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Neoplasia V Carcinogenesis

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Title: Neoplasia V Carcinogenesis


1
Neoplasia VCarcinogenesis
  • Husni Maqboul, M.D

2
Overview of Carcinogenic Agents
  • Chemical Carcinogens
  • Physical Agents
  • Ionizing Radiation
  • Oncogenic Viruses

3
Impact of Environmental Carcinogens
  • 80 - 90 of all cancers may be related to
    environmental agents including diets, lifestyles,
    and viruses.
  • Several environmental agents often act together
    (co-carcinogenesis).

4
Principles of Carcinogenesis
  • Neoplastic transformation is a progressive
    process involving multiple hits or genetic
    changes.
  • Alterations in DNA cause changes in one or both
    of the following types of genes
  • Proto-oncogenes
  • Tumor suppressor genes
  • Genes that regulate apoptosis

5
Chemical Carcinogenesis ,Mechanisms
  • Multi-Step Process Involving
  • Initiation
  • Promotion

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Initiation
  • Rapid ,Irreversible, and has memory
  • Results from interaction of chemical with DNA to
    activate a proto-oncogene or inactivate a tumor
    suppressor gene by formation of covalent adducts.
  • Chemicals that can form adducts are usually
    electrophiles.
  • Many chemical carcinogens require activation by
    metabolic pathways (pro-carcinogens or indirect
    acting carcinogens)
  • Initiation alone does not result in tumors.
  • Some initiators can subsequently act as promotors
    (these are complete carcinogens).

10
Initiation
  • Some procarcinogens (e.g benzopyrene ) are
    activated by P-450 dependant mono-oxygenases
  • 10 of whites have highly inducible form of this
    enzyme are at higher risk to develop smoke
    related lung cancer
  • Others are detoxified by glutathione
    -S-transferase
  • 50 of whites have deleted locus, and are at
    higher risk to develop tobacco related lung and
    bladder cancer

11
Initiation, molecular targets
  • Vast majority of initiating chemicals are
    mutagenic ( Ames Test )
  • Each class of carcinogenes causes limited DNA
    damage
  • Virtually any gene can be targeted, but RAS and
    TP53 ( aflatoxin B1) mutations are fairly common

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Chemical Carcinogenesis
  • Polycyclic hydrocarbons (benzopyrine in cigarette
    smoke, smoked meet ) ? epoxides ? covalent DNA
    links
  • Aromatic amines (ß naphthylamine) ? urinary
    bladder Ca
  • Nitrosamines and nitorsamides ( food amines with
    preservative nitrites, tobacco smoke)

14
The Initiated Cell
  • Must Survivethe insult
  • Must Fix the damage
  • Damaged DNA template must be replicated
  • Damaged DNA alone is not cancerous, so they must
    have other genotypic changes making them
    autonomous
  • Initiated cells are susceptible to promoters
    which induce proliferation, thus immortalizing
    the defect in a clone of proliferating neoplastic
    cells.

15
Promotion
  • Phorbol esters, phenols,hormones, ?bile acids
    ,and some durgs
  • Promoters are usually irritants or substances
    that produce cell activation and proliferation .
  • Powerful protein kinase C activators Clonal
    expansion of initiated cells
  • Effects of promoters are reversible.
  • Promoters cannot induce neoplasia i) alone, ii)
    if applied before initiator, iii) if applied in
    too small an amount for effect, or iv) if too
    much time elapses between applications.

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Radiation Oncogenesis
18
Ultraviolet Light
  • Strong epidemiologic relationship to squamous
    cell, basal cell, and melano-carcinoma in fair
    skinned people.
  • Causes formation of pyrimidine dimers in the DNA
    leading to mutations. ( RAS , TP53 )
  • Activation of T-suppressor cells facilitates
    emergence of tumor clones.
  • Individuals with defects in the enzymes that
    mediate DNA excision-repair are especially
    susceptible.
  • Xeroderma Pigmentosum
  • Necleotide excision repair mechanism is deficient

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Ionizing Radiation
  • Electrogagnetic X-rays, gamma rays
  • Particulate alpha, beta, positrons, protons,
    neutrons
  • Primary cosmic radiation
  • Bone Marrow Acute leukemia occurs before other
    radiation-induced neoplasia (Seven year mean
    latent period in atomic bomb survivors).
  • Thyroid Carcinoma occurs in 9 of those exposed
    during infancy or childhood.
  • Lung Increased frequency of lung cancer in
    miners exposed to Radon gas (an alpha particle
    emitter)
  • Skin, bone and GIT are relatively resistant

23
Mechanisms of Radiation Carcinogenesis
  • Two theories Direct interaction with the DNA or
    indirect damage mediated by free radicals
    generated from water or oxygen.
  • Mutation may result by either mechanism.
  • Mutagenicity of ionizing radiation correlates
    with
  • Radiation quality (High linear energy transfer is
    most dangerous).
  • Dose
  • Dose rate
  • Efficiency of host DNA repair
  • Other host factors such as age, immune deficiency

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Other Radiation and Cancer
  • Low Level Radiation Controversial as to whether
    exposure actually increases the risk of cancer.
  • Radon formed from the decay of uranium-radium
    series of elements. In the U.S.A., 4-5 of homes
    have 5 times background levels of radon. This
    may result in 16 excess lung cancer
    deaths/100,000 persons.
  • Other No firm data that microwave radiation,
    electromagnetic fields, and ultrasound cause
    cancer.

