Carcinogenesis

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"I think of life itself now as a wonderful play
that I've written for myself... and so my purpose
is to have the utmost fun playing my
part!" Shirley MacLaine, Actress and Author
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Carcinogenesis
Dr. Venkatesh M. Shashidhar. Senior Lecturer in
Pathology Fiji School of Medicine
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We owe, Sir Percival Pott the knowledge of
carcinogenesis. Pott, related the increased
incidence of scrotal cancer in chimney sweeps. On
his findings, Danish Chimney Sweeps Guild ruled
that its members must bathe daily.No public
health measure since that time, has so
successfully controlled a form of cancer!!!
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Key words

• Oncogenesis Pathogenesis of neoplasm (b/m)
• Carcinogenesis Pathogenesis of cancer (m)
• Carcinogen - agent causing cancer.
• Oncogen - agent causing neoplasm.
• Mutagen - agent causing mutation.
• Oncogenes genes causing cancer
• p-onc, v-onc, c-onc Proto/viral/cell - naming
  of oncogenes.

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Cell Cycle is controlled by genes.
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Genes control Cell division by cytokines.
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Molecular Basis of Carcinogenesis

• Genes control cell division by cytokines.
• Four classes of regulatory genes.
• Promotors Proto-oncogenes
• Inhibitors Cancer-suppressor genes p53
• Genes regulating Apoptosis.
• DNA repair genes.

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Non-lethal Genetic damage lies at the center of
carcinogenesis.

• Loss/damage to suppressor genes,
• Duplication of promotor genes
• Loss/damage to Apoptosis genes
• Loss/damage of DNA repair genes.

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Causes of Neoplasia

• Environmental causes (Carcinogens)
• Chemicals
• Viruses
• Radiation
• Hereditary causes- Genetic defects.
• Combination common.
• Obscure defects

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Carcinogenesis
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Chemical Carcinogenesis

• Initiation
• DNA damage eg.Benzpyrene
• Promotion
• Histologic change eg. Turpentine
  (co-carcinogens)
• Malignant transformation
• Visible tumor formation further DNA damage.

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Chemical Carcinogenesis

• Direct Acting Carcinogens
• Alkylating Agents Cyclophosphamide
• Procarcinogenes (needs activation)
• Polycyclinc hydrocarbons Benzpyrene
• Aromatic amines, dyes - Benzidine
• Natural products Aflotoxin
• Others Vinyl chloride, turpentine etc.

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Viral Oncogenesis

• Insertion of viral nucleic acids ? mutation
• Alterations in Oncogenes, cancer suppressor genes
  and genes regulating DNA repair resulting in
  up-regulation of cell division ? Carcinogenesis.
• Nobel Laureates Varmus and Bishop
• v-fes, v-sis ? proto-oncogenes.
• v-sis ? sis ? PDGF ? Brain tumours.

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Viral Oncogenesis

• Human Papilloma Virus
• Cervical neoplasia warts, papilloma, ca cx
• Epstein-Barr virus
• Burkitts Lymphoma, Nasopharyngeal ca.
• Hepatitis B C virus
• Hepatocellular carcinoma.

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Radiation Carcinogenesis

• Ionizing radiation ? dysjunction ? random fusion
  ? mutation.
• X Ray workers Leukemia
• Radio-isotopes Thyroid carcinoma
• Atomic explosion Skin cancer, Leukemia

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Hereditary Causes

• Due to inhereted abnormal genes.
• FAP gene C5, polyposis ? Adenocarcinoma colon
• Retinoblastoma Rb gene (C13)
• Neuroblastoma (C17)
• Trisomy 21 Downs syndrome Leukemias in
  infants.

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Molecular Basis of Neoplasia
Proto-oncogene
Oncogene
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Multi-step Process

• Tumor initiation and progression results from
  stepwise accumulation of DNA mutations.
• Several characters of malignant neoplasm are the
  result of multiple genetic defects.
• Initial steps reversible(e.g. dysplasia), but
  final Malignant transformation is irreversible.
  Hit Run

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Tumor Progression
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Multi-step Theory

• Stage of initiation
• Latent stage
• Stage of promotion
• Stage of malignant transformation

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p53 Gene

• p53 senses DNA damage, and induces G1 arrest and
  induces DNA repair process.
• Cell with un-repairable DNA is directed to
  apoptosis by p53 gene.
• P53 is a guardian of the genome.
• Its homozygous loss leads to accumulation of
  damaged DNA may result in malignancy
• Homozygous loss of p53 is seen in virtually every
  type of cancer.
• Over half of human malignant cells show loss of
  p53 gene by special tests.

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Summary

• DNA damage - loss of control over cell division.
• Radiation, Chemicals Viral infections are some
  known causes of cancers.
• Cancer evolves in multiple steps by sequentially
  acquiring different DNA damages.
• Initiation, Latent stage, Promotion and Malignant
  transformation are recognizable stages in
  carcinogenesis.
• Each character of malignancy depends on unique
  DNA alteration.

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Liver Metastasis
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Liver Metastasis
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Principle of Treatment

• Surgical therapy early stage/debulk
• Chemotherapy -
• Radiotherapy
• Immunotherapy

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Principle of Treatment

• Most anticancer treatment is directed towards
  killing actively dividing cells.
• Complications Marrow aplasia, alopecia,
  sterility, GIT, lung, kidney damage).
• Newer drugs target tumor cells by immune
  mechanisms or hormones.

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Self Assessment Questions

• Briefly describe molecular basis of
  carcinogenesis.
• What are Oncogenes? Give examples.
• Write brief note on p53 gene / carcinogenesis?
• Briefly describe multistep theory of
  carcinogenesis
• Briefly describe hereditary causes of cancer with
  an example?
• What are oncogenic viruses? Give examples.
• Give two examples of familial neoplasms.
• Write a short note on chemical/viral/radiation
  carcinogenesis.

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It is easy to kill cancer cells, but the
challenge is keeping the patient alive at the
same time..!
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Do not fear mistakes fear only the absence of
constructive and corrective responses to those
mistakes