Gen Path L22 23

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  1. oncogenes
    • regulate cell growth and differentiation
    • tissue-specific manner
    • members of phosphorylation-dephosphorylation cascades pathway
    • can be activated and deactivated
    • prone to malfunction - "protooncogenes", can't be modulated anymore
    • abnormal expression causes inappropriate cellular growth in an inappropriate place - a neoplasm.
  2. Cell proliferation
    • Normal - requires suitable microenvironment, nutrients, growth factors, etc.
    • Neoplastic - less need for external signals
  3. Growth factor -> membrane receptor -> signal transduction cascades -> gene expression...
  4. Growth factor receptors, or RAS, PI3K, MYC, and D cyclins are oncoproteins that are activated by mutations in various cancers.
    • GAPs apply brakes to RAS activation, and PTEN serves the same function for PI3K.
    • RAF activates MAPK -> C-Myc, cell cyclin -> cell growth
  5. MECHANISMS OF ONCOGENE ACTIVATION:
    • A. Viral invasion - rare in human
    • 1. A transduced proto-oncogene mutated and returned to the cell.
    • 2. A provirus inserted in the vicinity of a protooncogene.
    • B. Somatic mutation - inherited healthy gene mutated
    • C. Genetic rearrangements
    • 1. Gene amplification.
    • 2. Chromosomal translocations
  6. retrovirus
    • Non-transforming to start with
    • picks up normal proto-oncogene in animal cell
    • becomes transforming, carrying the oncogene, mutated
    • has a number of strong promoters that enhance transcription
    • very strong signal
    • humans are immunologically heterogeneous and less susceptible
  7. A provirus inserted in the vicinity of a protooncogene
    • over-expression of an oncogene due to acquisition of a transcriptional promoter
    • avaian provirus enhance c-myc in chicken and causes avian hematopoietic neoplasia (AHN, avian leukemia)
  8. Somatic mutation
    • normal proto-oncogene is damaged/mutated because of carcinogen and oncogene arises
    • mutation of Ras, can't be deactivated
  9. Gene amplification
    • Amplification of the N-MYC gene in human neuroblastomas.
    • Amplified N-MYC is seen as extra chromosomal double minutes (DM), or a chromosomally integrated, homogeneous staining region (HSR).
    • Huge amount of N-MYC produced
  10. Epidermal growth factor (EGF) family
    • 1. ERBB1 (the EGF receptor gene) over expressed
    • in squamous cell ca, lung, glioblastoma, head & neck Ts
    • 2. ERBB2 (HER-2/NEU) amplified in 25% Br ca, ovary, lung, etc; can also be overexpressed w/o being amplified - leads to increased aggressiveness and poor prognosis
    • 3. ERBB4 (HER-4) - mutations in melanomas (the most frequently mutated PTK in melanomas)
  11. HER-2 is a target for _______.
    Herceptin, antibody to HER-2
  12. Chromosomal translocation
    Burkitt’s lymphoma - when c-myc is translocated to chromosome coding Ig and chronic inflammation happens -> requires very strong expression of Ig -> also causes strong expression of c-myc -> lymphoma
  13. Conditions w/ c-myc activation
    • Viral promoter insertion - AHN
    • Chromosomal translocation - Burkitt’s lymphoma (8-14), plasmacytoma in mice
    • Amplification - chronic myelogenous leukemia (CML, no differentiation, no RBC and platelet produced, unusual bleeing, can be recognized by dentists; Breakage-Aberrant recombination mutations between chromosomes 9 and 22 forming BCR-ABL, involving tyrosine kinase activity, can be cured by tyrosine kinase inhibitor)
  14. Chromosomal lesions in human cancers
    • The Philadelphia chromosome in CML, first example
    • Leukemia and lymphomas - reciprocal translocations, non-random trisomy
    • Solid tumors - band deletion, chromosome loss (meningioma
    • Sub microscopic deletions
  15. Genes involved in tumor growth and it's control
    • Activated proto-oncogenes: c-myc (Burkit), Ras, ABL (CML), EGF (ERBB1 (sq ca, lung), ERBB2 (HER-2/NEU, br ca, ov ca), ERBB4 (HER-4, skin))
    • Tumor suppressor genes: BCRA-1/2 (br ca, ov ca), Rb (retinoblastoma), p53 (50%, carcinoma), APC (adenomatous polyposis coli), VHL (VHL syndrome, angiomas and angiosarcomas, neuroblastomas)
    • Cell death controlling genes:
    • (a) Suppression of apoptosis eg bcl-2 - oncogene-like
    • (b) Enhancement of apoptosis eg bax - TS gene-like
  16. Intrinsic and extrinsic apoptosis
    • Intrinsic - release of cytochrome C
    • Extrinsic - external signals
  17. Known carcinogenic factors
    • Extrinsic factors - Physical and chemical factors
    • Intrinsic factors
    • - Genomes
    • - Viruses
    • - Hormones
  18. Chemical carcinogens
    • Soot in chimney - scrotal Ca
    • coal tar -> skin Ca in mice
    • isolation of 3,4-benzpyrene, 3-methylcholanthrene, dimethylbenzanthracene
    • Dimethylnitrosamine
    • Aromatic amine - eg. naphthylamine
    • BeO
    • Aflatoxin - the most powerful carcinogen
    • N-methyl-BIS-amine - can be used in chemotherapy too
    • Heavy metals
  19. Mechanisms of chemical carcinogenesis
