21 - Carcinogenesis - molecular hallmarks Flashcards
carcinogens generally attack what
the tumour suppressor genes
caretaker gene definition
maintain genetic stability by repairing damaged DNA and replication errors
gatekeeper definition
play important roles in regulating normal growth
negative regulator gatekeeper does
regulator of cell cycle and proliferation
positive regulator gatekeeper
regulates apoptosis and cell differentiation
carcinogens do what
induce molecular abnormalities in TSGs that cause reduced/lack of protein expression or inactivation i.e. loss of function
inactivation of a TSG requires what
two hit hypothesis
how can a TSG be activated according to the two hit hypothesis
lost during chromosomal non-disjunction
or gene conversion
or mitotic recombination
retinoblastoma gene
RB1
li-fraumeni gene
p53
familial adenomatous polyposis gene
APC
HNPCC gene
hMLH1, hMSH2
which tumours are caretaker tumours
breast, ovarian
colon/endometrial
proto-oncogenes
promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
oncogenes
mutations lead to activated versions or increased expression of proto-oncogenes - GAIN of function`
RAS - what is it
commonest oncoprotein
member of guanine nucleotide binding proteins called G-proteins
RAS - problems
acquired a GTP molecule and shifted into an active state and unable to an inactive state.
RB protein
retinoblastoma protein
RB protein - what does it do?
non-proliferating cells behind here and suppresses activity.
may be epigenetically silenced
immortal tumour cells
cells have a finite replicative life span as after numerous divisions they die due to loss of DNA from the telomeres. Tumours cells express telomerase that replaces this and they become immortal.
TP53 involved with
apoptosis mainly
codes for transcription factor that induces transcription for >100 genes.
most common genetic abnormality in human tumours
TP53 mutation
TP53 mutation disease
Li-Fraumeni
Angiogenesis in tumours
> 2mm require a good blood supply
VEGF induced by tumours - angiogenic factor.
VEGF stands for
vascular endothelial growth factor
E-cadherin
holds epithelial cells together
tumours and E-cadherin
show loss of E-cadherin through mutation / hypermethylation of the gene… results in EMT
what does EMT stand for
epithelial-mesenchymal transition
Herceptin targets
targets HER2
What does HER2 gene do?
codes for +ve growth factor receptor which is overexpressed in 30% of breast tumours
