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Neoplasia Neoplasia Nomenclature Benign vs. Malignant tumors

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Neoplasia Neoplasia Nomenclature Benign vs. Malignant tumors Epidemiology Molecular basis Oncogenes- TSG Apoptosis Regulating Genes DNA Repair genes Steps in – PowerPoint PPT presentation

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Title: Neoplasia Neoplasia Nomenclature Benign vs. Malignant tumors


1
Neoplasia
2
  • 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

3
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

4
  • 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

5
  • 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

6
  • 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)

7
  • 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

8
  • 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

9
  • 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

10
  • 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
11
HPV GENES
12
EBV
13
  • 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
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