    carcinogen -> proximate carcinogen -> ultimate carcinogen, eg. carbonium ion (electrophillic center, attacks intracellular target)
  20. Heavy metals
    • immunosuppressant and carcinogenic: Mercury, Lead, Cadmium, Aluminum, Arsenic and Uranium.
    • causing ten-fold increase in cancer mortality.
  21. Detoxification
    • Phase I: Oxidation/reduction, hydration, hydrolysis, isomerization, etc; Produces reactive species
    • Phase II: conjugated -> more water soluble [eg GST, QR]
    • Phase III: Excretion
  22. General scheme of events in chemical carcinogenesis
    • Initiation: carcinogen goes through detoxification directly or goes through metabolic activation and becomes electrophilic intermediates (EI) before going in detoxification. Product of detox goes to excretion; EI can also bind to DNA (adduct formation); DNA repair happens and cell becomes normal OR no repair and cell death OR permanent DNA lesion happens and cell becomes initiated
    • Promotion: initiated cell -> cell proliferation -> altered differentiation -> preneoplastic clone ->
    • proliferation & additional mutations -> malignant neoplasm
  23. Intestinal bacteria may produce chemical carcinogens
    • carcinogenic aglycones
    • nitrosamines
    • steroid metabolites
    • amino acid metabolites
  24. Environmental carcinogen
    • smoking -> bronchogenic Ca
    • atmospheric pollution -> bronchogenic Ca
    • Food contaminants, aflatoxin ergot
    • Smoked food -> gastric Ca
    • Food additive, cyclamate
    • Insecticides, DDT
  25. Smoking causes
    • Cancers - Lip and oral cavity is a major site for cancer, squamous cell carcinoma; also the esophagus, lung, pancreas, bladder, kidney
    • Cardiovascular disease -> stroke and infarction
  26. Dr. Auerbach
    • US pathologist
    • smoking causes cancer
    • active in spreading this information
  27. Occupational carciogenics
    • Coal tar, shale oil workers -> squamous carcinoma of skin
    • aromatic amines in rubber and dyestuff industries -> cancer of bladder
    • luminescent dial painters -> Osteogenic sarcoma of bone
    • Uranium miners -> carcinoma of bronchus
    • Arsenic -> squamous carcinoma of skin
    • Asbestos factories -> carcinoma of bronchus and mesotheliomas (cancer around the body)
    • vinyl chloride monomer -> hemagioendotheliosarcoma of liver
  28. Diet -> cancer
    • High fat -> increase risk of breast and prostate Ca
    • Low roughage -> Ca large bowel
    • Additives
    • Cooking and preservation
    • >2/3 of cancer can be prevented by lifestyle
    • ~1/3 of cancer can be attributed to diet alone
    • Fruit and vegetable - reduces risk of many cancers
    • Due to compounds
    • - Antioxidants
    • - Induce apoptosis in preneoplastic cells
    • - Induce cytoprotective enzymes which detoxify carcinogens
  29. Chemopreventive agents
    • Blocking agents
    • - Prevent carcinogen activation
    • - Enhance detoxification
    • - Trap carcinogens
    • Suppressing agents
    • - prevent carcinogenesis after attack by carcinogens
  30. Iatrogenic causes of cancer
    • Thorotrast - sarcoma, other tumors
    • IM injections of iron for anemia - sarcoma
    • DES ( Diethylstilbestrol, synthetic estrogen) during pregnancy for reducing miscarriage risk -> Ca vagina in daughters
    • Oral contraceptives - No increase, some benign hepatic tumors
  31. Hormones responsive cancers
    • Breast - estrogens
    • Prostate - androgens
    • Endometrium - estrogens
    • Thyroid - TSH
  32. Physical carcinogens
    • Radiation
    • - gamma and x-ray -> leukemia in x-ray operators
    • - UV -> skin cancer in sailors
    • Mechanical
    • - burns -> occasional cancer by excessive scarring
    • - chronic irriation: clay pipes -> lip carcinoma; dentures -> oral cavity Ca
  33. Mechanisms of physical carcinogenesis
    • radiation -> DNA damage -> incomplete or faulty repair, perpetuated, promote pre-existing conditions
    • Chronic hyperplasia has a promotor-like effect
    • Increase the chance that a change in DNA is perpetuated
  34. Chronic irriation
    • foreign bodies eg. Bilharzia ova, in urinary bladder
    • gallstones
  35. Chronic inflammation
    • schistosomiasis
    • Ulcerative colitis
    • Liver cirrhosis
  36. Carcinogenesis -infectious agents
    • Bacteria - H. pylori - associated w/ B-cell lympohoma of stomach (MALTomas) and gastric carcinoma
    • RNA oncogenic viruses (retroviruses) - human T-cell leukemia virus type 1 -> target CD4 positive cells, Tax gene and GM-CSF, proliferating T-cells at increased risk for mutations
    • DNA viruses
    • - HPV 16 & 18 -> target p53 and Rb protein
    • - EBV -> Burkitt's?, B-cell lymphoma for HIV+
    • - HBV -> liver Ca
    • - HHV-8 -> vascular tumor

Card Set Information

Author:
neopho
ID:
323234
Filename:
Gen Path L22 23
Updated:
2016-09-26 01:54:14
Tags:
pathology
Folders:
GeneralPathology
Description:
Gen Path L22, 23 Oncogenes and Carcinogenesis
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