Carcinogenesis and Immunopathology

Carcinogenesis

• Carcinogenesis is the process of initiation and promotion of cancer
• A carcinogen is any agent or substance that initiates cancer, e.g. chemicals, radiation, viruses
• The process involves changes in the genome of cells, including mutations, over-expression of genes, or loss of activity of gene products
• Mutations may be gross defects (e.g. translocations or breaks in chromosome arms) or a defect involving a single base-pair of DNA (e.g. point mutations, substitutions, deletions)

Classes of Normal Regulatory Genes

• Four classes of normal regulatory genes are the principle targets of genetic damage:
  • Growth promoting proto-oncogenes (normally code for proteins involved in the control of normal cell growth and differentiation)
  • Growth-inhibiting tumour suppressor genes (normally discourage cell growth, or temporarily halt cell division to carry out DNA repair)
  • Genes that regulate apoptosis (normally allow programmed cell death to occur, preventing further cell growth)
  • Genes involved in DNA repair (normally allow repair of DNA following damage/mutations by stimuli)

Aetiology of Cancer

• Tumours have a multifactorial aetiology in which carcinogens play only one part
• Body factors (intrinsic factors) and environmental factors (extrinsic factors) both contribute to the causation of cancer
• Genetic makeup, racial background, climactic conditions, environmental agents, and diet may all contribute to cancer development

Intrinsic Factors

• 1. Genetic factors:
  • Leukaemia, e.g. Trisomy 21 in Down's Syndrome
  • Chronic myeloid leukaemia, e.g. Philadelphia chromosome
  • Polyposis coli, an autosomal dominant trait where hundreds of benign tumours form on the colonic mucosa
• 2. Racial and geographic factors:
  • Higher incidence of carcinoma of the breast in Australia compared to Japan
  • Higher incidence of hepatocarcinoma in SE Asia compared to Australia
• 3. Immunological factors:
  • Patients with immunodeficiency (e.g. AIDS) have a higher incidence of some cancers (e.g. Kaposi's sarcoma, lymphoma)
• 4. Sex and Hormonal Influences:
  • Hormonal stimulation can lead to some cancers, e.g. breast (oestrogen stimulation)
• 5. Age:
  • Cancer is more common with increasing age, e.g. carcinoma of the colon
• 6. Pre-existing Benign Neoplasms:
  • Benign tumours that are left untreated for long periods may undergo malignant change due to additional mutations, e.g. polyposis coli, adenomatous polyp

Extrinsic Factors

• 1. Chemical agents:
  • Percival Pott (1775) described the association between soot exposure and carcinoma of the scrotum in chimney sweeps
  • Polycyclic aromatic compounds are carcinogenic, e.g. 2-naphthylamine, 7,12-dimethylbenzanthracene (DMBA)
• 2. Physical agents:
  • Ionizing radiation, e.g. UV light, X-rays, g-rays, products of radioactive decay
  • Trauma, e.g. chronic injury and tissue damage, not single episode of trauma
  • Inert substances in the body, e.g. plastic films, glass, fibres, methylcellulose, metal foils and wires, asbestos fibres
• 3. Biological agents:
  • Parasites, e.g. Schistosoma spp cause a chronic infection of the bladder and predispose to carcinoma
  • Fungi and bacteria, e.g. Aspergillus flavus produces aflatoxin (carcinogen) in starchy foods, leading to primary hepatocarcinoma

Types of Hypersensitivities

• Type II Antibody Mediated Hypersensitivity:
  • Graves' disease (thyrotoxicosis), e.g. thyroid-stimulating Abs (TSI) bind to TSH receptor leading to excessive secretion of thyroid hormones and hyperplasia of thyroid follicular epithelium
  • Myasthenia gravis, e.g. Abs form against acetylcholine receptors of skeletal muscle cells, blocking action of acetylcholine, leading to fatigue, weakness of muscles, ocular, facial muscles involved early, ptosis, difficulty in speaking, chewing, swallowing
• Type III Immune Complex Mediated Hypersensitivity:
  • Soluble antigen combines with specific Abs to form immune (Ag-Ab) complexes, which circulate around body and localize in walls of vessels, leading to thrombosis, inflammation, tissue damage, necrosis
  • Examples: serum sickness, glomerulonephritis
• Type IV T Cell Mediated (Delayed) Hypersensitivity:
  • No antibodies involved, sensitized T-cells, killer cells, activated macrophages, and secretion of cytokines cause tissue damage
  • Examples: contact dermatitis, tuberculin reaction, Jones-Mote reaction

This quiz covers the fundamental concepts of carcinogenesis and immunopathology, exploring the relationship between cancer and the immune system.