causes of cancer

Chronic HBV infection gives a high relative risk for

primary liver cancer, and in at least some populations acts synergistically with exposure to aflatoxins.

mustard gas

-chemical carcinogen -chemically rather reactive

virus associated with hepatocellular carcinoma

HBV (Hepatitis B virus)

what parasite is associated with cancer

Schistosomes and bladder cancer

what is the best known promoter

TPA, which comes from the seeds of the tropical plant Croton tiglium. It mimics diacyl glycerol, agonist for protein kinase C

most potent carcinogen

aflotoxin

Aristolochic acids

from Aristolochia plant species are another example, causing kidney toxicity and kidney and liver cancer, and is present in some foods and traditional medicines.

Different kinds of radiation

give more or less damage for a given amount of energy absorbed

chronic infections are associated with a variety of

human cancers

Epidemiology worked for tobacco smoke because

it is easy to distinguish people heavily exposed (smokers) from those who are only lightly exposed (non-smokers), and the effect is large (5-10X risk even in earliest studies) and distinctive—squamous lung cancers are rare in non-smoking populations

Many carcinogens have a characteristic

target tissue

Asbestos inhalation causes

-mesothelioma, arising from the mesothelial lining of the pleural cavity. -Probably, small fibres that penetrate deep into the lung cause chronic inflammation and cell turnover of these cells

Xeroderma Pigmentosum

-patients who lack excision repair -cannot remove purine dimers that form upon UV irradiation

chemical carcinogens

-polycyclic hydrocarbons (smoke, tar, coal) -β-napthylamine, an aromatic amine (dye industry, also smoke, tar) -aflatoxin (natural product) -dimethyl nitrosamine (formed from meat products) -mustard gas = sulfur mustard = Bis(2-chloroethyl) sulfide

Causes of cancer are therefore

1. agents that directly damage DNA (ionising radiation, UV light, mutagenic chemicals) 2. Agents that do not directly damage DNA (non-mutagenic chemicals or 'promoters') 3. tumor viruses and other infections 4. other causes (chronic irritation, damage to tissue or abnormally high cell turnover; 'spontaneous', e.g. errors of DNA replication and cell division)

effect of alpha particles on DNA

-Alpha articles leave dense tracks of ions and radicals so that if they pass by a DNA helix they are likely to cause double-strand breaks or multiple chemical changes, which may be difficult to repair reliably -quality factor 20

effect of gamma rays on DNA

-Gamma rays on the other hand leave scattered ions and radicals and so will usually only damage one residue on one strand of a DNA molecule, which is usually repairable -qulity factor 1

what bacteria is most notably associated with cancer

-Helicobacter pylori association with gastric adenocarcinoma and MALT lymphoma (lymphoma associated with intestinal mucosa). -Gastric adenocarcinoma develops on a background of H pylori gastritis, and H pylori can usually be found; there is a strong epidemiological link; eradicating H pylori reduces the incidence of gastric adenocarcinoma; and H pylori infection induces gastric cancer in animal models

can in vitro testing be used to identify carcinogens?

-In vitro testing is less satisfactory but would be more humane, cheaper and quicker. -Many attempts have been made to devise in vitro tests for carcinogens, using bacterial or animal cells in culture. In general they are simpler, more reproducible, quicker and probably cheaper, but they are so artificial that it is difficult to know how useful they are. In particular they have only limited ability to reveal carcinogens that require metabolic activation.

Interpreting and using the results of carcinogenicity testing is difficult

-It is surprisingly difficult to interpret the results of carcinogenicity testing, even in animals, and even more difficult to decide how to use the information. -A review found that of the 800 compounds that had been tested, 65% gave a significant increase in tumours in at least one organ! -There is only around 2/3 concordance between mice and rats, which are much closer than humans to either. -The precise difficulty here is that the compounds concerned can be carcinogens in certain circumstances, but the dose at which they are effective is completely unknown, so the risk they pose is unknown.

carcinogen signatures

-Sequencing shows that some carcinogens give a characteristic pattern of mutation, and this may help in future to identify exposure. -Many mutations found in melanoma are those expected from UV exposure. -Aristolochic acid produces a characteristic mutation pattern, and this has been found in a subset of south-east-asian liver cancers, suggesting it might have been the cause.

how are animal models used to identify carcinogens?

-Since we cannot test potential carcinogens on human beings, the most straightforward alternative is to test on animals. -The technique is to expose animals to as high a dose as possible for as long as possible and look for tumours. Whether this works well is debatable.

HTLV-1 is a T-cell tropic retrovirus

-T-cell tropic retrovirus which causes leukaemias and lymphomas in a small proportion of infected individuals. - It is endemic particularly in SW Japan, the Caribbean and parts of Africa and South America, where up to 10% of the population may be infected.

