Session 11 - Neoplase III Flashcards
What is carcinogenisis?
Study of causes of cancer
Three intrinsic factors which lead to canc
Age
Sex
Heredity
What two factors account for cancer risk?
A combination of intrinsic host factors such as heredity, age and gender (especially hormonal),and extrinsicfactors related to the environment and behaviour
What are extrinsic causes of cancer?
Environment and lifestyle
What are the three main categories of extrinsic cancer risk?
Chemicals, radiation and infection
What are the five leading behavuioural and dietary risks
High BMI Low fruit and vegetable intake Tobbaco use Alcohol use Lack of physical activity
What are the two factors which are key to carcinogenesis?
The prescence of initators and promoters
What are initators?
Mutagens/carcinogens
What are promoters?
Substance which cause prolonged proliferation in target tissues
What does initiator and promoter action culminate in?
Amonoclonal expansion of mutant cells, and then become fully malignant via progression
Give three examples of inherited susceptibilty to the development of tumours
Retinitis (Xeroderma) Pigmentosum
Ataxia Telangiectasia
Fanconi’s Anaemia
What is retinitis (Xeroderma) pigmentosum
Increased risk of skin cancers when exposed to UV rays in sunlight
What is ataxia telangiectasia?
Defective response to radiation damage, profound susceptibility to lymphoid malignancies, usually die before age 20
What is fanconi’s anaemia?
Sensitivity to DNA cross-linking agents, marrow hypo function and multiple congenital anomalies, predisposition to cancer
Give three cancers and the genes they’re associated with
Familial Adenomatous Polyposis - APC
Breast Cancer - BRCA1/2
Li Fraumeni Syndrome - p53
What is a proto-oncogene?
A normal gene that can become an oncogene due to mutations or increased expression
What are the normal roles of proto-oncogene, and what about their DNA sequence makes them suspicous
Proto-oncogenes are present in all normal cells, and are involved in normal growth and differentiation.
They have a DNA sequence identical to viral oncogenes.
How can proto-oncogenes be modified to become oncogenes?
Mutation, amplification, translocation
What is the name of oncogene products?
Oncoproteins
What do oncoproteins from oncogenes allow the cell to do
To escape normal growth control, becoming self sufficient without external signals required to grow
Why are proto-oncogenes easily mutated to neoplasia? `
Only one allele of a proto-oncogene needs to be mutated to cause neoplasia
What is a tumour supressor gene?
A gene that encodes proteins that suppress growth and therefore cancer
What do tumour supressor genes do in cells?
Produce proteins which supress growth
What does loss or alteration of tumour supressor gene cuase to happen?
Loss of growth supression
What has to happen to tumour supressor genes in order to produce neoplasia?
Both alleles need to be mutated (2 hit hypothesis)
What is the two hit hypothesis?
Both alleles of a tumour supressor gene to be mutated in order for neoplasia to develop (suprresion rather than production)
How does the two hit hypothesis explain familial and sporadic cancers?
“First hit” can be inherited in families, increasing the incidence of the condition in related individuals. It can also occur sporadically in the population as a result of random first and second hits occuring.
Name three oncogenes
Ras
C-myc
HER-2
Discuss the role of RAS
- Normally transmits growth-promoting signals to the nucleus
- Mutant Ras is permanently activated resulting in continuous stimulation of cells
- 15-20% of all Cancers
- Colon and lung cancer
Discuss the role of C-myc
- Binds to DNA, stimulates synthesis
- Amplified (over-expressed)
o Neuroblastoma, breast cancer - Translocation 8 14
o Burkitt’s lymphoma
Discuss the role of HER-2
- Encodes for a growth factor receptor
- Amplified (over-expressed)
- ~25% of breast cancers
- Herceptin is a competitive antagonist at the HER-2 Receptor
Name two tumour supressor genes
pRb and P53
What does pRb control usually
- Passage beyond the R checkpoint at G1
- S boundary is governed by the phosphorylation of pRb.
What does def3ect in both alleles of pRb lead to?
- Cell escaping cell cycle control.
- Retinoblastoma
What proportion of tumours have P53 mutations?
Approximately 50%
What does P53 do usually?
- Gene encodes a nuclear protein, which binds to and modulates expression of genes important for cell-cycle arrest, DNA repair and Apoptosis
What are the two main stages of carcinogenesis?
Initiator
Promoter
What occurs in initiation?
- Exposure of cells to a sufficient dose of initiator
- Cell is altered, potentially capable of producing tumour
- Permanent DNA damage (mutations)
- Irreversible and has ‘memory’
- Effect modified by genetic factors, DNA repair
- Initiation alone is not sufficient for tumour formation
Extremely Agonising Pain Intrigues My Intellect
Name three promoters
Hormones, local tissue responses, immune responses
What happens in promotion?
