Session 11 Flashcards
The cause of cancer is multifactorial. A combination of intrinsic host factors and extrinsic factors account for cancer risk. Give some examples of intrinsic host factors
Heredity
Age
Gender (hormonal influence)
Much of the increased cancer incidence over the last century is due to prolonged life-span.
The cause of cancer is multifactorial. A combination of intrinsic host factors and extrinsic factors account for cancer risk. Give some examples of extrinsic factors
Related to the environment and behaviour (lifestyle) account for cancer risk.
About 30% of cancer deaths are due to the five leading behavioural and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. Tobacco smoke alone is associated with approximately a quarter of all cancer deaths.
Extrinsic factors account approximately85% of a population’s cancer risk.
Extrinsic carcinogens fall into 3 main categories: chemicals, radiation and infections
What important lessons about carcinogenesis do chemicals teach?
2-napthylamine is an Industrial carcinogenused in the dye manufacturing industry. Malignant neoplasms caused by 2-napthylamine showed that:
(1) there is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset (it is a long, drawn out process)
(2) the risk of cancer depends on total carcinogen dosage
(3) there is sometimes organ specificity for particular carcinogens, e.g. 2-napthylamine causes bladder carcinoma.
The dependence on dosage is why industrial carcinogens (e.g. asbestos, coal tars and vinyl chloride) and tobacco smoke (associated with bronchial carcinoma), are especially important causes of cancer.
What do Chemical Carcinogenesis involve Initiation and Promotion?
Animal experiments show that the sequence in which carcinogens are administered is critical. Some chemical carcinogens, called initiators, must be given first followed by a second class of carcinogens called promoters.
The Ames test shows that initiators are mutagens while promoters cause prolonged proliferation in target tissues. This culminates in a monoclonal expansion of mutant cells which eventually becomes fully malignant through a further process called progression.
Describe the nature of chemical carcinogens
Mutagenic chemical carcinogens (i.e. initiators) can be classified as polycyclic aromatic hydrocarbons, aromatic amines, N-nitroso compounds, alkylating agents and diverse natural products, e.g. aflatoxin, asbestos
Some of these chemicals are pro-carcinogens and are only converted to carcinogens by the cytochrome P450 enzymes in the liver.Carcinogens that act as both initiators and promoters are called complete carcinogens.
Discuss certain types of radiation damage
Radiation is any type of energy travelling through space and some forms are mutagenic.
Ultraviolet (UV) light does not penetrate deeper than skin.
Ionising radiation strips electrons from atoms and includes X-rays and nuclear radiation arising from radioactive elements.
Nuclear radiation comprises alpha particles, beta particles and gamma rays
Radiation can damage DNA directly and also indirectly by generating free radicals.
The most important type of radiation is UV because we are exposed daily from sunlight leading to increased skin cancer risk.
For most people the main exposure to ionising radiation is natural background radiation from radon, which seeps from the earth’s crust. Ionising radiation damages DNA bases and causes single and double strand DNA breaks.
How are some infections carcinogenic?
Some infections directly affect genes that control cell growth. Others do so indirectly by causing chronic tissue injury, where the resulting regeneration acts either as a promoter for any pre-existing mutations or else causes new mutations from DNA replication errors.
Human Papilloma virus (HPV), which is strongly linked to cervical carcinoma, is a direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB (retinoblastoma) protein function respectively, both of which are important in cell proliferation.
In contrast Hepatitis B and C viruses are indirect carcinogens that causechronic liver cell injury and regeneration. Bacteria and parasites can also indirectly lead to neoplasms.
Helicobacter pylori causes chronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio- and bladder carcinomas respectively.
Human Immunodeficiency virus (HIV) acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur.
How can inherited predisposition to neoplasia occur through germline mutations?
In the 1800s a type of malignant retinal tumour called retinoblastoma was reported in multiple members of the same family. A dominant pattern of inheritance was seen.
As well as running in families, this tumour occurred sporadically. In the 1970s Knudson postulated a two hit hypothesis to explain the differences between tumours occurring in families and those occurring in the general population.
For familial cancers, the first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation. In the case of retinoblastoma this was in one of the 10 million+ retinal cells already carrying the first hit.
In contrast, sporadic retinoblastoma has no germline mutation and so requires both hits to be somatic mutations and to occur in the same cell. In 1986 the actual gene, RB, was identified.
Several other malignant neoplasms are now recognised that have both familial and sporadic counterparts and that follow the same two hit genetic basis as retinoblastoma.
How do initiation and promotion lead to neoplasms when they affect proto-oncogenes and tumour suppressor genes?
