, and chlordane)

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• Chemical carcinogensPromoters
• Endogenous ? hormones and Bile salts
• Exogenous
• Diethylstilbestrol (used for Threatened Abortion)
• Postmenopausal? endometrial carcinoma
• offspring exposed in- utero? vaginal cancer
• Fat colon cancer
• Estrogen liver tumors
• Tobacco and viral infection tissue damage and
  reactive hyperplasia

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• Radiation Carcinogenesis UVB, Ionizing Radiation
• Synergism with other carcinogens
• 1. UVB (280-320nm)
• also causes mutation in Oncogenes and TSG (RAS
  p53)
• induction of cutaneous cancers
• Carcinogenicity
• Pyrimidine dimers in DNA
• Higher risk in Defective NER repair genes
  Xeroderma pigmentosum
• 2. Ionizing Radiation
• Electromagnetic (x-rays ? rays) and particulate
  (a particles, ß particles, protons, neutrons) ?
  all CARCINOGENIC
• Order of Vulnerability
• High risk Hematological (Leukemia), Thyroid
• Intermediate risk Breast, lungs, salivary gland
• Resistant GIT, Skin, bone

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• Microbial carcinogenesis
• DNA Oncogenic Viruses HPV, EBV, HBV, Kaposi
  Sarcoma, Herpes Virus
• Human Papilloma virus (HPV)
• Squamous Cell Carcinoma ? Cervix and Anogenital,
  Oral and Laryngeal regions
• HPV serotypes 16/18, 31/33/35/51 ( High risk
  group)
• Integration of viral DNA ? malignant
  transformation
• Over expression of the E6 and E7 Viral proteins
  (mainly 16 , 18 )
• E6 inactivate p53 by enhancing its degradation
  through ubiquitin-dependent proteolysis)
• E7 disable p53 pRb by disrupting the E2F/RB
  complex and promoting the degradation of RB
• Epstein Barr Virus (EBV)
• Herpes family
• self-limited disorder ?infectious mononucleosis
• Pathogenesis of human tumors
• Burkett Lymphoma
• B-cell Lymphomas (NHL) in immunosuppressed
  individuals (HIV)
• Hodgkins Disease
• Naso -Pharyngeal Carcinoma (100 EBV association)
• Viral genes? dysregulate normal proliferative
  and survival signals in infected cells
• Examples

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• Microbial carcinogenesis
• HBV
• Carcinogenic effect ? indirect and multifactorial
• HBx Protein ? binds to p53 and interferes with
  its growth suppressing activities
• RNA Oncogenic Viruses
• Human T-Cell Leukemia Virus Type 1 (HTLV-1)
• Non Neoplastic
• Tropical Spastic Paraparesis ? Demyelinating
  neurological disorder
• Uveitis Arthritis
• Endemic in Japan Caribbean
• Tropism for CD4 T-CELLS
• Neoplastic 1 ( in 1 of infected)
• TAX region ? Activate the transcription of host
  cell genes
• HCV
• Pathogenesis of HCC - ?
• chronic Hepatitis? Regeneration ? Neoplastic
  change

CD4 tropism - ?another infection ? drug
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HPV GENES
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EBV
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• Helicobacter Pylori
• Non Neoplastic Chronic Gastritis (90 of
  patients )
• Neoplastic
• 1. Gastric Lymphomas (B-cell) or
• MALTomas or Marginal Zone Lymphoma
• Treatment with antibiotics ? Regression of
  lymphoma
• 2. Gastric Carcinomas
• Mechanism H. pylori? Activate reactive T-cells?
  activate Polyclonal (infection) B-cells ?
  Continue on with Monoclonal ( Malignant) B-cells