7.5 about 26 minDeep Learning viewL7 p.9, 15–17

Carcinogens: chemicals, viruses, radiation and bacteria

Carcinogens damage DNA directly, after metabolic activation, by inserting viral oncogenes or through chronic inflammation. Learn the few signature pairings that point to one exposure, and keep them apart from broad risk factors.

Initiation and promotion; direct- and indirect-acting carcinogens

L7 p.9, 15–16

Chemical carcinogenesis has at least two steps, which animal experiments separate cleanly. Initiation is a permanent change in DNA caused by a mutagen (the initiator); it is quick and irreversible, but an initiated cell looks normal and may stay quiet for life. Promotion is repeated stimulation of proliferation by a promoter (hormones, phorbol esters, chronic tissue injury); promoters are not mutagenic, their effect is reversible if exposure stops, and they cause tumors only in cells that have already been initiated. Progression follows as dividing initiated cells acquire further mutations.

Teaching schematic

TumorsInitiator once, then repeated promoter: tumors.
No tumorsInitiator alone: a mutated cell, but nothing expands it.
No tumorsPromoter alone: proliferation with no mutation to expand.
No tumorsPromoter before initiator: the proliferation has faded by the time the mutation arrives.
No tumorsPromoter too far apart: its effect is reversible, so the clone does not build up.

I = initiator (mutagen, irreversible) · P = promoter (proliferation, reversible, not mutagenic)

The classic skin experiments. Initiator followed by promoter gives tumors, even when the promoter starts months later. Initiator alone, promoter alone, or promoter before initiator gives none. Promoter applied too sparsely gives none: its effect fades.L7 p.9

Direct-acting carcinogens

  • Reactive as they are: no metabolic activation
  • Usually weak
  • Alkylating agents used in chemotherapy (cyclophosphamide, busulfan) → later leukemia/lymphoma

Indirect-acting (procarcinogens)

  • Need activation, mostly by cytochrome P-450 in the liver
  • Polycyclic aromatic hydrocarbons (tobacco smoke, smoked meat), aromatic amines (naphthylamine), aflatoxin B1, nitrosamines, vinyl chloride
  • Individual P-450 activity changes individual risk
L7 p.9, 16

Aflatoxin: a carcinogen with a fingerprint

  1. Aspergillus grows on stored grains and peanuts → aflatoxin B1
  2. Liver P-450 converts it to a reactive epoxide
  3. Epoxide binds guanine → G:C → T:A transversion at TP53 codon 249
  4. Hepatocytes lose p53 → hepatocellular carcinoma (risk multiplied by HBV)
L7 p.16Ref. · Robbins

Chemical carcinogens: signature pairings and broad risks

L7 p.16

Chemical carcinogens in the lectureL7 p.16

  • Cigarette smoke (polycyclic hydrocarbons)

    Cancer
    Oropharynx, esophagus, lung, kidney, bladder, pancreas
    Source and comment
    The most common carcinogen worldwide

  • Alcohol

    Cancer
    Squamous carcinoma of oropharynx and upper esophagus; hepatocellular carcinoma
    Source and comment
    Synergistic with tobacco in the upper aerodigestive tract; HCC through cirrhosis

  • Nitrosamines

    Cancer
    Stomach carcinoma
    Source and comment
    Smoked and preserved foods; high gastric cancer rates in Japan

  • Naphthylamine (aromatic amine)

    Cancer
    Urothelial carcinoma of the bladder
    Source and comment
    Aniline dye and rubber industries; also in cigarette smoke

  • Aflatoxins

    Cancer
    Hepatocellular carcinoma
    Source and comment
    Aspergillus on stored rice, grains and peanuts

  • Alkylating agents

    Cancer
    Leukemia / lymphoma
    Source and comment
    Side effect of chemotherapy

  • Arsenic

    Cancer
    Squamous carcinoma of skin, lung cancer, angiosarcoma of liver
    Source and comment
    Contaminated water, pesticides; also in cigarette smoke

