Week 4.2

• Principles of Pathology: Molecular causes of carcinogenesis
• Lecture Overview


  • What causes tumours to form?
  • Chemical carcinogenesis
  • Hormonal carcinogenesis
  • Viral carcinogenesis
  • Bacterial/parasitic carcinogenesis
  • Chronic inflammation carcinogenesis
• When were carcinogens first identified?
• Lecture Overview


  • Overview of carcinogenesis
  • Chemical carcinogenesis
  • Hormonal carcinogenesis
  • Viral carcinogenesis
  • Bacterial/parasitic carcinogenesis
  • Chronic inflammation carcinogenesis
• Carcinogen


  Any agent that produces cancer
• Examples Carcinogens


  • tobacco smoke
  • certain industrial chemicals
  • ionizing radiation (such as X-rays and ultraviolet rays)
• Types of Carcinogens


  • Genotoxic (direct DNA damaging carcinogens)
  • Non-Genotoxic (damage DNA as result of secondary interactions, e.g. increase of oxidative stress, inflammation)
• Types of Genotoxic Carcinogens

  • Direct - no modification needed (eg. anti-tumoral chemotherapeutic drugs)
  • Pro-carcinogens - modified by intracellular enzymes to become carcinogenic
• Polycyclic aromatic hydrocarbons (PAHs)

  1. Benzo[a]pyrene is initially oxidized, primarily by the microsomal NADPH- dependent cytochrome P-450, to several arene oxides
  2. Benzo[a]pyrene derivates can bind and damage DNA
  3. Benzo[a]pyrene itself can bind AR (Aryl hydrocarbon receptor) and activate gene expression: cytochromes, MAP kinases, IGF-1 (insulin-like growth factor-1)
• Certain strains of the fungi Aspergillus flavus and A. parasiticus produce Aflatoxin B1
• Oltipraz


  Inhibits activation by p450s, and induces detoxification pathways
• Evidence that aflatoxin ingestion through contaminated foodstuffs is one of the major etiological factors in human hepatocellular carcinoma (HCC) in China and sub-Saharan Africa
• Tumor Promoters


  • Promoting agents are not carcinogenic per se; they cannot cause cancer on their own
  • Can promote cancer if administered after very small doses of initiating (true carcinogenic) agents
  • Promoting agents can 'wake up' tumours a long time after administration of initiating agent
• Initiation, promotion and persistence

  Latency is represented by the time interval between exposure to the initiating agent and the growth of a detectable neoplasm
• Professions and industries associated with high risk of cancer

  • Aluminium industry (polycyclic aromatic hydrocarbons (PAHs)) - lung and bladder
  • Coal industry (polycyclic aromatic hydrocarbons (PAHs)) - lungs, bladder, skin, scrotum cancer
  • Shoemaking (Benzene) - lymphomas, leukemias
  • Furniture making (Wood dust) - nasopharyngeal cancer
  • Fuchsin dye production (Fuchsin, ortho-toluidine) - bladder cancer
  • Rubber industry (Aromatic amines, solvents) - lung, colon, stomach, bladder, etc
• How to block carcinogen-dependent tumorigenesis

  • Block carcinogen uptake into body/cells
  • Inhibition of carcinogen formation/activation by blocking Cyt P450
  • Stimulate carcinogen deactivation
  • Inhibit DNA adduct formation (antioxidants)
  • Stimulation of DNA repair
• Hormonal carcinogenesis


  • Oestrogens stimulate proliferation of epithelial cells and oestrogen metabolites are genotoxic
  • Xeno-oestrogens (DDE and other insecticides) are structurally similar to diethylstibestron
  • Genistein from Soybean and other phytoestrogenes
  • Digitalis, Sulfonamide antimicrobials
  • Oral contraception, Hormone Replacement Therapy (oestrogen should be counterbalanced by progesterone)
• DNA-containing Oncoviruses


  • Polyomaviridae
  • Papillomaviridae (Human papillomavirus (HPV 16, 18))
  • Adenoviridae
  • Poxviridae (Jabavirus, tanapoxvirus, Contagious mollusc virus)
  • Herpesviridae (Epstein-Barr virus (EBV), Kaposi' sarcoma virus (KHSV), Marek disease virus, American rabbit virus)
  • Hepadnaviridae (Hepatitis B virus, Woodchuck hepatitis virus, Duck hepatitis virus)
• Mechanism of DNA-containing Oncoviruses

