Causes of cancer Flashcards
Cancer incidence and the environment
Epidemiologists have studied migrant populations such as Japanese immigrants to the west coast of the USA. They changed from having the Japanese pattern of cancer (high incidence of stomach cancer, but low incidence of breast cancer) to the American pattern (the other way around) within a generation or two, hence it’s clearly not primarily genetic. SImilar changes are observed as Japan has become westernised. There are probably some genetic differences, but environment seems to dominate
Environmental factors that drive cancer: infectious agents
a) Bacteria and parasites
b) Viruses - HPV
c) Viruses - HBV
a) Schistosomes are associated with bladder cancer. Helicobacter pylori is associated with gastric adenocarcinoma and MALT lymphoma. Gastric adenocarcinoma develops on a background of H pylori gastritis (there is a strong epidemiological link) and eradicating H pylori reduces the incidence of gastric adenocarcinoma and H pylori infection induces gastric cancer in animal models
b) HPVs are wart viruses, and cause a range of warts and flat lesions, but among the sexually transmitted HPVs, there are a few where chronic infection creates a high risk of cervical cancer (HPV 16 and 18). There is now a vaccine for the major high-risk types.
c) Chronic HBV infection gives a high relative risk for primary liver cancer, and actis synergistically with exposure to aflatoxins
Environmental factors that drive cancer: infectious agents
a) Viruses - HHV8
b) Viruses - HTLV-1
c) Viruses - Epstein-Barr
a) Immune-suppressed or elderly people infected with HHV8 seem to develop Kaposi’s sarcoma
b) HTLV-1 is a T cell tropic retrovirus, which causes leukaemias and lymphomas in a small proportion of infected individuals.
c) Infects mostly adult humans and is classically tranmitted in the West by young adults kissing, but the vast majority of those infected don’t develop cancers unless they are immune suppressed (eg in malaria-endemic areas and people are largely infected with EBV from a young age). The virus infects B cells and nasopharyngeal epithelium. For unknown reasons, particularly in ethnic Chinese populations, infection can cause nasopharyngeal carcinoma. In malaria-endemic areas infected children may develop the aggressive B-cel lymphoma, Burkitt Lymphoma. However, not all mechanisms have been fully elucidated and are likely indirect through other induced processes like chronic inflammation. (see image)
Environmental factors that drive cancer
a) natural compounds
b) ultraviolet light
a) Aflatoxin B1 is said to be the most powerful carcinogen known. It is a natural contaminant of peanuts, produced by the fungus Aspergillus flavus which sometimes grows on peanuts in warm humid conditions. Like some other carcinogens, it is activated by metabolism (aflatoxin B1 is oxidised to aflatoxin epoxide which is the active carcinogen)
b) UV’s principal effect is to phototactivate pyrimidine residues in DNA so that they form dimers where two thymines or a thymine and a cytosine occur sequentially in the DNA and base pairing can be disrupted (prime target for DNA excision repair, hence UV sensitivity of Xeroderman Pigmentosum patients who lack excision repair)
Environmental factors that drive cancer
a) mutagenic chemicals
b) asbestos
a) Most chemicals that we know to be potent carcinogens are mutagenic (they damage DNA). Most potent chemical carcinogens have to be metabolically activated while some chemical carcinogens, such as alkylating agents, are already chemically reactive. Enzymes that activate carcinogens are generally part of the xenobiotic metabolism systems that have evolved to detoxify lipid-soluble molecules that the body needs to get rid of. This occurs by the generation of more soluble derivatives that can be excreted (eg Benzopyrene in cigarette smoke). The metabolising enzyme has to be expressed in the tissue for the carcinogen to become active. So, many carcinogens have a characteristic target tissue. eg β-napthylamine - it is activated by hydroxylation, but then rapidly made soluble and harmless by addition of glucuronic acid. However, if the glucuronate is hydrolysed again, the reactive form is regenerated. β-napthylamine acts primarily in the bladder, where the glucuronic acid conjugate is removed by glucuronidase. This bladder specificity made it possible to identify it as a carcinogen of importance in humans
b) Asbestos inhalation causes mesothelioma, arising from the mesothelial lining of the pleural cavity. Small fibres that penetrate deep into the lung cause chronic inflammation and rapid turnover of these cells. It seems more likely that asbestos is a promoter that drives chronic inflammation where the production of ROS and growth factors drive cancer development essentially by encouraging DNA damage, and/or the growth of mutated cells as tumours. These are called tumour promoters in contrast to mutagens which are tumour initiators
Environmental factors that drive cancer indirectly - promoters versus initiators
Promoters are substances that promote the development of tumours without damaging DNA. Classical experiments painting substances on mouse skin distinguised initiators (mutagens) from promoters. If an initiator was applied, it would give the occasional tumour, but far more tumours would appeat if a promoter was repeatedly applied following the application of the initiator. Promoters only work after initiators have been applied. The most potent promoters are natural products, the best known is TPA, which comes from the seeds of Croton tiglium and mimics diacyl glycerol, an agonist for protein kinase C
Environmental factors that drive cancer - exposure to cancer at specific stages of development
When the mutagen NMU was fed to female rats of different ages, the rats were most susceptible to developing mammary tumours when pubescent, when the mammary epithelium is proliferating
Similarly, breast cancer in human survivors of Japanese atomic bombs occurred mainly in those who were teenagers when exposed.
Additionally, the risk of breast cancer is a function of lifestyle, related to cell proliferation. The risk is roughly proportional to the interval between menarche and the first pregnancy (for childbearing women) (see image)
a) role of carcinogen signatures
b) Overview of identifying cancer-causing agents and assessing their importance
a) sequencing shows that some carcinogens give a characteristic pattern of mutation, and this may help in future to identify exposure. eg, many mutations found in melanoma are those expected from UV exposure, predominantly C>T. In contrast, NMU produces a characteristic mutation pattern, predominantly causing AT:GC transitions
b) Very difficult to test substances to see if they are carcinogens of significance, the scale of the problem is huge, we are exposed to 60,000 natural or synthetic chemicals. Need to know: i) whether a substance is capable of acting as a mutagen or promoter ii) how potent it is (need to know which ones we really need to eliminate, as even things like oxygen are mutagenic!)
Identifying cancer-causing agents - methods
a) Epidemiology
b) In vivo
c) In vitro
a) Can suggest a cause of cancer, but has limitations. Only really works well where a specific group of people is exposed to a strong carcinogen, and the cancer is relatively specific to those people - eg. dyestuffs workers were exposed to β-napthylamine and got bladder cancer, construction workers inhaled asbestos and got mesothelioma. Epidemiology worked for tobacco smoke as it is easy to distinguish people heavily exposed, and those lightly exposed, and the effect is large (5-10x risk) and distinctive (squamous lung cancers are rare in non-smoking populations).
b) Expose animals to as high dose as possible, for as long as possible and look for tumours. Effectiveness of this is debateable, as there is low concordance between animals and humans, also reviews suggest compounds found to increase tumours would only be responsible for a tiny fraction of cases. The difficulty is that many compounds can be carcinogens sometimes, but the effective dose and the risk they pose is unknown.
c) Less satisfactory, but more humane, cheaper, quicker and more statistically robust. Use bacterial or animal cells in culture. Simpler and more reproducible, but are artificial so might be unreliable. They only have limited ability to reveal carcinogens that require metabolic activation, though a rat liver can be added to try and provide this.
