Lect 21 - Carcinogenesis: Molecular Hallmarks of Cancer Cells Flashcards
how can carcinogenesis be modelled using a Darwinian process of natural selection
spontaneous replication errors in a cell population can give a selective growth advantage
what are caretaker genes?
Caretaker genes - maintain genetic stability by repairing damaged DNA and replication errors
Mutant forms of these genes cause genomic instability
what are the types of Tumour suppressor genes (TSGs)
GATEKEEPERS
CARETAKERS
what are GATEKEEPERS
Negative regulators of the cell cycle and proliferation
Positive regulators of apoptosis
Positive regulators of cell differentiation
what is the idea of a second hit?
as two copies of genes, two mutations are required to completely take out a TSG.
in terms of caner “hits” what is significant about familial cancer syndromes?
In the case of a familial cancer syndrome every cell in the individuals body will carry the first hit, meaning only one is required to inactivate a TSG.
what gene is affected in Familial breast cancer
BRCA1, BRCA2 (both care
what gene is affected in Hereditary non-polyposis colorectal cancer?
hMLH1, hMSH2 (both care)
what gene is affected in Familial adenomatous polyposis?
APC (gate)
what gene is affected in Li-Fraumeni?
p53 (gate AND care)
what gene is affected in Retinoblastoma
RB1 (gate)
what is the lifetime risk of a carrier of a familial cancer syndrome developing cancer?
70-90%
what are proto-oncogenes?
promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
what casues proto-oncogenes to become Oncogenes
mutations leading to activated versions or increased expression of proto-oncogenes
how can translocation activate an oncogene?
Translocation of a proto-oncogene from a low transcriptionally active site to an active site - aberrant expression of the oncogene
how can a point mutation activate an oncogene?
substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive
how can amplification cause activation of an oncogene?
by insertion of multiple copies of an oncogene – increased expression
how many genetic alterations are required to transform a normal cell into a neoplastic cell?
Minimum of 3. there will be loads before there are 3 important enough to cause neoplasm.
tumorigenesis has many many steps.
what are the hallmarks of cancer cells?
self sufficient for growth signals insensitive to antigrowth signals tissue invasion and metastasis limitless potential for replication sustained angiogenesis evasion of apoptosis.
give an example by which cancer cells become self sufficient for growth signals
mutated RAS which is always active as it is unable to cleave phosphate from GTP to become inactive.
makes cell think there is GF around.
how do cancer cells become resistant to negative growth factors
Inactivation of the RB gene
what is the RB gene?
a key regulator of cell cycle by preventing progression from G1 to S phase.
why are cancer cells immortal?
Tumour cells express telomerase that replaces the lost material and cells become immortal.
why do normal cells have a limited lifespan?
After a number of cell divisions they die due to loss of DNA from the telomeres.
which two genes are important in cancer cells avoiding apoptosis?
TP53 and P53.
what does P53 do?
induces cell cycle arrest to allow repair of DNA damage, and causes apoptosis if damage is too great
what does TP53 do?
codes for transcription factor that induces transcription of >100 genes.
TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours
what is angiogenesis
new blood vessels
at what size do tumours need angiogenesis to get any bigger
2mm
what growth factors are released by tumour cells to cause angiogenesis?
vascular endothelial growth factor
what molecule that holds Epithelial cells together is lost in cancerous cells?
E-cadherin
what does loss of E-cadherin cause?
epithelial-mesenchymal transition (EMT)
allows cells to break through basement membrane and invade the underlying stroma
what genetic testing can be used to estimate prognosis of cancers?
Gene expression profiling - for example subtypes with different translocations can be better or worse for outcome.
give an example of a drug that can only be used in cancers expressing certain types of mutated receptors.
Herceptin is an antibody drug targeted to HER2 and dampens the effects of an overactive HER2 receptor
(HER2 (erbB2/neu) codes for a +ve growth factor receptor)