  • Asbestos

    Cancer
    Lung carcinoma and mesothelioma
    Source and comment
    Lung carcinoma is the more common result, especially in smokers

  • Vinyl chloride

    Cancer
    Angiosarcoma of the liver
    Source and comment
    Occupational: polyvinyl chloride (PVC) manufacture

  • Nickel, chromium, beryllium, silica

    Cancer
    Lung carcinoma
    Source and comment
    Occupational exposure

Read the association in both directions

Signature pairings (a rare tumor points back to one exposure)

  • Hepatic angiosarcoma → vinyl chloride (or arsenic)
  • Mesothelioma → asbestos
  • Bladder urothelial carcinoma in a dye or rubber worker → naphthylamine
  • HCC with TP53 codon 249 mutation → aflatoxin
  • Leukemia after chemotherapy → alkylating agents

Broad associations (one exposure raises many common cancers)

  • Tobacco: lung, mouth, larynx, esophagus, pancreas, kidney, bladder, cervix
  • Alcohol: mouth, pharynx, esophagus, liver (and breast)
  • Asbestos raises lung carcinoma more often than mesothelioma
  • A common tumor in an exposed person is usually not 'caused by' that agent alone
L7 p.16

Oncogenic viruses

L7 p.15, 17

Viruses cause cancer in three ways: their genes encode proteins that disable the cell's brakes (HPV), they insert into or activate host growth genes (HTLV-1, EBV), or they cause years of chronic inflammation and regeneration in which mutations accumulate (HBV, HCV). The lecture lists five.

Teaching schematic

E6 → p53

  1. E6 binds p53
  2. p53 is ubiquitinated and degraded
  3. No G1 arrest, no apoptosis after DNA damage
  4. Damaged cells survive and keep dividing

E7 → RB

  1. E7 binds RB
  2. E2F is released without a growth signal
  3. S-phase genes transcribed
  4. Continuous proliferation of infected cells

Integration of the viral genome disrupts E2, which normally restrains E6 and E7, so both are overexpressed. Both G1 brakes are gone at once: proliferation without a signal, and no response to the damage that proliferation causes.

High-risk HPV removes both G1 brakes. E6 marks p53 for degradation, so damaged cells neither arrest nor die; E7 binds RB, so E2F is released and the cell enters S phase.L7 p.17Ref. · Robbins

Human papillomavirus. High-risk types (16, 18, 31, 33) cause squamous carcinoma of the cervix, vulva, vagina and anus (and cervical adenocarcinoma). Their genome often integrates into host DNA; integration breaks the viral E2 gene that normally restrains E6 and E7, so both oncoproteins are overexpressed. E6 binds p53 and targets it for ubiquitin-mediated degradation; E7 binds RB and releases E2F. The cell loses both its G1 checkpoint and its ability to die after DNA damage, and mutations accumulate. Low-risk types (6, 11) cause warts (condylomas), which rarely become malignant.

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

A cervical squamous cell at the transformation zone is infected by HPV 16, and the viral genome integrates into host DNA. Complete the chain to a dividing, mutating clone.

Two gaps ask for a mechanism, the link that explains how one event causes the next. Don't put an event there.

  1. High-risk HPV 16 integrates into the host genome
  2. integration disrupts viral E2, which normally restrains E6 and E7
  5. p53 protein is degraded
  6. no p53 means no p21, no DNA-repair induction and no apoptosis signal
  9. Continuous proliferation of cells carrying unrepaired DNA damage
  10. each division adds mutations the cell can no longer check
  11. Dysplasia → carcinoma in situ → invasive squamous cell carcinoma

Cards

Tap or drag a card. Placing a used card moves it.

