Session 10 - Neoplasia 3 Flashcards
Give some examples of intrinsic host factors which influence neoplasms formation
- Age
- Gender
- Hereditary factors
Generally speaking, why does the risk of cancer increase with age?
-The longer the lifespan the greater the chance of mutation occuring
What are the two groups of extrinsic factors which influence neoplasms formation?
- Environment
- Behaviour
What are the 5 leading dietary and behavioural risks?
- High body mass index
- Low fruit and vegetable intake
- Lack of physical activity (independant from high BMI)
- Tobacco use
- Alcohol use
Do intrinsic factors or extrinsic factors have the most influence of neoplasm formation?
-Extrinsic factors
What are the three categories of extrinsic carcinogens?
- Chemicals
- Radiation
- Infection
What 3 characteristics did 2-napthylamine show about carcinogenesis?
1) There is a long delay between carcinogen exposure and malignant neoplasm onset (sometimes decades)
2) The risk of cancer depends on total carcinogen dosage
3) There is sometimes organ specificity for particular carcinogens
Why does 2-napthylamine effect the bladder?
-The dye is excreted via urine and thus becomes concentrated in the bladder
Name some industrial causes of neoplasms
- Asbestos
- Coal tars/dust
- Vinyl chloride
What is pneumoconiosis?
-Any fibrotic lung disease caused by an occupation
What is asbestosis?
-Pneumoconiosis (fibrous lung disease) caused by the inhalation of asbestos fibres (white and blue)
What is asbestos?
- Naturally occuring, thick fibres of silicate which is mined and predominantly used for insulation
- Two types white and blue (blue is worse as harder to eliminate from body as stiffer)
What is an initator?
-Anything which induces a mutation in a cell (a mutagen)
What is a promotor?
-Anything which causes prolonged proliferation in target tissues
What is the end result of initiation and promotion?
-Monoclonal expanded population of mutant cells
Through what process does a monoclonal mutant population become fully malignant?
-Progression
What are the classifications of chemical carcinogens?
- Polycyclic aromatic hydrocarbons
- Aromatic amines
- N-nitroso compounds
- Alkylating agents
- Diverse natrual compounds eg aflatoxin and asbestos
What are pro-carcinogens?
-Chemicals which are only comverted to carcinogens by cytochrome P450 enzymes in the liver
What is a complete carcinogen?
-Carcinogen that acts as both an initiator and a promotor
Provide an example of a complete carcinogen
-Smoking
What four types of ionising radiation are significant in neoplasia?
- UV
- Xrays
- Gamma rays
- Nuclear radiation (a and b particles)
Where is UV penetration limited to?
-Cannot go deeper than the skin
In what two ways does radiation damage DNA?
- Directly damages DNA bases and causes DNA breaks
- Indirectly through free radicals
What is the main exposure to ionising radiation in most people?
-Natural background radiation from radon which seeps from the earths crust
Is UV ionising radiation?
-No, it is electromagnetic radiation
In what two ways can infections influence neoplasia formation?
- Directly by affecting genes that control cell cycle
- Indirectly by causing chronic tissue injury and regeneration
How does chronic tissue injury and regeneration act as initiators and promotor?
- Chronic tissue injury causes inflammation which releases free radicals (initiator)
- Regeneration can either act as a promotor for pre-existing mutations or cause new mutations from DNA replication errors
- Increasing the rounds of replication increases the chances of a mutation occuring
What is p53?
-A tumour suppressor gene which mediates whether a cell can be repaired or whether it needs to undergo apoptosis
What is pRB?
-A TSG which prevents excessive cell growth by inhibiting the cell cycle at the restriction point. When the cell is ready to divide pRB becomes phosphorylated and inactive allowing the cell to pass the restriction point
Why is HPV a direct carcinogen? What cancer does it cause?
- Cervical cancer
- HPV expresses E6 and E7 proteins which inhibit both alleles of p53 and pRB function respectively
- Without p53 damaged cells do not undergo apoptosis
- Without pRB there is unrestrained passage of cells through the restriction point
Why is hepatitis B/C an indirect carcinogen?
-Hep b/c causes chronic hepatocyte injury and regeneration
Name a bacteria which increases the risk of gastric carcinomas and state how it does it?
- Helicobactor Pylori
- Indirectly through chronic grastic inflammation (free radicals and regeneration)
Name a parasite which increases the risk of bladder carcinoma and how it does it?
- Schistosomiasis
- Snails release worms which burrow into skin -> infect liver -> eggs get laid in bladder -> indirct carcinogen as causes chronic injury and regeneration
- Also can cause squamous cell metaplasia of the bladder which predisposes to dysplasia and neoplasm formation
Name a parasite which can increase the risk of cholangiocarcinoma and state how?