Estimating the risk of cancer due to radiation

-The "accurate data points" come from people exposed to high doses. -For example, some patients with the disease Ankylosing spondylitis were treated with X-rays in 1935-1954, on average 3 Gray. They showed a five-fold increase in leukaemia. -Most information comes from 120,000 survivors of the atomic bombs dropped on Hiroshima and Nagasaki in 1945. This is too scattered to show which of the above curves is correct. -Recent results on vast numbers of radiation workers1 show that there is cancer at low doses, so Curve C is unlikely.

how have epidemiologists shown that cancer incidence is largely determined by environment

-The variation between human populations could be due to genetic differences or to environment and behaviour. -To distinguish between these, epidemiologists have studied migrant populations such as Japanese immigrants to the west coast of the United States. They changed from having the Japanese pattern of cancer, a high incidence of stomach cancer, but a low incidence of breast cancer, to the American pattern, which is the other way round, within a generation or two: clearly not primarily genetic. Similar changes have occurred in Japan as it has become westernized. There probably are some genetic differences, but environment seems to dominate.

difficulties in Identifying causes of cancer and assessing their importance

-There are great difficulties in trying to test substances to see if they are carcinogens of significance to human populations. 1. The size of the problem is enormous - it is estimated that we are exposed to 60,000 natural or synthetic chemicals. -We need to know two things: (1) whether a substance is capable of acting as a mutagen or promoter; (2) how potent it is - how much can we afford to be exposed to. We need to know how potent mutagens are because it is unrealistic to eliminate all of them entirely from our environment. Among the substances that have been shown to be mutagenic in in vitro assays are oxygen and tomatoes. 2. A further problem is that we have some methods for testing for mutagenicity but we do not have assays for promoter action.

why do mutagenic chemicals show species-specificity?

-This is probably down to variations in metabolism, either activation or detoxification of the carcinogen, -e.g. β-naphthylamine is a potent bladder carcinogen only in species that have glucuronidase in the bladder, such as dog and man

Dose-cancer relationship for Radiation

-To estimate the effect of doses we experience such as 0.01 Gy we need to extrapolate from high doses such as 3 to 5 Gy -see slides. -We have to draw a line from the data at high doses to a low dose - but should the line be straight, a curve up or down? Experimentally, all of these patterns can be found. -Curve A and curve C can both be obtained experimentally by irradiating cells in culture with different kinds of radiation and measuring numbers of mutations. -Curve C is observed for gamma rays, where low levels of damage are repaired more efficiently than high levels. -The linear relationship A is given by energetic particles like neutrons. -Curve B is obtained when mice are irradiated and leukaemia measured—here there is a plateau at high doses, possibly because some cells that might give leukaemias are killed

Estimating the risk of exposure to agents that cause cancer

-We need to know how much cancer potential carcinogens will cause in real situations. This is best discussed in terms of risk. -Usually the data comes from the effect of a relatively large dose that causes a high incidence of cancer, because then the rate of extra cancers can be measured. -However, we are most interested in doses that cause a small increase, as these are likely to be of practical importance. -Extrapolating from the effects of high doses to the effect of a small dose is a very uncertain as shown below.

Most of the carcinogens that are known to cause cancer in humans were discovered because

-a particular set of people were exposed to them and developed particular kinds of tumour. -For example, β-napthylamine and asbestos -Unfortunately, this approach only works well where a specific group of people are exposed to a strong carcinogen, and the cancer is relatively specific to those people—dyestuffs workers were exposed to β-napthylamine and got bladder cancer, which is relatively uncommon; construction workers inhaled asbestos and got mesothelioma, which is almost unique to asbestos-exposed individuals

β - napthylamine

-activated by hydroxylation, but then rapidly made soluble and harmless by addition of glucuronic acid. -However, if the glucuronate is hydrolysed off again, the reactive form is regenerated. -an aromatic amine -a potent bladder carcinogen only in species that have glucuronidase in the bladder, such as dog and man -acts primarily on the bladder in man, 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.

Two examples of potent carcinogens explode a myth about carcinogens - that they are man-made.

-aflatoxin B1 -aristolochic acids

Ultraviolet light in causing cancer

-agent that directly damages DNA -Ultraviolet light's principal effect is to photoactivate pyrimidine residues in DNA so that they form dimers where two thymines or a thymine and a cytosine occur sequentially in the DNA (diagram), and base pairing can be disrupted. (Prime target for DNA excision repair -hence UV sensitivity of Xeroderma Pigmentosum patients who lack excision repair).

Many of the 'causes of cancer' that we recognise are

-agents that damage DNA directly, such as chemicals that react with it and alter its structure, and nuclear radiation, which breaks strands of DNA. -However, there are other factors that do not directly damage DNA, but encourage DNA damage, or encourage the growth of mutated cells as tumours

reactivity of most potent chemical carcinogens

-are more or less inert in the form we are exposed, but get activated by metabolism. -Highly reactive chemicals if introduced into the body would react with something else before they could reach the DNA. -Ironically, the enzymes that activate carcinogens are generally part of systems that have evolved to render harmless or 'detoxify' lipid-soluble molecules that the body needs to get rid of, by making more soluble derivatives of them, that can be excreted

mechanisms for inducing tumor growth via chronic infection

-chronic cell death and turnover, -perhaps chronic inflammation may contribute. -Some viruses bring oncogenic genes/proteins into the cell, notably proteins that inactivate p53 and/or Rb, e.g. the E6 and E7 proteins of the HPVs

Kaposi's Sarcoma seems to develop in

-in immune-suppressed or elderly people infected with HHV8. -Although known for some time, it came to prominence as a common problem in AIDS/HIV patients.

