Neoplasia 3 Flashcards
(32 cards)
What is carcinogenesis?
The causes of cancer
What factors make you more suseptible to cancer?
A combination of intrinsic host factors such as heredity (mediliam trait or subtle genetic risk factors), age, gender (especially hormonal) and extrinsic factors related to the environment and behavior account fir cancer risk. Much of the increased cancer incidence over the last century is due to prolonged life span.
What are 30% of cancer deaths due to?
About 30% of cancer deaths are due to the five leading behavioral and dietary risks:
- High BMI
- Low fruit and vegtable intake
- Lack of physical activity
- Tobacco use (associated with 25% of cancer deaths)
- Alcohol (carcinogenic - oropharangeal cancer)
Where does most of the evidence for cancer risk come from?
Epidemiological and animal studies
What percentage of a populations cancer risk comes from extrinsic factors?
Extrinsic factors account for approximately 85% of a population’s cancer risk. Extrinsic carcinogens fall into 3 main categories:
- Chemicals
- Radiation
- Infection
2 Napthylamine is an industrial carcinogen used in the dye manafacturing industry. What does the malignant neoplasms caused by this chemical teach us?
- There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
- The risk of cancer depends on total carcinogen dose
- There is cometimes organ spcificy for particular carcinogens e.g. 2-napthylamine causes bladder carcinoma.
The dependance on dosage is why industrial carcinogens e.g. asbestos, coal tars, vinyl chloride have an effect primarily on the relevent workers and tobacco smoke’s effect is largely limited to smokers.
What seqeuence must carcinogens be administered in?
Some chemical carcinogens called initiators must be given first followed by a second class of carcinogens called promoters. This was shown by experimenrs on animals.
What is the Ames test?
The ames test shows that initiators are mutagens while promoters cause prolonged proliferation in target tissue.
This culminates in a monoclonal expantion of mutant cells. Mutant monoclonal antibodies eventually become fully malignant through a furthr process called progression.
What is 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
Why need to use rat liver?
Because some of these chemicals are pro-carcinogens and are only converted to carcinogens by cytochrome P450 enzymes in the liver.
What are complete carcinogens?
Carcinogens that act as both initiators and promoters.
What are some different types of radiation?
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 comprmises alpha particles, beta particles and gamma rays.
How does radiation damage DNA?
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 stand DNA breaks.
How can infection cause cancer?
Thet act directly or indirectly.
Some infections directly affect genes that control cell growth. Others affect growth indirectly by causing chronic tissue injury where the resulting regeneration acts either as a promotor for any pre-existing mutations or else causes new mutations from DNA replication errors.
How does HPV cause cancer?
Human papilloma virus which is storgly linked to cervical carcinoma is a direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function retrospecctively, both of which are important in cell proliferation.
What things pathogens can indirectly lead to cancer?
Hep B and Hep C are indirect carcinogens that cause chronic liver cell injury and regeneration. Bacteria and parasites can also indirectly lead to neoplasms. Helicobacter pylori causes cronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio- and bladder carcinoma respoectively.
How does HIV cause cancer?
HIV acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur
How do germ line mutations cause cancer?
Inherited predisposition to neoplasia can occur through germ line mutations.
In the 1800s a type of malignant retinal tumour called retinoblastoma was reported in multiple members of the same family. A dominent pattern of inherience was seen. As well as running in families, this tumour occured sporadically.
What is the difference between inherited and sporadic retinoblastoma?
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
The timing of the two hits differs between familial and sporadic retinal blastoma.
How can initiation and promotion lead to neoplasms?
Initiations and promotions lead to neoplasms when they affect proto-oncogenes and tumour suppressor gene.
Tumour suppressor geen = inhibit neoplasm growth (same genes as Knudson described)
They act like breaks on tumour growth, both alleles much be inactivatd which explains why they need two hits, ie one for each allele.
Oncogenes = genes that enhance neoplastic growth.
Proto-oncogenes = Mutated oncogene (abnormally activated).
Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.
What is the RAS gene?
The first oncogene to be discovered was RAS and this is mutated in approximately a third of all malignant neoplasms.
The RAS proto-oncogene encodes a 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.
What is the RB gene?
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.
Give examples of proto-oncogenes.
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),
- Apoptosis regulators (e.g. BCL2).
Tumour suppressor genes encode proteins in the same pathways but with anti-growth effects (e.g. TP53).
How do mutations in DNA repair genes lead to malignant neoplasms?
Some inherited cancer syndromes have germline mutations that cause malignant neoplasms indirectly by affecting DNA. There are three ways it can be damaged:
- Mismatch repair
- Nucleotide excision repair
- Double strand breaks
