MoD session 10: carcinogenesis Flashcards
Describe intrinsic and extrinsic causes of neoplasia
Intrinsic: hereditary, age, gender (especially women’s hormonal influences)
Extrinsic: environmental and behaviour. About 30% of all cancers are due to: high BMI, low fruit an veg intake, physical inactivity, tobacco and excess alcohol use
What were the lessons learned from the industrial chemical that caused factory workers to develop bladder cancer?
- There can be a long delay between carcinogen exposure and malignant neoplasm onset
- Risk of cancer depends on carcinogen dosage
- Some carcinogens show organ specificity
What types of substance can be mutagenic carcinogens (initiators)?
Polycyclic aromatic hydrocarbons Aromatic amines N-nitroso compounds Alkylating agents Natural products e.g. aflatoxin, asbestos
What is a pro-carcinogen?
A chemical that is only converted to a carcinogen by cytochrome P450 enzymes in the liver
This is why need liver in Ames test to test if mutagen is a carcinogen
What is a complete carcinogen?
A chemical carcinogen that acts as both an initiator and a promoter
Give an example of a complete carcinogen
Cigarette smoking: the chemicals it contains plus the hot smoke causing bronchial metaplasia both contribute to carcinogenesis
Why do younger age groups tend to develop germ line cancers?
The mutations bypass the step in carcinogenesis that takes years
Describe the sequence in which carcinogens are administered
Initiators must be given first, followed by a second class of carcinogens called promoters Ames test shows initiators are mutagens whilst promoters are not (they cause prolong proliferation in targets) Monoclonal expansion of mutation cells then become fully malignant by progression
Which types of radiation can cause cancer?
UV light: exposed daily so increased risk of skin cancer, especially from UVB. Doesn’t penetrate deeper than skin
Ionising radiation: strips electrons from atoms as very high energy. Includes X-rays, nuclear radiation and natural background radiation from radon seeping from the earth’s crust (dangerous as broken down to polonium then inhaled, so people living in areas with high activity need well-ventilated homes)
How does radiation damage cells?
Directly by altering bases or causing single or double stranded breaks
Indirectly by generation of free radicals
How can infection cause cancer?
Directly: affecting genes that control cell growth
Indirectly: causing chronic tissue injury where resulting regeneration acts as a promoter for pre-existing mutation or causes new mutations from errors of DNA replication
Role of Human Papilloma Virus and cervical cancer
A direct carcinogen
It expresses proteins E6 (inhibits p53: tumour suppressor gene, so inhibited activates telomerase) and E7 (inhibits pRB so cells speed through G1S checkpoint), thus causing abnormal cell proliferation
Mutations in epithelial cells occur
Role of hepatitis B and C viruses in liver cancer
Indirect carcinogens
Cause chronic liver cell injury and regeneration: repeatedly damage hepatocytes, hepatocytes respond by cell division and so increase chances of mutations occur
Role of HIV in cancer
Indirect carcinogen
Lowers immunity and allows for other potentially-carcinogenic infections to occur
Role of helicobacter pylori in stomach cancer
Indirect
Chronic gastric inflammation increases risk of gastric carcinomas
Role of parasitic flukes in cancer
Indirect
Chronic inflammation in bile ducts and bladder mucosa increases risk of cholangio- and bladder carcinomas
Describe the observations that were made when studying retinoblastoma
Can be sporadic or dominantly-inherited. Two-hit hypothesis explains the differences:
- Familial: first hit in gremline affecting all cells, second hit a somatic mutation in one of the retinal cells (RBI gene). Usually bilateral
- Sporadic: no gremlin mutation so both hits are somatic and occur in the same cell, so usually unilateral
RB gene normally restrains cell proliferation by inhibiting passage past the restriction point in the cell cycle, so inactivation of both RB alleles allows unrestrained passage and therefore proliferation.
What are tumour suppressor genes?
Genes which inhibit neoplastic growth by acting like brakes on tumour development. Need 2 hits to be inactivated: 1 for each allele
What are oncogenes?
Genes that enhance neoplastic growth. They abnormally-activated versions of normal genes (proto-oncogenes). Only need 1 allele of each porto-oncogene activated to favour neoplastic growth
RAS
The first human oncogene discovered, which is mutated in about 1/3 of all cancers. The RAS porto-oncogene encodes a small G protein which relays signals into the cell and pushes cells past the cell cycle restriction point.
Mutant RAS encodes a protein that is always active, producing a constant signal to pass through the restriction point (phosphorylates)
What can proto-oncogenes and tumour suppressor genes encode? Give an example for each
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
TSGs encode proteins in the same pathways but with antigrowth effects, e.g. TP53
Xeroderma pigmentosum
Autosomal recessive condition due to mutation in genes for nucleotide excision repair
Patients very sensitive to UV damage and develop skin cancer at a young age
Hereditary non-polyposis colon cancer
Autosomal dominant. Germline mutations in genes for DNA mismatch repairs, causing micro satellite instability
APC gene is responsible
BRCA1 and BRCA2
Used for repair of ds DNA breaks, so mutated versions predispose to breast, ovarian, fallopian tube and peritoneal cancers
What is genetic instability ?
Accelerate mutation rate of malignant cells
What are caretaker genes?
A type of TSG that maintains genetic stability
What is cancer progression?