Epstein-Barr virus

-infects most adult humans, and is classically transmitted in the West in young adults by kissing, but the vast majority of those infected do not seem to develop cancers unless they are immune suppressed. -The virus infects B cells and nasopharyngeal epithelium. -For unknown reasons, particularly in ethnic Chinese populations, infection can cause nasopharyngeal carcinoma; and in malaria-endemic areas infected children may develop the aggressive B-cell lymphoma Burkitt's Lymphoma.

radiation

-ionising radiation, occurs in various forms and comes from various sources. -It includes X-rays, which can come from medical sources and electrical equipment; and the products of radioactive decay and cosmic rays, which include γ rays, neutrons, β particles (free electrons), and α particles, (charged helium nuclei). -Radiation damages DNA by producing free radicals and ions as it passes through tissue; these then react with DNA and alter the structure of bases or cause strand breaks.

NMU (nitroso-methyl-urea) when fed to pubescent female rats caused

-mainly mammary tumours, but when it was fed to pregnant rats, the principal effect was that their offspring develop tumours after birth, predominantly in cells of the nervous system -suggests that rapid cell proliferation makes the tissue susceptible

Non-mutagenic agents that increase the effect of mutagens are called

-promote the development of tumours without damaging DNA. -Classical experiments painting substances on mouse skin distinguished 'initiators' (mutagens) from 'promoters'. -Just as the most potent mutagenic carcinogen known, aflatoxin, is a natural product, so are the most potent promoters. -The best known promoter is TPA, which comes from the seeds of the tropical plant Croton tiglium. It mimics diacyl glycerol, agonist for protein kinase C

aflatoxin B1

-said to be the most powerful carcinogen known to man, at least when assayed in rats, and it is a natural contaminant of peanuts, produced by the fungus Aspergillus flavus, which sometimes grows on peanuts in warm humid conditions.

confirmed environmental causes of cancer

-smoking tobacco, -some important tumour viruses, -some occupational exposures such as asbestos

quality factor

-specific to the type of radiation (gamma rays less harmful than alpha particles) -measure of exposure of radiontion in Gray is multiplied by this factor to give an approximate measure of biological damage or dose equivalent measured in Sieverts (Sv). -Quality factor is 1 for Xrays and gamma rays and ranges up to 20 for alpha particles

HPV

-the wart viruses, and cause a range of warts and flat lesions, -but among the sexually transmitted HPVs are a few where infection creates a high risk of cervical cancer, notably but not exclusively HPV types 16 and 18. -A vaccine is available for the major high-risk types. Some other squamous cancers can also be associated with HPVs.

HBV and aflatoxin exposure were measured by

-urinary metabolites -both strongly associated with liver cancer, with a combined risk factor of around 50X

mutagenic chemicals in causing cancer

Among the chemicals that we know are potent carcinogens, most are mutagenic (rather than promoters)

virus associated with nasopharyngeal carcinoma and Burkitt's lymphoma

EBV (Epstein-Barr virus)

what are 'environmental' cancer causing agents?

Environment could be environmental agents that cause mutations in DNA, but could also include lifestyle factors (e.g. reproductive behaviour, nutrition) that affect the rate of 'spontaneous', DNA damage such as errors in replication that go uncorrected.

virus associated with Kaposi's sarcoma

HHV8 (human Herpesvirus 8)

only viral cancers of major concern in the west

HPV and cervical cancer

virus associated with T-cell leukaemia and lymphoma

HTLV1 (human T-cell lymph tropic virus type 1)

virus associated with cervical cancer

High-risk HPVs (human papillomaviruses)

are hormones promoters? initiators? what about cigarettes smoke?

Hormones can be regarded as promoters, and cigarette smoke may be both a promoter and an initiator

what is the only agent for which the risk of exposure in causing cancer is known

The only agent for which the risk of exposure has been estimated is ionising radiation, because for chemical carcinogens we generally don't know how many tumours a given dose will give.

Both aflatoxins and Aristolochic acid require

metabolic activation

what gives carcinogens tissue specificity

not fully understood, but these examples suggest that one factor is tissue-specific metabolism, while the female rat suggests that rapid cell proliferation makes the tissue susceptible

exposure to radiation is measured as

the amount of energy absorbed per unit of tissue: the unit used is the Gray (Gy) (the Gray supersedes the rad: 1 Gray = 100 rads), which is joules absorbed per Kg tissue