Neoplasia V Carcinogenesis

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Neoplasia VCarcinogenesis

• Husni Maqboul, M.D

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Overview of Carcinogenic Agents

• Chemical Carcinogens
• Physical Agents
• Ionizing Radiation
• Oncogenic Viruses

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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).

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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

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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).

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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

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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)

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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.

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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
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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

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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.

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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.

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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

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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.

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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)

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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

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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

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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

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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 )

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TCLL
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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