The steady accumulation of multiple mutations. Number of mutations needed for malignancy is thought to be fewer than 10
Describe the adenoma-carcinoma sequence
Colon cancer usually starts as a colonic adenoma, from which arises a carcinoma due to mutation accumulation over decades
What are the six hallmark cellular behaviours of cancer? Give an example for each
- Self-sufficient growth signals: e.g. amplification of HER2 in breast cancer
- Resistance to growth stop signals. E.g. removal of RB gene in retinoblastoma
- Cell immortalisation by telomerase activation-most cancers
- Angiogenesis. E.g. activation of VEGF in many cancers
- Resistance to apoptosis. E.g. translocation of BCL2 gene in lymphoma
- Invasion and production of metastases. E.g. E-cadherin mutation in gastric cancers
n.b. hallmarks 1 to 5 also apply to benign neoplasms
Epstein-Barr virus can lead to lymphoma, how?
Virus is especially prevalent in immunocompromised patients living in tropical areas. The virus counteracts the cells’ natural ability to undergo apoptosis, causing excessive proliferation of B lymphocytes so more chance of mutations in DNA that will cause a tumour
In patients with malaria for example (common in Africa), they are more likely to get infectious mononucleosis (caused by EBV) because the malaria has weakened their immune system. Inability to clear EBV infection can reactive a latent EBV infection, so there are more chances for EBV to drive B cell proliferation
How is fibre thought to reduce the incidence of colonic carcinoma?
Fibre adds “bulk” to digestive system so reduces the time that carcinogens are in contact with the bowel mucosa, so carcinogens are removed faster from the body
How does Schistosomiasis (bilharzia) lead to bladder carcinoma?
Parasitic worms induce squamous metaplasia in transitional epithelium. This epithelium is unstable as has a tendency to proliferate and cause dysplasia
How can aflatoxins lead to liver cell carcinoma?
Fungal origin substance that builds up in the liver and is directly incorporated into hepatocyte DNA therefore is a direct mutagen. Hepatitis B and C viruses help aflatoxin do this so act as promoters
What is asbestos and what health problems does it cause?
Tiny fibres of a rock in crystalline hydrated silicate form.
Fibres get trapped in airways. This can cause:
-fibrosis
-asbestosis (inflammatory lung condition)
-pleural plaques (benign conditions above more common)
-MALIGNANT MESOTHELIOMA: cancerous tumours of mesothelial cells in the pleura. Usually develops 20-40 years after even a brief exposure
How does asbestos cause malignant mesothelioma?
Chronic damage–>increased proliferation
Generates free radicals to damage tissue
Acts as a substrate for other toxic carcinogens that are inhaled (e.g. smoking makes chance of developing cancer higher as damage the mucociliary escalator so not able to clear secretions)
So, both an initiator and a promoter
What do the 3 most common skin cancers look like macroscopically and microscopically?
Malignant melanoma: abnormal mole. Melanocytes invade epithelium forming nests with brown pigmentation. Prognosis determined by whether it has invaded the basement membrane
Squamous cell carcinoma: irregular margin with raised edges, middle part ulcerated. See atypical squamous cells, intercellular bridges and pink areas of keratinisation (squamous cell)
Basal cell carcinoma: ‘rodent ulcer’ with pearly white edges. Lots of mitotic bodies showing high proliferation, basal cell layer thick (basalloid cells are big with a dark blue nucleus), may have a dermal nodule that shouldn’t be there and an empty space around it (retraction artefact). Invades and destroys local subcutaneous tissue then can erode into bone, but very rarely metastasises
What germline mutations confer an increased risk for breast cancer?
BRCA1, BRCA2, RECQL, RAD51C, p53
What does triple negative mean with respect to breast cancers?
Those associated with BRCA1 often don’t have any of the 3 receptors commonly found on cancer cells: oestrogen, progesterone and HER2 receptors
Means the won’t be given tamoxifen (affects oestrogen and progesterone receptors) or herceptin (affects HER2 receptors)
What in cigarette smoke is carcinogenic?
Benzene, polonium-210, benzopyrene and nitrosamines
How does smoking cause lung cancer?
Causes squamous metaplasia
What cancers are associated with smoking?
Lungs: especially bronchial small cell and bronchial squamous cell Oesophagus Mouth Larynx Kidney Bladder Liver Pancreas Stomach Cervix Rectum Acute myeloid leukaemia
Familial adenomatous polyposis
Presence of 100-1000 tubular adenomas throughout the colon. Usually autosomal dominant but can be sporadic. Polyps occur in teenage and 20s. 100% malignant potential. Bleeding indicates malignancy. Due to APC gene. Adenoma-carcinoma sequence
Kaposi’s sarcoma
A rare cancer which starts in endothelial cells in blood and lymph vessels, so can develop in multiple areas at the same time (so different to other cancers). Caused by human herpes virus 8 - now called Kaposi’s sarcoma-associated herpesvirus (KSHV).
Presents with lesions on skin or mucous membranes or in organs. Pathology shows spindle cells which are highly vascular and may be surrounding inflammation.
Incurable
Risk factors include immune deficiency, being of mediterranean or north african origin and being male
Name some viral causes of cancer
HPV-anal, cervical and penile
HHV8-Kaposi’s sarcoma
Describe some ways in which DNA is involved in carcinogenesis
Deficient DNA repair mechanisms
Point mutation can cause porto-oncogene activation
Frame shift mutation can cause loss of TSG expression
Name some conditions which predispose to malignancy
Familial adenomatous polyposis
Paget’s disease of bone
Schistosomiasis of bladder