Oncogenic virusesL7 p.17

  • HPV 16, 18, 31, 33

    Cancers
    Squamous carcinoma of cervix, vulva, vagina, anus; cervical adenocarcinoma
    How
    E6 → p53 degraded; E7 → RB inactivated

  • EBV

    Cancers
    Burkitt lymphoma, nasopharyngeal carcinoma, CNS lymphoma in AIDS (also Hodgkin and post-transplant lymphomas)
    How
    Drives B-cell proliferation (LMP-1); Burkitt cells carry t(8;14) MYC

  • HBV and HCV

    Cancers
    Hepatocellular carcinoma
    How
    Chronic hepatitis: cell death, regeneration, inflammation-generated free radicals; HBx protein

  • HTLV-1

    Cancers
    Adult T-cell leukemia/lymphoma
    How
    Tax protein activates T-cell growth genes; patients often have hypercalcemia

  • HHV-8 (KSHV)

    Cancers
    Kaposi sarcoma
    How
    Viral cyclin and cytokine homologues; flourishes in immunodeficiency (AIDS)

Radiation: ionizing and ultraviolet

L7 p.15, 17

Ionizing radiation

  • Nuclear accidents, atomic bombs, radiotherapy
  • Ionizes water → hydroxyl free radicals; double-strand DNA breaks and translocations
  • AML, CML; papillary thyroid carcinoma (especially after childhood exposure)
  • Leukemias appear first (years); solid tumors after decades

Ultraviolet (UVB)

  • Sunlight is the main source
  • Forms pyrimidine (thymine) dimers that distort the helix
  • Removed by nucleotide excision repair; defective in xeroderma pigmentosum
  • Basal cell carcinoma, squamous cell carcinoma, melanoma of sun-exposed skin; more common in fair skin
L7 p.15, 17

Helicobacter pylori: a bacterium that causes cancer

Ref. · Robbins

Helicobacter pylori is the one bacterium firmly linked to human cancer. It does not carry oncogenes; it causes chronic gastritis, and the cancer grows out of decades of inflammation and repair. Two different tumors result:

  • Gastric adenocarcinoma (intestinal type): chronic gastritis → mucosal atrophy → intestinal metaplasia → dysplasia → carcinoma, the same metaplasia–dysplasia sequence as Chapter 1. Strains carrying the CagA protein carry more risk.
  • Gastric MALT lymphoma (extranodal marginal zone lymphoma): H. pylori-specific T cells drive polyclonal, then monoclonal, B-cell proliferation in the gastric mucosa. Early lesions still depend on that drive, so eradicating the bacterium with antibiotics can make the lymphoma regress.
Ref. · Robbins

Knowledge check · 7.5

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 6 correct
  1. Q1HPV E6 and p53L7 p.17, 19

    A cervical carcinoma contains integrated HPV 16 DNA. The tumor cells continue to divide after their DNA is damaged by radiation, without arresting in G1 or undergoing apoptosis.

    Which viral action best explains this behavior?

  2. Q2Aflatoxin and HCCL7 p.16

    A 50-year-old farmer from a region where grain is stored in hot, humid conditions develops hepatocellular carcinoma. His tumor carries a G:C → T:A transversion in codon 249 of TP53.

    Which exposure is most likely responsible?

  3. Q3Initiation versus promotionL7 p.9

    In a skin experiment, one group receives a single dose of an initiator and then repeated doses of a promoter for 20 weeks; a second group receives the same substances in the opposite order.

    Why do tumors appear only in the first group?

  4. Q4Signature pairing: vinyl chlorideL7 p.16

    A 68-year-old man who worked for 30 years in a plant making polyvinyl chloride pipes develops a liver tumor. Microscopically it is composed of malignant cells forming irregular vascular channels filled with blood.

    Which exposure best explains this tumor?

  5. Q5UV, pyrimidine dimers and xeroderma pigmentosumL7 p.15, 17

    A 9-year-old boy has had hundreds of freckle-like macules and two skin cancers on his face and arms. His parents are first cousins and avoid taking him outdoors in daylight.

    Which repair pathway is defective?

  6. Q6H. pylori and MALT lymphomaRef. · Robbins: H. pylori and MALT lymphoma

    A 56-year-old man has a gastric mass. Biopsy shows a dense monoclonal B-cell infiltrate in the mucosa; Helicobacter pylori is present. He is treated with antibiotics and a proton pump inhibitor, and the lesion regresses completely.

    What does the response to antibiotics show about this tumor?

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