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Aetiology of cancer

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Introduction

Predisposition

  1. Geographic/ethnic
  2. Environment/culture (exogenous carcinogenic factors)
  3. Age (many types of cancer occur at an older age)
  4. Genetic factors (e.g. retinoblastoma, familial adenomatosis coli, xeroderma pigmentosum, familial carcinoma syndrome)
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Cancer risk factors

As a rule, carcinogenesis is a process caused not by a single factor but by collaborative action of several agents.

Major carcinogenic factors:
  1. Chemical carcinogens (tobacco, asbestos, etc.)
  2. Radiation (UV, ionising)
  3. Oncogenic viruses
Other risk factors
  1. Diet
  2. Chronic infections [helicobacter pylori (stomach), hepatitis C and B viruses (liver), human papillomaviruses (HPV; cervix, oral?)]
  3. Genetic predisposition
Smoking, which is responsible for approx. 25-30% of all cancer deaths, is the preventable risk factor with a major significance. Diet is, presumably, a similarly significant risk factor. Approx. 20-40% of all cancer deaths are caused by an unbalanced diet, ie general over-nutrition, too many animal fats, and reduced intake of certain vitamins, minerals and fibres of fresh fruit and vegetables. Further risk factors include infections, genetic predisposition, alcohol abuse, occupational exposition to carcinogenic agents and environmental effects, such as solar irradiation as well as indoor exposition to radon, and passive smoking.

Chemical carcinogens

The carcinogenic effect of all chemical substances is based on their ability to react with intracellular macromolecules, especially DNA and RNA, and thus induce malfunctions in the cells. The primary targets of chemical carcinogens are the oncogenes and tumour suppressor genes. Chemical carcinogens are broadly divided into two classes: complete (initiator + promoter) and the more frequently occurring incomplete (only initiator) agents. Their action may be direct or indirect (procarcinogens – activation after metabolic conversion). The carcinogenic effect of pro-carcinogens is primarily dependent on the site of their metabolic conversion. With ubiquitary enzymes, carcinogenesis occurs at the site of entrance (e.g. benzo[a]pyrene in tobacco smoke, metabolic conversion in the lungs, bronchial carcinoma). Substances that require organ-specific enzymes for metabolic conversion, e.g. aromatic amines (conversion at first in the liver, then in the kidney, carcinogenic effect only in the urinary bladder) will induce malignancy far away from the entrance

Major chemical carcinogens in humans

Major chemical carciogens in humans

Carcinogenic substance Tumour Source


Direct-acting carcinogens
Alkylating agents:    
Cyclophosphamide Leukaemia, lymphoma Cytostatic drugs


Indirect-acting carcinogens

Polycyclic aromatic hydrocarbons:
   
Carbon black, tar, mineral oils
benzo[a]pyrene
Skin cancer
Bronchial carcinoma
Occupational exposition,
Cigarette smoke

Aromatic amines, azo dyes:
   
2-naphthylamine
benzidine (butter yellow)
2-acetylaminofluorene
Urinary bladder cancer
Liver cancer
Rubber industry
Dye industry

Nitrosamines and nitrosamides:
   
Dimethyl-,
Diethylnitrosamine
Stomach, colon, liver cancer Nitrates and nitrites in food (preservatives),
Fertilisers,
Tobacco smoke

Organic substances/solvents:
   
Vinyl chloride
benzene
Liver angiosarcoma, glioblastoma,
Leukaemia
PVC production
Chemical industry

Anorganic substances:
   
Arsenic Skin, bronchial, liver cancer Ore extraction,
Heat technology,
Construction industry, mining,
Fossil fuel refinery
Asbestos Mesothelioma, bronchial carcinoma
Chromium Bronchial carcinoma
Nickel Carcinoma of the nasal cavity

Biological substances:
   
Aflatoxin B1
Diethylstilbestrol
Liver cancer
Endometrial cancer
Aspergillus flavus (fungus)
Synthetic oestrogen

Risk behaviour: Smoking and chronic alcohol abuse

Tobacco is by far the most important risk factor for oral cancer and pre-cancer. Tobacco is smoked, chewed or sniffed worldwide. Processed tobacco contains at least 3050 compounds, many of which are toxic and/or carcinogenic. Besides aromatic hydrocarbons (e.g. benzo[a]pyrene), the tobacco-specific N-nitrosamines (TSNA) are the major carcinogens. TSNAs are causative agents for oral cancer and precancer (oral leukoplakias). Cigarette smoke is also directly associated with the development of laryngeal and bronchial carcinoma. Moreover, about one third of all cancer-related deaths worldwide are attributed to smoking. Smokers have a significantly increased risk of developing cancer, not only in the upper and lower respiratory tract but also in the following organs:
  • Stomach
  • Esophagus
  • Bladder
  • Kidney
  • Pancreas
  • Uterine cervix
  • Breast
  • Colon
A correlation between smoking and leukaemia is also discussed. Beside the increased risk of cancer, the hazard of developing diseases of the cardiovascular system and the lungs is generally recognised. The number of tobacco-related deaths in Germany is more than 100,000 per year; approx. 50% of smokers die of smoking-related diseases. The early starting age (at present 13.5 years) gives rise to particular concern.

Currently, extensive anti-smoking campaigns are run in countries of the European Union including information, counselling and therapy for smoking cessation.

In these programmes, active participation of dentists, oral and maxillo-facial surgeons is indispensable.