26
Asbestos
  • Asbestos fiber diameter is important
  • Thick fibers lodge in upper respiratory tract
  • Thin fibers lodge in terminal alveoli
  • Malignant mesothelioma of the pleural and
    peritoneal cavities is the characteristic tumor
    associated with asbestos.
  • Association between cancer of the lung and
    asbestos exposure in smokers.

27
Foreign Body Carcinogenesis
  • Humans are highly resistant to foreign body
    carcinogenesis.
  • Tumors associated with parasitic infections
  • Squamous carcinoma of the bladder in persons
    harboring Schistosoma Haematobium
  • Cancer of the bile ducts following infection by
    the liver fluke Clonorchis sinensis

28
Viral Carcinogenesis
  • DNA oncogenic viruses
  • Transforming DNA viruses integrate into the host
    genome, during this process , they loose some
    genes essential for their complete replication.
    Early viral genes, however, are transcribed , and
    expressed in transformed cells.

29
Viral oncogenesis, DN A viruses
  • Human Papillomavirus
  • Types 1,2,4, and 7 cause squamous papillomata and
    linked to SCC of the cervix, anogenital region,
    oral and laryngeal cancers
  • Types 16,18 and to a lesser extent 31,33,35 and
    51 are found in 85 of invasive SCC of the cervix
    and its precursors
  • Types 6 and 11 genital warts with low malignant
    potential ( Episomal non integrated viral genome)

30
Viral oncogenesis, DN A viruses
  • Early viral E7
  • protein binds to underphosphorylated pRb,
    releasing E2F transcription factor
  • Inactivates CDK inhibitors
  • Activates cyclins
  • E6 protein
  • binds to and facilitates degradation of TP53
  • Promotes degradation of BAX
  • Activates telomerase
  • These viral products bind with high affinity in
    high risk forms of HPV
  • Some TP53 alleles are more susceptible to
    degradation by E6 viral gene product ( arginine
    -instead of porline form )
  • Co-factor role of smoking, infection etc.

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Viral oncogenesis, DN A viruses
  • Epstein-Barr Virus
  • Burkitt lymphoma ( African Form )
  • Naso-Pharyngeal Carcinoma
  • Some cases of H.D
  • B- Cell NHL
  • Acts as a polyclonal B-Cell Mitogen

34
Latent infection EBV circularizes into a nuclear
Episome No viral replication, and no cell death
( Immortalization) Expression of viral
proteins Latent Membrane Protein 1 (LMP1) Up
regulation of BCL2 preventing apoptosis
Activation of growth (mimicking CD40 surface
signal) EBNA-2 Activates Cyclin D src forming
genes
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Viral oncogenesis, DNA viruses
  • Kaposi Sarcoma Herpesvirus ( KSHV )
  • Genomic sequences found in all cases including
    HIV negative cases
  • Encodes several genes that participate in cell
    proliferation ( IL-6, chemokine MIP-1alpha, G
    protein, Cyclin D and BCL-2 )
  • Encodes growth promoting factors such as IL-1,
    TNF-a that stimulate growth of spindle cells in
    autocrine and paracrine fashion
  • HIV infected B cells encode soluble tat (
    transactivating proteins )

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Viral oncogenesis, DN A viruses
  • Hepatitis B Virus
  • Hepatocellular Carcinoma
  • Indirect, possibly multifactorial effect
  • Injury and regenerative hyperplasia
  • HBx protein Activation of growth promoting
    genes , activation of RAS-MAP kinase ,
  • Rearrangement of chromosomes
  • Interferes with TP53 activity
  • Hepatitis C virus
  • Liver injury and regeneration ( Fertile soil for
    mutations

39
Viral oncogenesis, RNA viruses
  • Acute transforming viruses
  • All except one ( Rous Sarcom Virus ) have lost
    their replication genes, and placed new set (
    V-oncs ) instead
  • V-oncs ( V-SRC, V-ABL, V-MYB) integration into
    genome ? C-oncs
  • Slow transforming viruses
  • Dont have oncogens, replication competent
  • Leukemia in rodents
  • Insertional mutagenesis

40
Viral oncogenesis, RNA viruses
  • Human T-Cell Leukemia Virus 1 (HTLV-1)
  • Associated with T-cell leukemia\lymphoma in Japan
    and Caribbean basin
  • Tropism for CD4 T-Cells
  • No V-oncs
  • Contains pX region in the genome, includes tax
    gene, that activates transcription of c-fos,
    c-sis that code for cytokine IL-2 and its
    receptor and GM-CSF
  • tax also inhibits CDK4 and TP53 normal inhibition
  • Demyelinating neurologic disorder (Tropical
    spastic paraparesis )

41
TCLL
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43
Helicobacter pylori
  • Gastric carcinoma in about 3 of infected
    individuals after decades
  • Chronic gastritis ? atrophy? intestinal
    metaplasia ? dysplasia ? cancer
  • Gastric lymphoma
  • B-cell lymphoma
  • MALToma
  • H. pylori ? reactive T-cells ? polyclonal B-cell
    activation
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