14 - Neoplasia 3 Flashcards
What is carcinogenesis and what are the factors involved in this?
Extrinsic: prolonged life span
What are the five behaviours that we undertake that can lead to cancer?
- High BMI
- Low fruit and veg intake
- Lack of physical activity
- Tobacco use
- Alcohol use
What are the categories of extrinsic carcinogens?
- Infections
- Chemicals
- Radiation
How is neoplasia multifactorial?
What is 2-Napthylamine and what lessons does it teach us?
- Chemical carcinogen used in the dye industry
1. There is a long delay between carcinogen exposure and malignant neoplasm onset
2. Risk of cancer depends on carcinogen dosage
3. Carcinogens can be organ specific, e.g this carcinogen causes bladder carcinoma
Why is it mainly roof workers that develop cancer from asbestos exposure?
Dosage of carcinogen highest in these populations, industrial scale
What does the Ames test teach us about carcinogenesis?
- Initiators are mutagens
- Promoters cause prolonged proliferation
Initiators must be followed by promoters, leading to progression as there is a monoclonal expansion of mutant cells
How can chemical carcinogens be classified?
What are pro-carcinogens?
Chemicals that are not carcinogenic until they are converted into carcinogens by cytochrome P450 enzymes in the liver e.g nitrites
What is a complete carcinogen?
Acts as both an initiator and a promoter
What is radiation?
Any type of energy travelling through space.
What are the properties of the following radiation?
- UV radiation
- Ionising radiation
- Nuclear radiation
Where do people’s radiation exposure come from?
How does radiation damage DNA in general?
How are infections carcinogenic?
Directly: affect genes that control cell growth
Indirectly: chronic tissue injury where the resulting regeneration acts either as a promoter for pre-existing mutations / initiator for new mutations
How do the following pathogens act as carcinogens?
- Human Papilloma Virus
- Hepatitis B & C Viruses
- Helicobacter pylori
- Parasitic flukes
- Human Immunodeficiency Virus
- HPV expresses E6 and E7 proteins which directly inhibit p53 and pRB protein function in cell proliferation (cervical carcinoma)
- Hepatitis B,C act indirectly and cause chronic liver cell injury and regeneration
- Helicobacter pylori causes chronic gastric inflammation (gastric carcinoma)
- Parasitic flukes act indirectly to cause inflammation in bile ducts and bladder mucosa (cholangio- and bladder carcinomas)
- HIV acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur
What is Knudson’s two hit hypothesis for carcinogenesis in sporadic and familial cases?
Explain why initiation and promotion lead to neoplasms when they affect proto-oncogenes and tumour suppressor genes
- Tumour suppressor genes are genes which inhibit neoplastic growth – both alleles must be inactivated to allow neoplastic growth (two hits)
- Oncogenes are genes which enhance neoplastic growth and are the abnormally activated versions of normal proto-oncogenes – only one allele of each proto-oncogene needs to be activated to favour neoplastic growth
How can the regulation point in the cell cycle be deregulated by a combination of mutations in TSG and POG?
⇒ The RAS proto-oncogene encodes a small G protein that relays signals into the cell & pushes the cell past the cell cycle restriction point
⇒ The mutant RAS oncogene encodes a protein that is always active, producing a constant signal to pass through the cell cycle’s restriction point
⇒ 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
What are some examples of protooncogenes and TSG?
POG:
- GF receptors (HER2)
- GF (PDGF)
- Intracellular kinases (BRAF)
- Apoptosis regulators
TSG:
- Anti-growth effect (TP53)
What are caretaker genes?
- Genes that maintain genetic stability, type of tumour suppressor gene
e. g nucleotide excision repair, double strand repair
For the following conditions, describe the type of repair system which is mutated and its overal effect on the genome:
- Xeroderma pigmentosum
- Hereditary non-polyposis colon cancer syndrome
- Familial breast carcinoma
- Xeroderma pigmentosum: nucleotide excision repair → nucleotide instability
- HNPCC syndrome: mismatch repair → microsatellite instability
- Familial breast carcinoma: double strand break (BRCA1&2) → chromosomal instability
What is genetic instability?
Genetic instability are a series of alterations in chromosome segregation during mitosis which account for the accelerated mutation rate found in malignant neoplasms
This steady accumulation of multiple mutations is called cancer progression.
In terms of a colon carcinoma, illustrate how multiple mutations are required to make a neoplasm
