Carcinogens: Molecular hallmarks of cancer cells Flashcards
Why is genetic instability important and how can it be caused?
- Caused by mutant forms of caretaker genes
- Important for enabling specific genetic alterations to accumulate in carcinogenesis
- Common feature of tumour cells
What are the two types of tumour suppressor genes?
- Gatekeeper
- Caretaker
What is the function of gatekeepers?
- Regulating normal growth
- Positive regulators of apoptosis
- -Positive regulators of cell differentiation
- Negative regulators of cell cycle and proliferation
What is the function of caretakers?
- Maintain genetic stability
- DNA repair genes
- Controlling accuracy of mitosis
How do carcinogens affect tumour suppressor genes?
-Induce molecular abnormalities that cause reduced/lack of protein expression or inactivation of protein
How are TSGs inactivated?
- First hit normally a point mutation
- Remaining normal copy of the TSG capable of doing the job itself
- Second hit required for complete loss of function
What are the genes affected , types of tumour suppressor and principal tumours produced by these cancer syndromes?
- Retinoblastoma
- Li-Fraumeni
- Familial adenomatous polyposis
- Famililal breast cancer
- Hereditary non-polyposis colorectal cancer
- Retinoblastoma= RB1 gene= principal tumour: retinoblastoma and gatekeeper
- Li-fraumeni=p53 gene= principal tumour: sarcomas, breast, gatekeeper & caretaker
- F.A.P= APC= colorectal and gatekeeper
- F.B.C= BRCA1, BRCA2, breast and ovarian and caretaker
- H.N.C.C= hMLH1, hMSH2 and colon and endometrial and caretaker
What is the function of proto-oncogens?
- Promote cell proliferation -Survival
- Angiogenesis
- Negative regulation of apoptosis
What can mutations in oncogenes lead to?
- Activated versions
- Increased expression of proto-oncogenes
- Gain of function
What can oncogenes cause?
-Increased levels of cell proliferation, survival, angiogenesis, inhibition of apoptosis
What are the mechanisms of oncogene activation?
- Translocation (from a low transcriptionally active site to an active site) aberrant expression
- Point mutation (substitution of a single base pair can alter an amino acid in the protein leading to hyperactive)
- Amplification (insertion of multiple copies of an oncogene= increased expression)
What are the stages that turn normal epithelium into invasion & metastasis
1) Loss of APC
2) Hyperplastic epithelium
3) DNA hypomethylation
4) Activation of K-ras (early)
5) Loss of 18q TSG (late)
6) Loss of p53
7) Carcinomas
8) invasion & metastasis
What are the hallmarks of cancer cells?
- Evading apoptosis
- Tissue invasion and metastasis
- Sustained angiogenesis
- Self-sufficiency in growth signals
- Limitless potential for replication
- Insensitivity to antigrowth signals
How does insensitivity to antigrowth signals occur?
When required level of cell division has occurred normal cells will respond to negative growth factors and leave the cell cycle tumour cells do not respond
What is the function of RB protein?
Key regulator of cell cycle by preventing progression from G1 to S phase
What is the role of negative GFs?
Inhibit progression of cell cycle by activating Rb protein.
What does inactivation of the RB gene result in?
Resistance to negative growth regulation- common event in tumours
How is immortality achieved in tumour cells?
Rapid proliferation can overexposes the telomerase enzyme to maintain normal telomere length
Why do normal cells have a finite replicative lifespan?
Due to shortening of chromosome ends (telomeres) after each cell division
How are tumour cells resistance to apoptosis?
- TP53 key player in apoptosis
- -TP53 codes for transcription factor inducing transcription of >100 genes
- P53 induced cell cycle arrest allowing DNA repair or apoptosis if too much repair needed
- TP53 inactivation leading to loss of apoptotic response
- Inherited mutations= Li-Fraumeni syndrome
What is angiogenesis key for?
Metastatic spread of malignant tumours
How does hypoxia cause angiogenesis?
- Stabalises HIF-1 transcription factor inducing vascular endothelial growth factor (VEGF)
- This actively recruits endothelial cells which construct new capillaries and vessels
How are epithelial cells held together?
Adhesion molecule E-Cadherin
What do mesenchymal cells secrete? What does this allow?
- Motile secreting proteases
- Allows them to break through basement membrane & invade underlying stroma
In terms of invasion/metastasis what do tumours show a loss of?
E-Cadherin through mutation/hypermethylation of the gene
What is Herceptin?
Antibody drug targeted to HER2 and dampens the effect of an overactive HER2 receptor- prone to breast tumours
