L21: Mechanisms Of Oncogenesis Flashcards
What is cancer characterised by?
→Abnormal cell proliferation
→ Tumour formation
→Invasion of neighbouring normal tissue
→Metastasis to form new tumours at distant sites
What are the two enabling characteristics of cancer?
→genome instability
→tumour inflammation
What are the two emerging hallmarks of cancer?
→avoiding immune destruction
→ reprogramming energy metabolism
What are the hallmarks of cancer?
→sustaining proliferative signalling →resisting cell death →genome instability →enabling replicative immortality →evading growth suppressors
How has long life span increased risk of cancers?
→longer we live the more time there is for DNA to accumulate
mutations that may lead to cancer
What type of developmental is cancer?
→clonal
How does heterogeneity arise in tumour cells?
→Tumour cells can ‘evolve’- sub clonal selection allowing a growth advantage
→Dependent on interaction with other tumour cells and the tumour microenvironment
What are proto-oncogenes?
→Normal genes that can be activated to be oncogenic
What is an oncogene?
→a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth
What are tumour suppressor genes?
→inhibit both growth and tumour formation
→braking signals during phase G1 of the cell cycle, to stop
or slow the cell cycle before S phase.
What are the 3 assumptions in multistage carcinogenesis?
→Malignant transformation of a single cell is sufficient to give rise to a tumour
→Any cell in a tissue is as likely to be transformed as any other of the same type
→Once a malignant cell is generated the mean time to tumour detection is generally constant
What are the five models of carcinogenesis?
→mutational →genome instability →non-genotoxic →Darwinian →tissue organisation
What supports that cancer arises through the accumulation of irreversible DNA damage?
→presence of multiple mutations in critical genes is a distinctive feature of cancer cells
What are the 4 classes of carcinogens?
→chemical
→physical
→heritable
→viral
What are the two types of physical carcinogens?
→radiation eg ionisation or ultraviolet
→asbestos
What are two examples of viral carcinogens?
→Hepatitis B
→Epstein Barr
How do chemical carcinogens exert their effects?
→effects by adding functional groups to DNA bases called DNA adducts
Give an example of a chemical carcinogens
→coal tar, which contains benzo[a]pyrene, a polycyclic hydrocarbon
What chemical carcinogen is easiest to enter cells?
→Benzo[a]pyrene
Which enzymes in the body activate benzopyrene?
→cytochrome p450
What is the function of Ames test?
→determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
How does the Ames test work?
Point mutations are made in the histidine (Salmonella typhimurium) or the tryptophan (Escherichia coli) operon,
→the bacteria incapable of producing the corresponding amino acid
→organisms that cannot grow unless histidine or tryptophan is supplied.
→culturing His-Salmonellais in a media containing certain chemicals, causes mutation in histidine encoding gene, such that they regain the ability to synthesize histidine
how do physical carcinogens exert their effects?
→imparting energy into the biological material
→DNA breaks Pyrimidine dimers
→Translocations
Mutations as a result of failed repair
What type of mutations are found in hereditary malignant syndromes?
→mutation of a single gene
What are some DNA repair defects syndromes predisposing to cancer?→
→ataxia telangiectasia →Bloom’s syndrome →Fanconi’s anaemia →Li-Fraumeni syndrome →Lynch type II →xeroderma pigmentosum
What are some chromosomal abnormalities predisposing to cancer?
→Down’s syndrome
→Klinefelter’s syndrome
What is ataxia telangiectasia?
→neuromotor dysfunction, dilation of blood vessels,
telangiectasia = spider veins
How does ataxia tenlangiectasia?
→Mutation in ATM gene
What is the function of the ATM gene activation?
→cell cycle arrest(p53), DNA repair and apoptosis -cell cycle arrest
What is the ATM gene activated by?
→dsDNA breaks leading to cell cycle arrest
What are the cancer predispositions of ATM mutation?
→lymphoma,
→leukaemia
→breast cancer
What causes Bloom’s syndrome?
→Mutation in BLM gene
What is the function of the BLM gene?
→that provides instructions for coding a member of the RecQ helicase family
that help maintain the structure and integrity of DNA
What are the signs of Bloom’s syndrome?
→short stature
→rarely exceed 5 feet tall,
→skin rash that develops after exposure to the sun
What are the cancer dispositions of Bloom’s syndrome?
→skin cancer
→basal cell carcinoma
→squamous cell carcinoma
What mutations cause Lynch type?
→Mutations in DNA mismatch repair (MMR) genes, notably MLH1, MSH2, MSH6 and PMS2
What are the symptoms of Lynch type?
→doesn’t cause any symptoms
What are the caner predispositions of Lynch type?
→colorectal cancer
At what stage of a virus does it have restricted gene expression?
→latent phase
What are the properties required of tumorigenic viruses?
→stable association with cells
→must not kill cells
→must evade immune surveillance of infected cells
What does the latent phase of viruses express?
→express non immunogenic to allow virus to survive within the host
What are some RNA retroviruses associated with cancer?
→HTLV-I = Adult T-cell leukaemia, lymphoma
What is genome instability of the cancer model?
→At least two events are necessary for carcinogenesis and that the cell with the first event must survive in the tissue long enough to sustain a second event.
What is the non-genotoxic model of cancer?
→do not seem to act through a structural change in DNA but rather through functional changes including epigenetic events
What are the group of carcinogens that induce cancer via non-genotoxic mechanis?
→tumour promoters (1,4-dichlorobenzene),
→endocrine-modifiers (17β-estradiol),
→receptor-mediators (2,3,7,8tetrachlorodibenzo-p-dioxin),
→immunosuppressants (cyclosporine) or
→inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium), also in model 1
What is the Darwinian model of cancer?
→Sequential accumulation of mutations due to exposure to carcinogens
→Tumour cells will be selected for ability to grow and invade
→Selection will include resistance to therapy
→Some mutations may be deleterious for tumour
What are the two forces driving carcinogens?
→somatic mutation theory (SMT)
→the tissue organization field theory (TOFT
What is the SMT approach to cancer?
→cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations
→those mutations damage the genes which control cell proliferation and cell cycle
What is the TOFT approach to cancer?
→Carcinogenesis is primarily a problem of tissue organization
→carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity
What is the difference between the SMT and TOFT approach to cancer?
→SMT= single catastrophic event triggering carcinogenesis
→TOFT=carcinogenesis as general deterioration of the tissue microenvironment due to extracellular causes
What are the three Es of cancer immnunoediting?
→elimination
→equilibrium
→escape-expanding tumour populations becomes
clinically detectable
What can happen during the equilibrium of cancer immunoediting?
→some of the tumour may mutate
or give rise to genetic variants that
survive, grow and enter the next phase