  • The viral genome is integrated into host cell DNA
  • Neoplastic transformation is a postulated consequence
• RNA-containing Oncoviruses


  • Alpharetrovirus (Rous sarcoma virus (RSV), Chicken lympholeukosis)
  • Betaretrovirus (Mouse mammary tumor virus (MMTV))
  • Gammaretrovirus (Moloney sarcoma virus (mouse), Feline sarcoma (FSV))
  • Deltaretrovirus (Bovine leukosis, Human adult T-cell leukemia virus (HTLV))
• Mechanism of 'Acute' Transforming RNA Virus

  • Transduction into the host cell of an RNA transcript of a cellular oncogene picked up from another cell
  • DNA transcripts are made from the RNA conveyed by the virus using the enzyme reverse transcriptase
• Mechanism of 'Slow' Transforming RNA Virus


  • DNA transcripts are made from the RNA conveyed by the virus using the enzyme reverse transcriptase
  • Insertion of a viral promoter gene next to a cellular oncogene
• HTLV-1 (human T-cell lymphotropic virus)

  1. Sexually transmitted
  2. Endemic to Japan and the Caribbean
  3. causes Adult T-cell leukemia (Sezary T-cell leukemia)
• HTLV-2


  1. T variant of hairy cell leukemia
  2. endemic to Native American Indian populations
  3. seroprevalence is over 50%
• Pathogenesis of HTLV-1-induced T-cell leukemia/lymphoma
• Human papillomaviruses - HPV6 and HPV18


  • Causative agents for female cervical carcinomas, as well as for genital and regular warts
  • May integrate into the genome or persist as episomal form
• Bacterial and parasitic carcinogenesis

  • Helicobacter pylori (stomach lymphomas/ gastric tumours)
  • Schistosomiasis (bladder carcinoma)
• Helicobacter pylori


  • Linked to MALT lymphoma and gastric carcinoma
  • Both cellular and humoural immune responses are activated but the bacteria still manage to persist lifelong unless eradicated with antibiotics
  • H. pylori overlies and enters the gastric epithelial cells
  • H. pylori causes more than 90% of duodenal ulcers and up to 80% of gastric ulcers
• Infected persons have a 2- to 6-fold increased risk of developing gastric tumor
• Treatment of gastric and duodenal ulcers

  • Lowering of gastric acidity (life-long, relapse after cesation of therapy): H2-receptor blockers, proton pump inhibitors
  • Antibiotics (10 days to 2 weeks): Amoxicillin or metronidazole, or clarithromycin, plus either: ranitidine bismuth citrate or bismuth subsalicylate
  • Eradication rates range from 61% to 94% depending on the regimen used
• Schistosomiasis


  • Fresh water snail is an intermediate host
  • On contact with humans, the parasite burrows into the skin, matures into another larval stage (schistosomula), then migrates to the lungs and liver (where it matures into the adult form)
  • The adult worm then migrates to the intestine, liver or bladder
• In Egypt, schistosomiasis linked with cancer is the primary cause of death among men aged 20 - 44
• Inflammatory carcinogenesis


  • All pro-inflammatory agents are tumour promoters
  • Anti-inflammatory agents can reverse action of some tumor promoters (e.g. anti-inflammatory steroids (dexamethasone))
  • Any type of chronic tissue wounding can promote carcinogeneis – e.g. tumour can arise on chronic ulcer, burn, trauma site
• Reading: Tortora and Derrickson, Principles of Anatomy and Physiology. Chapter 24.
• Reading: Vogelstein, B., Sur, S. & Prives, C., 2010. p53: The Most Frequently Altered Gene in Human Cancers. Nature Education. 3:6: http://www.nature.com/scitable/topicpage/p53-the-most-frequently-altered-gene-in-14192717
• Reading: Chow, A. Y., 2010. Cell Cycle Control by Oncogenes and Tumor Suppressors: Driving the Transformation of Normal Cells into Cancerous Cells. Nature Education. 3:7. http://www.nature.com/scitable/topicpage/cell-cycle-control-by-oncogenes-and-tumor-14191459
• Reading: Ralston, A., Hoopes, L. & Shaw, K., 2008. Environmental factors like viral infections play a role in the onset of complex disease. Nature Education. 1:123 http://www.nature.com/scitable/topicpage/environmental-factors-like-viral-infections-play-a-996
• Types of Genotoxic Carcinogens

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