L21- Carcinogenesis: molecular hallmarks of cancer cells Flashcards
What do Caretaker genes do:
maintain genetic stability by repairing damaged DNA and replication errors
If these get mutated — > Genetic instability is a common feature of most tumour cells
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 do Carcinogens do to TSGs?
Carcinogens induce molecular abnormalities in TSGs
cause reduced/lack of protein expression or inactivation of protein – LOSS OF FUNCTION
What gene is affected in Retinoblastoma?
Gene: RB1
Gatekeeper
What gene is affected in Li-Fraumeni?
p53
gatekeeper/caretaker
What gene is affected in Familial adenomatous polyposis?
APC
Gatekeeper
What gene is affected in Familial breast cancer?
BRCA1, BRCA2
Caretaker
What gene is affected in Hereditary non-polyposis colorectal cancer?
hMLH1, hMSH2
Caretaker
What are Proto-oncogenes ?
promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
What are Oncogenes?
mutations lead to activated versions or increased expression of proto-oncogenes – GAIN OF FUNCTION
—> inc levels of proliferation, survival, angiogenesis and inhibition of apoptosis
Only 1 copy of the gene needs to be activated to induce a gain of function
Mechanisms of oncogene activation : Translocation
Translocation of a proto-oncogene from a low transcriptionally active site to an active site
Mechanisms of oncogene activation: Point mutation
substitution of a single base pair can alter an amino acid in the protein causing it to become hyperactive
Mechanisms of oncogene activation: Amplification
by insertion of multiple copies of an oncogene – increased expression
Multi-step tumorigenesis …briefly discuss steps leading to a neoplastic cell
activation of oncogenes
inactivation of TSGs
Minimum of 3 genetic alterations are needed to transform a normal cell into a neoplastic cell
Do tumour cells need the presence of positive growth factors before dividing?
Tumour cells acquire the ability to grow in the absence of these factors
Tumour cells are also unable to respond to negative growth factors
What is the role of the RB (Retinoblastoma protein) gene
key regulator of cell cycle by preventing progression from G1 to S phase
-ve GFs inhibit progression of cell cycle by activating Rb protein
What happens to the telomeres of Tumour cell’s DNA?
Tumour cells express telomerase that replaces the lost material and cells become immortal
Function of p53
P53 induces cell cycle arrest to allow repair of DNA damage
But also induces apoptosis if too much damage
TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours —> Li-Fraumeni
What is angiogenesis?
Generation of new blood channels
vascular endothelial growth factor (VEGF) – an angiogenic factor plays an important role
Why do Invasion and metastasis occur?
Many tumours show loss of E-cadherin through mutation/hypermethylation of the gene (epithelial cells are held tightly by this)
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
What are clinical applications of tumour markers?
Screening
- Detection of tumour
- Detection of predisposition
Diagnosis
-Identification of type and sub-type
Prognosis
-Certain mutations confer worse survival
Therapy
- Predictive markers for therapeutic response
- Development of targeted drugs or gene therapies
Monitoring
- Response to treatment
- Detecting relapse
The Prostate-specific antigen (PSA) marker is useful to diagnose…?
prostate cancer
The CA125 serum antigen is a marker useful to diagnose?
ovarian cancer
Predictive markers for therapeutic response : HER2
codes for a +ve growth factor receptor
Overexpression found in ~30% of breast tumours (gene amplification)
Herceptin is an antibody drug targeted to HER2 and dampens the effects of an overactive HER2 receptor
Only patients with HER2 overexpression have Herceptin treatment as individuals without overactive HER2 receptors will have no beneficial effect
