Principles of carcinogenesis-1

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Principles of carcinogenesis-12

• Dr D Ponraj
• Bioscience/SHS/NYP

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Introduction

• Carcinogenesis
• Its the process which results in the
  transformation of normal cells to neoplastic
  cells by causing permanent genetic alterations
  (it strictly applies to malignant tumours).
• Oncogenesis It includes the causation of all
  tumours, benign and malignant
• Carcinogen Its an agent known or suspected to
  participate in the causation of tumours (and
  called carcinogenic agents).
• Genetic alterations are absolutely fundamental in
  carcinogenic process

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Identification of carcinogens

• Epidemiological studies (colorectal cancers,
  oesophagial Ca)
• Assessment of occupational risks (scrotal Ca in
  chimney sweeps)
• Direct accidental exposure (throtrast in
  angisarcoma of liver, Chernobyl nuclear reactor
  accident)
• Carcinogenic effects on lab animals
• Transforming effects on cell cultures
• Mutagenicity testing in bacteria

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Main classes of carcinogens

• 1. Chemicals
• 2. Viruses Genetic- oncogenes
• 3. Ionising radiation non-ionising radiation
• 4. Hormones, mycotoxins and parasites
• 5. Miscellaneous agents (asbestos metal like
  nickel)
• Genetic

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Cellular molecular events in carcinogenesis

• Its a multistep process
• May require a initiating (polycyclic hydrocarbon)
  and promoting (croton oil) agent. If an agent
  possess both these agents its called complete
  carcinogen, if it has only one action its called
  incomplete carcinogen
• Growth persists even in the absence of the
  causative agent.
• Genetic alteration of oncogenes and tumour
  suppressor genes (Ca colon).

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Chemical carcinogensis

• Direct-acting compounds
• which do not require chemical transformation for
  carcinogenity.
• They are highly reactive electrophiles (have
  electron-deficient atoms) that can react with
  neuleophilic (electron rich) sites in cell.
• Indirect-acting compounds or procarcinogens
  which require metabolic conversion in vivo to
  produce the ultimate carcinogen capable of
  transforming cells.

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Chemical carcinogens

• 1. Polycyclic hydrocarbons
• the first carcinogen discovered in soot, a tary
  residue of coal combustion.
• Responsible for scrotal ca in chimney sweeps of
  London.
• The most active component is benzoalphapyrene
  and dibenzanthracene.
• Benzopyrene in tobacco smoke is the most
  important carcinogenic agent.

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• 2. Cigarette smoking
• Including cigar and pipes-is associated
• with Ca lung, oesophagus, bladder, oropharynx.
• Passive smokers also affected
• Inhaled polycyclic hydrocarbons (tars) are
  converted in the liver to an epoxide by a
  microsomal enzyme, aryl hydrocarbon hydroxylase.
• This epoxide (ultimate carcinogen) is an active
  compound that combines with guanine in DNA,
  leading to neoplastic transformation.
• 10 pack years an increase in 10 times for
  cancer for some one who smokes a pack of
  cigarette a day

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3. Aromatic amines

• Such as benzidine and naphthylamine is associated
  with bladder cancers.
• They are mostly procarcinogens and enters through
  skin, lung (leather and dye industries) or
  intestine.
• Cause cancer in animals, but varies in different
  species of animals tested. Controlled by FDA.
• Detected by measuring urine levels.

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• 4. Cyclamates and Saccharin
• These are artificial sweeteners used in
  diabetes.
• No carcinogenic effect in humans but have
  carcinogenic effect in animals.
• 5. Azo dyes
• These are dyes used for colouring of food
  (scarlet red butter yellow).
• They were shown to cause liver cancer in animals.

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6. Aflatoxins

• Its the most potent carcinogen known.
• Its a toxic metabolite produced by the fungus
  Apergillus flavus, known to cause liver cancer in
  man. In Africa, dietary intake of large amounts
  of aflatoxins have shown to result in
  hepatocellular carcinoma.
• Ingested aflatoxin is oxidised in the liver to an
  ultimate carcinogen that binds with guanine in
  the DNA of hepatic cells.
• First the liver goes for acute liver cell
  necrosis followed by regenerative hyperplasia and
  possibly cancer.

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• 7. Nitrosamines
• Their ability to react with both nucleic acids
  and cytoplasmic macromolecules provides a
  theoretical basis for carcinogenic action.
• Nitrosamines are derived mainly by conversion of
  nitrites in stomach.
• Nitrites are ubiquitous in food because of their
  common use as preservatives, mainly in processed
  meat, ham, bacon, sausage...

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• Better refrigeration of food for past 20 years
  has decreased use of preservatives and hence
  cancer
• The high incidence of gastric cancer in Japan is
  thought to be due to high intake of smoked foods
  which contain more polycyclic hydrocarbons than
  to high nitrosamine levels.

