Molecular hallmarks of cancer cells Flashcards
What are caretaker genes?
Maintain genetic stability by repairing damaged DNA and replication errors. I.e. tumour suppressor genes when active
What is a common feature of most tumour cells?
Genetic instability
What are driver mutations?
Mutations in proto-oncogenes/tumour-suppressor genes that drive cancinogenesis.
What are the two different types of tumour suppressor gene?
Gatekeepers and caretakers
What are gatekeeper genes?
Play important roles in regulating normal growth:
- negative regulators of the cell cycle and proliferation
- positive regulators of apoptosis
- positive regulators of cell differentiation
What are caretaker genes?
Maintain genetic stability
- DNA repair genes
- controlling accuracy of mitosis
What sort of mutations are required of tumour suppressor genes for carcinogenics?
Loss of function - point mutations, deletions/insertions, chromosomal rearrangements, epigenetic silencing
Do loss of function mutations contribute directly to the tumourigenic phenotype?
No - such mutations simply create the conditions whereby mutations have a chance to arise in gatekeeper TSGs.
What kind of mutation usually provides the first hit for a TSG?
Point mutation in the coding sequence.
What kind(s) of mutation provide the second hit for a TSG and why?
Chromosomal non-disjunction
Gene conversion
Mitotic recombination
Epigenetic inactivation through promotor methylation
These types of mutational events are 3x more common than point mutations.
Which gene is involved in retinoblastoma?
Gene: RB1
Tumour: retinoblastoma
What gene and principle tumours are involved in Li-Fraumeni?
Gene: p53
Tumour: sarcomas, breast
What gene and principle tumour is involved in familial adenomatous polyposis?
Gene: APC
Tumour: colorectal
What genes and principle tumours are involved in familial breast cancer?
Genes: BRCA1, BRCA2
Tumours: breast, ovarian
What genes and principle tumours are involved in HNPCC?
Genes: hMLH1, hMSH2
Tumours: colon, endometrial
What is typically inherited in familial cancer syndromes?
Mutant copy of gatekeeper or caretaker gene.
What is the lifetime risk of a carrier developing cancer?
70-90% depending on the syndrome
What are proto-oncogenes?
Genes that promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis.
What are the features of oncogenes?
- Mutations lead to activated versions or increased expression of proto-oncogenes – GAIN OF FUNCTION.
- Cause increased levels of cell proliferation, survival, angiogenesis and inhibition of apoptosis.
- Only 1 copy of the gene needs to be activated to induce a gain of function. Mutated gene is dominant to the other normal parental gene.
What are the mechanisms of oncogene activation?
Translocation
Point mutation
Amplification
What is translocation?
Movement of a proto-oncogene from a low transcriptionally active site on a chomosome to an active site on the same/different chromosome - aberrant expression of the oncogene.
eg Burkitt’s lymphoma
How does amplification work?
Insertion of multiple copies of an oncogene – increased expression
What is the minimum number of genetic mutations required to transform a normal cell into a neoplastic cell?
3
What are the hallmarks of cancer cells?
- Self-sufficiency in growth
- Insensitivity to antigrowth signals
- Tissue invasion and metastasis
- Limitless potential for replication
- Sustained angiogenesis
- Evading apoptosis
What is ‘self-sufficiency in growth factors’?
Independence from positive growth factors e.g. EGFR (receptor for TGF alpha)
What is RAS?
Single subunit small GTPase indirectly coupled to EGFR (tyrosine kinase)
What happens to RAS when it becomes an oncoprotein?
It loses its GTPase function - remains permanently active.
What is the function of the retinoblastoma protein?
In quiescent cells the RB protein binds to and inactivates pro-growth factors.
In proliferating cells the RB protein is deactivated by phosphorylation by kinases switched on via proliferation signal transduction pathway.
Negative growth factors, such as TGFbeta, activate RB by stimulating the expression of proteins that inhibit kinases.
How can cancer cells escape the inhibition of proliferation?
By acquiring mutation activation or epigenetic silencing.
How do cancer cells gain immortality?
They express telomerase - replaces lost telomere sequences at each replication. Prevents the karyotypic chaos and apoptosis that results from fusion from the exposed ends of chromosomes,
What is the function of p53?
Codes for TxF that induces Txn of >100 genes. Induces cell cycle arrest to allow repair of DNA damage but also induces apoptosis if there is too much damage.
What results from in inactivation of p53?
Loss of apoptotic response - most common genetic abnormality in human tumours.
What are the possible triggers of the p53 apoptotic response?
DNA damage Hypoxia Demethylation of DNA Viral infection Depletion of ribonucleotides Blockage of RNA/DNA synthesis
How big can a tumour become without requiring angiogenesis?
2mm
What is the mechanism for angiogenesis?
- Hypoxia stabilizes HIF-1 transcription factor, which induces vascular endothelial growth factor (VEGF) – an angiogenic factor
- This actively recruit endothelial cells that proceed to construct new capillaries and vessels
What is the function of E-cadherin?
Adhesion molecule that holds epithelial cells together.
What happens if e-cadherin is lost?
- Results in epithelial-mesenchymal transition (EMT)
- Mesenchymal cells are motile and secrete proteases - allows them to break through basement membrane and invade the underlying stroma
- Metastasis involves the spread of malignant cells via the blood/lymphatic system to secondary sites and the formation of secondary tumours
How might a specific tumour marker be used for better treatment?
- HER2 (+ve growth factor receptor) over-expression found in ~30% of breast tumours
- Makes cells more responsive too, or independent of, +ve growth factors
- Only patients with HER2 will benefit from Herceptin - monoclonal Ab to HER2