-Parasitic fluke which causes inflammation in the bile duct, indirectly increasing the risk of neoplasm formation
How does HIV act as an indirect carinogen?
-Lowers immunity, allowing other potentially carcinogenic infections to occur
What is a germline mutation and why are they significant in neoplasm formation?
- A mutation which occurs in the germline and affects all cells of the body
- Predisposes the individual to neoplasm formation as in familial cancers, the first hit has already been delivered and only one somatic mutation is needed. ie it gives the neoplasm a head start compared to sporadically occurring tumours which require two somatic hits
What is the two-hit hypothesis?
-Cells require both alleles of a gene to be mutated within the same cell in order to become affected
In what cancer was the two-hit hypothesis postulated?
-Retinoblastoma
What is a tumour supressor gene?
-Genes that inhibit neoplastic growth
How many hits do TSG require?
-2 (both alleles)
How many hits do proto-oncogenes require?
-1 (to become activated)
What is an oncogene?
-Genes which enhance neoplastic growth
What is ras?
-A proto-oncogene which encodes a small g-protein that relays signals into the cell which eventually pushes the cell past its restriction point
What happens when RAS is mutated?
-Becomes an oncogene and becomes constituently active, always producing a signal to pass through the cell cycle’s restriction point
What do proto-oncogenes often encode?
- GF and GFReceptors
- G proteins
- Intracellular kinases/transcription factors
- Apoptosis regulators
What is xeroderma pigmentosum?
-An autosomal recessive disease which effects DNA nucleotide excision repair resulting in increased sensitivity to UV damage and the development of skin cancer at a young age
What is hereditary non-polyposis colon cancer syndrome?
-Autosomal dominant condition associated with colon carcinoma as there is a germline mutation which affects a DNA mismatch repair gene
What genes is familial breast carcinoma associated with?
-Mutations in BRCA1 and BRCA2 genes which are important in repairing double strand breaks
What is genetic instability?
-Alterations within cells which account for an accelerated mutation rate eg abnormal chromosome segregation during mitosis, mutations in DNA repair mechanisms
What are caretaker genes?
-Tumour suppressor genes which maintain generic stability (ie genes which control DNA repair and chromosome segregation)
What is the adenoma-carcinoma sequence?
-The development of a colonic adenoma into a carcinoma as there is a stepwise accumulation of mutations (can take decades)
Do malignant tumours arise from one mutation?
-No, most malignant tumours require alterations in multiple TSG and proto-oncogenes
What is progression?
-The steady accumulation of multiple mutations producing a fully malignant cell population
What are the 6 hallmarks of a fully evolved malignant neoplasm?
1) Self-sufficiency in growth signals
2) Resistance to growth-stop signals
3) No limit on the number of times it can divide (immortalisation)
4) Sustained ability to induce angiogenesis
5) Resistance to apoptosis
6) The ability to invade ad produce metastases
What is an enabling characteristic? Provide an example
- A characteristic of cells which would favour neoplasm formation
- Eg genetic instability
Briefly summarise cancer pathogenesis
- Somatic cells exposed to environmental carcinogen that are either initiators or promotors -> monoclonal population of mutant cells
- By chance, some mutant cells harbour mutations affecting proto-oncogene or TSG which are involved in cell signalling pathways affecting “hallmark” changes
- During progression cells acquire further activated oncogenes of inactivated TSG including those which cause genetic instability
- Eventually leads to a new population of cells with hallmarks of cancer
How does Epstein-Barr Virus predispose to Burkitts lymphoma?
-EBV infects B cells and immortalises the B cells as they escape apoptosis and undergo increased proliferation. This indirectly pre-disposes to Burkitts lymphoma as there is more chance of gaining a mutation
Why is EBV associated with malaria?
-Malaria reduces the immunity to EBV
Why is a high fibre diet associated with low incidence of colonic cancer?
-Decreases transit time of faeces and thus decreased time colon exposed to possible toxic substances
What is mesothelioma?
-Malignancy of the mesothelial tissue of pleura/pericardium or peritineum
How are asbestos and smoking associated?
-If there is exposure to asbestos and the patient smokes there is a great increased risk of mesothelioma as asbestos absorbs toxins onto surface which sit in the lung
What is the difference between basal cell carcinoma and squamous cell carcinoma?
- Squamous cell becomes malignant later in differentiation to keratinocytes
- Basal cell is a malignancy of the basal layer
What is meant by the cause of neoplasms being multifactorial?
-A combination of intrinsic and extrinsic factors account for the formation of neoplasms
