MoD 11 Neoplasia 3 Flashcards
What is cancinogenesis?
causes of cancer
Give examples of some intrinsic and extrinsic factors leading to cancer
Intrinsic- Age, sex (hormonal), heredity
Extrinsic- environment, lifestyle
What are the 5 leading behavioural risks leading to cancer?
High BMI Low fruit and veg intake Lack of physical activity Tobacco use Alcohol use
What 3 main categories do extrinsic carcingoens fall into?
Chemicals
Radiation
Infections
What three things did malignant neoplasms caused by the dye 2-napthylamine show?
Long delay (sometimes decades) between exposure and malignant neoplasm onset Risk of cancer depends on total carcinogen dosage Sometimes organ specificity for particular carcinogens e.g 2-napthylamine causes bladder carcinoma
What did the Ames test show?
That initiators are mutagens while promoters cause prolonged proliferation in target tissues
What kinds of chemicals are initiators (mutagens)?
Polycyclic aromatic hydrocarbons, aromatic amines, N-nitroso compunds, natural products
What is asbestos?
Mutagen originating from a rock which was used industrially due to its fire retardant properties
Inhalation of its needle shaped dust causes cancer as the fibres get into the lung pleura
How are N-nitroso ocmpounds formed?
Stomach converts nitrates in cured and pickled food to these
What are pro-carcinogens?
Chemicals that become carcinogenic when converted to carcinogens by cytochrome P450 enzymes in the liver
What are complete carcinogens?
Carcinogens that act as both initiators and promoters
What types of radiation are mutagenic?
alpha and beta particles
gamma rays
x rays
UV rays
What is ionising radiation?
Radiation that strips electrons from atoms
Includes x rays and nuclear radiation
What comprises nuclear radiation?
Alpha particles, beta particels, gamma rays
In what ways can radiation damage DNA?
Directly by altering bases and causing single/ double strand DNA breaks
indirectly by generating free radicals
How do infections behave carcinogenically?
Directly affect genes that control cell growth
Indirectly by causing chronic tissue injury where resulting regeneration either acts as a promoter for a pre-existing mutations or else causes new mutations from DNA replication errors
How does HPV act as a carcinogen?
Direct carcingoen that expresses E6 and E7 proteins which inhibit p53 and pRB respectively, both of which important in cell proliferation
How do hepatitis viruses act as carcinogens?
Indirectly as cause chronic liver injury and regeneration
How does HIV act as a carcinogen?
Indirectly by lowering immunity so other potentially carcinogenic infections can occur
What is the inheritance pattern of retinoblastoma?
dominant
What is the two hit hypothesis?
Two mutations must occur for a cancer to develop. so in familial cancers one mutation is present in the germ-line so one somatic mutation has to occur for cancer to develop whereas in sporadic cancers, both mutations must be somatic mutations in the same one cell
How do tumour suppressor gene mutations support the two hit hypothesis?
Tumour supressor gene will have two alleles and both these alleles must be hit and inactivated for neoplastic growth to occur
Do both alleles of a proto-oncogene need to be mutated to favour neoplastic growth?
No, just one
What is RAS?
First human oncogene to be discovered
Proto-oncogene for RAS encodes a small G protein that relays signals to push cell past cell cycle restriction point/ Mutant RAS is constantly activated so constantly signals cell past restriction point
What does RBp do?
Tumour suppressor that inhibits passage through cell cycle restriction point
What proteins can proto-oncogenes encode?
Growth factors e.g PDGF, growth factor receptors, plasma membrane signal transducers e.g RAS, intracellular kinases, transcription factors, cell cycle regulators, apoptosis regulators
Apart from tumour suppressor and proto-oncogenes, what other genes can be mutated to cause cancer?
DNA repair genes
Give an example of a cancer caused by mutation to nucleotide excision repair genes
Xeroderma Pigmentosum (XP)
Inherited, autosomal recessive, with germline mutation to one of 7 genes that affect nucleotide excision repair (NER)
These patients are very sensitive to UV damage and develop skin cancer at a young age
Causes nucleotide instability
What is Hereditary non-polyposis colon cancer (HNPCC) syndrome?
Hereditary, autosomal dominant, associated with colon carcinoma with germline mutation of a DNA mismatch repair gene causing microsatellite instability
Which genes are familial breast carcinoma associated with?
BRCA 1 BRCA 2 genes that are important in repairing double stranded DNA breaks causing chromosomal instability
What is the accelerated mutation rate in malignant neoplasms called?
Genetic instability
How does chromosomal segregation affect genetic instability?
Increases it as can be abnormal in malignant cells
What is progression?
The steady accumulation of multiple mutations
e.g progression from early adenoma> later adenoma > primary carcinoma >metastatic carcinomas
Time frame typically decades
How many mutations is it thought are needed for a fully evolved malignant neoplasm? What does a fully evolved malignant neoplasm exhibit?
10 or less
Must exhibit 6 hallmarks of cancer and one enabling feature
What are the 6 hallmarks of cancer?
- Self sufficiency in growth signals
- Resistance to growth stop signals
- No limit on number of times cell can divide
- Sustained ability to induce new blood vessels (angiogenesis)
- Resistance to apoptosis
- Ability to invade and produce metastases
(1-5 also apply to benign)
What is an enabling characteristic for a malignant neoplasm?
Genetic instability
Summarise the model of cancer pathogenesis
Somatic cells exposed to environmental carcinogens that are either initiators or promoters giving monoclonal pop of mutant cells
By chance some of clones have mutations affecting proto-oncogne or tumour supressor gene whose protein transcripts have crucial role in pathway affecting hallmark changes
During progression cells acquire further activated oncogenes inc those causing genetic instability
Eventually this leasa to a population of cells with all the hallmarks of cancer