- Induce tumours in initiated cells
- Non-tumourigenic on their own
- Need exposure after initiation
- Cellular changes are reversible
o Remove promoter and cell should be okay and return to normal - Enhance proliferations, especially in mutated cells and increase incidence of further mutations – can result in cancer
o Think of all the mutations necessary for metastasis… this makes it more likely
What does radiation do to DNA? What does its effect depend on?
A whole range of damage
- single/double strand breaks and base damage
- DNA breaks
Indirectly - free radicals
The effect depend on the quality of radiation and the dose.
What does radiation need to do to cause cancer?
Overwhelm DNA repair mechanisms, leaving DNA damage unrepaired. Mutations in oncogenes/tumour supressor genes lead to cancer
Give two types of radiation and the types of cancer they cause
- Ionising radiation
o E.g. Hiroshima (Early leukaemia/lymphoma Late Thyroid/breast) - Ultraviolet radiation
oE.g. Squamous cell carcinoma, Basal cell carcinoma, Malignant melanoma
How do chemical carcinogens interact with DNA?
Directly, others require metabolic conversion to an active form
Name three chemical carcinogens
Polycyclic aromatic hydrocarbons
- Aromatic Amines
- Alkylating Agents
What are polycyclic aromatic hydrocarbons produced from? How do they have an effect? What types of cancer do they form?
o Produced in combustion of tobacco and fossil fueld
o Hydroxylated to active form
o Lung Cancer, bladder cancer, skin cancer (scrotal skin in chimney sweeps)
What happens to aromatic amines to cause cancer? What cancer do they cause?
o Hydroxylated in liver and conjugated with glucuronic acid (Phase 2 drug metabolism, non toxic)
oDeconjugated to active form in urinary tract by urinary glucuronidase
oActive form sits in bladder Bladder cancer
What kind of workers are exposed to aromatic amines?
Rubber and dye workers
What are three infective viruses which can cause cancer?
Hepatitis B
Epstein Barr
Human papilloma
Describe hepatitis B’s action in the body, and the cancer it’s associated wtih
o Associated with hepatocellular carcinoma
o Viral DNA integrated into host cell genome
o Virus causes liver cell injury –>Chronic inflammation causing regenerative hyperplasia
o Increased cell division gives increased risk of genetic changes
What cancers is epstein barr implicated in?
pathogenesis of Burkitt’s Lymphoma, Some Hodgkin’s lymphoma, Nasopharyneal carcinoma
How does epstein barr have an effect
oInfects epithelial cells or oropharynx and B cells
oViral genes dysregulate normal proliferative and survival signals
oSets the stage for acquisition of mutations
How does human papilomma cuase cancer?
oHPV genes disrupt normal cell cycle
- releases E6 (p53 inhibition) and E7 (pRb inhibition )
oViral genes incorporated into host cell genome, driving proliferation
Name five other agents which cause cancer and the cancers they cause
- Asbestos o Malignant mesothelioma, lung cancer - Aflatoxins o Hepatocellular carcinoma (collaborates with HBV) - Schistosoma o Bladder cancer - Helicobacter o Gastric cancer and lymphoma - Hormones o Androgens and hepatocellular carcinoma
Name three conditions which predispose to tumours
Ulcerative colitis
Cirrhosis
Adenoma of colon/rectum
What cancer does ulcerative colitis cause and how?
- Colorectal carcinoma
- DNA damage and microsatellite instability
- May mask symptom of cancer
What cancer do cirrhosis cause and why?
hepatocellular carcinoma
Some of association due to chronic viral hepatitis
How does adenoma of colon/rectum cause cancer
Transforms to malignant neoplasia
What is the Ames test?
Bacteria homogenised with liver cells (p450 required) and mutagens, which allows them to grow in environments which would usually inhibit proliferation.
How can a pro-carcinogen cause cancer?
Converted to carcinogen by P450
What is a complete carcinoge?
Initiator + promoter
Where does radiation come from?
UV B
Ionising - radon + medical tests
Three types if repair
Nucleotide excision repair (xeroderma pigmentosa - ub damage! Mismatch repair (HNPCC) Double strand break (breast/ovarian cancer)
Give type I DNA damage in each condition
Nucleotide excision repair (xeroderma pigmentosa - ub damage!
Nucleotide instability
Mismatch repair (HNPCC) Micro satellite
Double strand break (breast/ovarian cancer)
Chromosomal instability
Retinoblastoma mechanism?
RAS (gprotein, bound to GTP)
Causes up regulation cyclic D
Cycline dependent kinase activated
Rb phosphorylated, so mitosis occurs (already deleted in retinoblastoma!)
Final model?
Initiation - promotion - progression (additional mutations)
Intrinsic
Chronic inflammation can acts as promoter
Genetic activation of indicators abs promoters
Progression leads to deregulation of cell cycle