While most people are aware of the dangers of smoking, awareness of the consequences of alcohol abuse for the development of malignant tumours, particularly oral and pharyngeal carcinomas, is lacking. The risk for smokers who do not drink alcohol is twice to four times as high as that for non-smokers; this risk is increased 5 to 15-fold with excessive smoking and alcohol consumption (alcohol increases the permeability of the oral mucosa, thus intensifying the carcinogenic effect of smoking). Three glasses of wine a day are also supposed to increase the risk in non-smokers by factor 13.
Results of a metaanalysis of all epidemiological data available so far on the hazardous effects of mild, moderate, or heavy chronic alcohol abuse suggest an increasing rate of cancer. Every drink taken on an average daily basis (mean alcohol content approx. 10 g) increases the risk of a malignancy by 5 to 30%, with the highest risk being that of oral, pharyngeal, or oesophageal tumours (Longnecker MP & Engner S. 1996)

Radiation carcinogenesis

All types of shortvawe radiation, especially ionising radiation, can cause cancer. Principally, the effects of ionising radiation and ultraviolet rays are distinguished.

Mechanism of damaging action

The carcinogenic effect of radiation is related to its mutagenic effects, e.g. damage to DNA through the surrounding hydrogen molecules. Water molecules will be split by photons into free radicals (H+,OH-,e-) which will finally damage the DNA.

The radiation energy
  • Causes chromosome breakage, translocation and point mutations
  • Changes the protein structure
  • Inactivates enzymes
  • Destroys membranes.

Ultraviolet rays (UV)

Effect of UV rays on skin:
  • Inactivation of enzymes
  • Inhibition of cell division
  • Activation of T-suppressor cells
  • Activation of tumour suppressor gene p53
  • Induction of mutations
  • Cell death

The most common types of UV-induced skin tumours are:
  • Squamous cell carcinoma (epidermis)
  • Malignant melanoma (melanocytes)
  • Basocellular carcinoma (pluripotent stem cell?)

The melanin pigment in melanocytes provides protection against UV-radiation. Therefore, malignant melanoma occurs more rarely in people with dark skin than in fair-skinned individuals. Albinos and patients with xeroderma pigmentosum (defect of a DNA-repair gene) are at extremely high risk of developing UV-related tumours.

Ionising radiation (alpha, beta and gamma rays)

  • Alpha rays consist of protons and neutrons
  • Beta rays consist of electrons
  • Gamma rays include photons and X-rays

The carcinogenic effect of ionising radiation depends on:
  • Type of radiation (alpha rays are more dangerous than gamma)
  • Dose-incidence relation
  • DNA-repair mechanisms
  • Host factors (age, immune status, hormones, tissue characteristics)

Hierarchy of radiation sensitivity between different organs:
  1. Testis/ovaries
  2. Bone marrow (leukaemia)
  3. Thyroid gland
  4. Gastro-intestinal tract
  5. Breast
  6. Lung
  7. Salivary gland tissues
  8. Skin
  9. Bone
Note!
  • Survivors of radiation catastrophes (Hiroshima, Nagasaki, Chernobyl) disclosed a markedly increased incidence of: myeloid leukaemia (bone marrow), carcinomas of the thyroid gland, breast and lung.
  • Many physicians from the early X-ray era died of radiation-induced cancers.

Oncogenic viruses

RNA viruses

The oncogenic RNA viruses are referred to as retroviruses since they contain a reverse transcriptase (in the infected cell, a virus DNA is synthetised by the virus RNA which will be incorporated into the host genome).

Two types are distinguished:
  1. Acute transforming retroviruses
  2. Slow transforming retroviruses

Human retrovirus infections (tumours)
  • Human T-cell leukaemia/lymphoma virus (HTLV) type I and III
  • HTLV-III is identical with the causative agent of AIDS (HIV=human immunodeficiency virus). Its association with human malignancies is indirect: Kaposi’s sarcoma, malignant non-Hodgkin lymphomas, leukaemias.
Despite their high number, the role of retroviruses in human carcinogenesis has so far only been proved in the above-mentioned two tumours.

Oncogenic DNA viruses

They are the main responsibles for the development of malignant tumours in humans. Some viruses are particularly characteristic for certain diseases. The mechanisms of the neoplastic effect of DNA viruses are manifold: some of them, like HPV, include transforming sequences (oncogenes) which will be incorporated into the host genome, others have an indirect effect. HPV gene sequences can be detected in some oropharyngeal carcinomas, particularly those of the tonsils and the larynx. Their role in the development of these tumours is the subject of intensive research.

The most significant oncogenic DNA viruses in humans

Virus family Type Tumour
Papova viruses Human papillomavirus
(HPV):
 
  -Different types (1, 2, 4, and 7) Verruca vulgaris
  - Types 6, 8, 11 (low-risk) Genital warts (condyloma acuminatum)
Laryngeal papilloma
  - Types 16, 18, 31, 33 (high-risk) Cervical carcinoma
Oro-pharyngeal carcinoma
Laryngeal carcinoma
Herpes viruses Type 2 herpes-simplex virus
(HSV-2)
Cervical carcinoma
Vulvar carcinoma
  Epstein-Barr virus
(EBV)
Malignant B-cell lymphoma
(Burkitt-lymphoma)
Hodgkin lymphoma
Nasopharyngeal carcinoma
  Human herpes virus 8
(HHV-8)
Kaposi's sarcoma
Hep-a-DNA viruses Hepatitis B virus (HBV) Hepatocellular carcinoma
  Hepatitis C virus Hepatocellular carcinoma


sources

  • Kumar V, Cotran RS, Robbins SL (1993)   Grundlagen der Allgemeinen Pathologie   Gustav Fischer Verlag Stuttgart-Jena-New York 1993
  • Reichart PA (2000)   Primary prevention of mouth carcinoma and oral precancerous conditions   Mund Kiefer Gesichtschir. 2000 Nov;4(6):357-64