Genes that inhibit neoplastic growth are known as tumour suppressor genes and are the same genes that Knudson described. Because they act like brakes on tumour growth, both alleles must be inactivated, which explains why they need two hits, i.e. one for each allele.
In contrast, genes that enhance neoplastic growth are known oncogenes and are abnormally activated versions of normal genes called proto-oncogenes. Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.
Describe how proto-oncogenes and tumour suppressor genes play opposing roles in cell signalling pathways?
The first human oncogene to be discovered was RAS and this is mutated in approximately a third of all malignant neoplasms.
The RAS proto-oncogene encodes small G protein that relays signals into the cell that eventually pushes the cell past the cell cycle restriction point.
Mutant RAS encodes a protein that is always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point.
In contrast, the RB gene restrains cell proliferation by inhibiting passage through the restriction point. Inactivation of both RB alleles therefore allows unrestrained passage through the restriction point.
This illustrates how one component of growth control, the restriction point, can be deregulated either by an activated oncogene or inactivated TS gene.
This key idea can be extended to other master regulators of growth and the respective proto-oncogenes and TS genes that affect them.
Proto-oncogenes can encode growth factors (e.g. PDGF), growth factor receptors (e.g. HER2), plasma membrane signal transducers (e.g. RAS), intracellular kinases (e.g. BRAF), transcription factors (e.g. MYC), cell cycle regulators (e.g. CYCLIN D1) or apoptosis regulators (e.g. BCL2).
TS genes encode proteins in the same pathways but with anti-growth effects (e.g. TP53).
Explain about mutations in DNA repair genes
Some inherited cancer syndromes have germline mutations that cause malignant neoplasms indirectly by affecting DNA repair.
XP, which is autosomal recessive, is due to mutations in one of 7 genes that affect DNA nucleotide excision repair (NER). These patients are very sensitive to UV damage and develop skin cancer at a young age.
Hereditary non-polyposis colon cancer (HNPCC) syndrome, which is autosomal dominant,is associated with colon carcinoma and the germline mutation affects one of several DNA mismatch repair genes.
Familial breast carcinoma is associated with either BRCA1 or BRCA2 genes that are important for repairing double strand DNA breaks. These various mutations can also be found in sporadic malignant neoplasms.
Chromosome segregation during mitosis can also be abnormal in malignant cells.
Together, these alterations account for the accelerated mutation rate found in malignant neoplasms that is known as genetic instability.
Explain how multiple mutations are required to make a malignant neoplasm
Most malignant tumours require alterations affecting a combination of multiple TS genes and proto-oncogenes. This is illustrated by colon carcinoma, which usually starts as a colonic adenoma, from which arises a carcinoma. This is known as the adenoma-carcinoma sequence.
Analysis of early adenomas, later adenomas, primary carcinomas and metastatic carcinomas showed that mutations accumulate during this sequence and the time frame is typically decades.
This illustrates a general principle of step-wise accumulation of mutations in malignant neoplasms.
This steady accumulation of multiple mutations is called cancer progression.
Therefore cancer evolves by initiation and promotion as described above and finally by progression.
The exact number of mutation needed for a fully evolved malignant neoplasm is unknown but is thought to be approximately ten or less.
What are the 6 hallmarks of cancer?
It is now believed that a fully evolved malignant neoplasm exhibits six hallmarks of cancer plus one enabling feature:
(1) self-sufficiency in growth signals
(2) resistance to growth stop signals
(3) no limit on the number of times a cell can divide (cell immortalisation)
(4) sustained ability to induce new blood vessels (angiogenesis)
(5) resistance to apoptosis
(6) the ability to invade and produce metastases.
Hallmarks 1 to 5 are primarily about increased growth and are therefore likely to be relevant to both benign and malignant neoplasms.
Hallmark 6 is exclusively relevant to malignant neoplasms.
Genetic instability is regarded as an enabling characteristic.
Summarise cancer pathogenesis
First, somatic cells are exposed to environmental carcinogens(chemicals, radiation, infections) that are either initiators (that cause mutation) or promoters(that cause sustained proliferation) culminating in a monoclonal population of mutant cells . In about 5% of cancers are inherited mutations in the germline can be present. By chance, some of these clones harbour mutations affecting a proto-oncogene or a tumour suppressor gene, whose protein transcripts play crucial roles in cell signalling pathways affecting “hallmark” changes. During progression the cells acquire further activated oncogenes or inactivated tumour suppressor genes, including ones that cause genetic instability. This is eventually results, after many years or even decades, in a population of cells that have acquired a set of mutations that produce all of the “hallmarks of cancer”.