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8. Asbestos

• Crocidolite, the variety of asbestos having the
  finest diameter fibres (lt0.25 mm), presents the
  greatest hazards
• Asbestosis also leads to fibrous proliferation in
  the pleura, where it results in fibrous plaques
  that are reliable radiological indicator.
• It results in 2 types of cancer
• a.Malignant mesothelioma, which involves the
  pleura, peritonium and pericardium
• b. Bronchogenic Carcinoma this risk is greatly
  magnified by smoking

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• 9. Betel leaf
• Associated with oral cancers, common in India,
  srilanka.
• The carcinogenic agent is either Areca nut or the
  crushed limestone or tobacco that is commonly
  chewed along with betel leaf
• 10. Anticancer drugs
• Leukaemia is the most common neoplastic disorder
  associated with alkylating agents, such as
  cyclophosphamide, busulfan, chlorambucil.
• These interfere with nucleic acid synthesis in
  normal cells and may cause oncogenic mutation

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11. Other industrial carcinogens

• Heavy metals
• nickel, chromium, and cadmium show an increased
  incidence of lung cancer
• Arsenic exposure,
• in agricultural workers exposed to arsenic
  -containing pesticide, is associated with skin
  cancer and to lesser extent, lung cancer
• Vinyl chloride,
• a gas used to manufacture PVC, has been shown to
  induce malignant vascular neoplasm in liver
  (angiosarcoma)

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Viral Genetic Oncogenesis

• Dr D Ponraj
• Bioscience/SHS/NYP

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Introduction

• Cluster of cancer cases in space and time suggest
  a viral aetiology
• Tumours associated with viruses tend to be more
  common in youth
• Immunosuppression favours viral oncogenesis
• Viruses implicated in human carcinogenesis
  include EB virus (Burkitts lymphoma) and HPV
  (cancer cervix)

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Types of oncogenic virus

• Both DNA and RNA viruses can cause neoplasia.
• DNA viruses insert their nucleic acid directly
  into the genome of the host cell.
• The replication is sporadic or absent
• However, DNA may persist and produce an oncogene
  like effect

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• RNA viruses require RNA-directed DNA polymerase
  (reverse transcriptase), an enzyme that causes
  production of a DNA copy of the RNA viral genome.
  
• Some RNA viruses contain built-in oncogene that
  directly activates cell.
• Others insert adjacent to an endogenous cellular
  oncogene that directly activates the cell.

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RNA viruses

• Only few are implicated in human neoplasms
• HTLV-I Japanese T cell leukaemia was first
  described in Japan.
• HIV associated with B cell lymphoma. (In
  patients with AIDS Kaposi sarcoma is the
  commonest malignancy)
• All others mostly cause cancer in experimental
  animals (eg mouse mammary tumour virus MMTV)

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DNA viruses

• HPV subtypes 16 18 are the common cause of
  malignancy in 85 of in invasive squamous cell
  ca.
• They suppress tumour suppressor gene Rb and P53.
• Cotransfection with ras gene results in full
  malignant transformation.
• Normally HPV cause anogenital warts.

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Epstein-Barr virus

• Discovered first in cell cultures from Burkitts
  lymphoma, a B-cell lymphoma endemic in Africa. It
  also cause infectious mononucleosis.
• It also results in nasopharyngeal Ca.
• EB virus is not the sole cause of Burkitts
  lymphoma, its one of the multistep factor in
  development of Burkitts lymphoma.
• It involves mutation affecting N-ras oncogene
  and t(814) translocation.

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Others

• Hepatitis B virus
• liver cancer
• Herpes simple virus
• Ca cervix

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Genetic mechanism

• Cancer now is increasingly regarded as a genetic
  disease.
• Some times they are consistently associated with
  chromosomal defect (eg, Philadelphia chromosome
  in CML)
• There are two mechanisms leading to tumour
  growth
• 1.Loss or inactivation of recessive inhibitory
  genes- Tumour suppressor genes.
• E.g. P53 (guardian of genome), Rb1,APC...

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• 2. Enhanced or abnormal expression of dominant
  stimulatory genes-Oncogenes.
• They govern the neoplastic behaviour of cells.
• More than 600 such genes have been identified
• Based on their function they are classified into
  4 types
• eg (ras, myc, sis, erb)
• Both mechanisms operate in most tumours (e.g. Ca
  colon), but inactivation of tumour suppressor
  genes explain inherited predisposition of
  development of tumour (e.g. retinoblastoma).
• Note A 3rd category of genes that control
  apoptosis are also involved in tumour growth.

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Mechanisms of genetic mutation
Virus
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Mutations that "turn on" the oncogenes
stimulate growth. Mutations that result in loss
of tumor suppressor genes and their products
inhibit growth.
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Apoptosis (programmed cell death)

• It is an energy-dependent process for deletion of
  unwanted individual cells. It has a role in
  morphogenesis, organ size.
• Individual cell deletion in physiological growth
  disease
• Reduced apoptosis contributes to cell
  accumulation in neoplasia
• Increased apoptosis results in excessive cell
  loss (atrophy)
• Activated or prevented by several stimuli
• Mechanism of cell death is different from necrosis

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Modes of inheritance

• IN MAN 23 (221) PAIRS OF CHROMOSOMES
• Autosomal dominant (only one copy of genes need
  to be inherited, thus both hetero homozygous
  are affected)
• Autosoaml recessive (both copies of genes must be
  abnormal, thus homozygous individuals are
  affected)
• Sex chromosome (X)- linked (defective gene is in
  the X chromosome, males are sufferers, females
  are carriers)

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