Cellular + Molecular events in carcinogenesis Flashcards
What is the reason for the long interval between exposure to a carcinogen and clinical recognition of the tumour
Tumours result from clonal proliferation of single cells
It takes a large time for one cell to grow into a nodule of cells
Describe the initiation stage of tumour formation
- When carcinogens induce a genetic alteration that gives transformed cell neoplastic potential
Describe the promotion stage of tumour formation
- Stimulation of clonal proliferation of the initiated transformed cell
Describe the progression stage of tumour formation
- Process culminating in malignant behaviour characterised by invasion and its consequences
How does successive applications of a carcinogen and promotor cause a malignant tumour on a mouse
- A single application results in a visible tumour if it is followed by repeated painting of the site with the promotor
- Carcinogen is the initiator which induces the lesions on the DNA of target cells
- Promoter is the one that promotes the growth of the initiated cells - further events lead to malignancy
How many genetic alterations are needed to transform a normal cell to a neoplastic cell and what are they
Many:
- Expression of telomerase
- Loss or inactivation of both copies of a tumour suppressor gene to remove inhibitory control of cellular replication
- Activation or abnormal expression of oncogenes to self-stimulate cell proliferation
How do tumour suppressor gene inactivation and abnormal oncogene expression work together to form neoplastic cells
Drive cells from their normal state of regulated growth to deregulated and uncontrolled growth
How is genomic instability effected by age
Increases with age
What are the two types of tumour suppressor genes
Caretaker
Gatekeeper
What are caretaker genes
Maintain the integrity of genome by repairing DNA damage
Role of BRCA 1
Tumour suppressor caretaker gene involved in DNA repair
Role of BRCA2
Involved in DNA repair
Mutation of BRCA1 and BRCA2 can cause what
Breast, prostate and pancreatic cancer
What are gatekeeper genes
Genes inhibiting the proliferation or promote the death of cells with damaged DNA
What is p53
Transcription factors that responds to DNA damage
Where is p53 found
Chromosome 17
What are the normal functions of p53
- Repair of damaged DNA before S phase in the cell cycle by arresting it in G1 until damage is repaired
- Apoptotic cells each if there is extensive DNA damage
What happens to p53 levels in cells with sustained DNA damage
They rise until damage is repaired or cell goes through apoptosis
How can p53 lose its function
Non-sense mutation - Unreadable
Missense mutation - defective protein
Complexes of normal and mutant p53 prevent normal function
Binding of normal p53 to proteins encoded by oncogenic DNA viruses
What syndrome does INHERITED mutation of p53 result in
Li-fraumeni syndrome
What is RB1
Transcriptional regulatory - controls cell cycle G1/S checkpoint
What are RB1 associated with
retinoblastoma
What are retinoblastoma
Bilateral Malignant tumours derived from the retina in children
When can retinoblastoma become unilateral
Sporadic when there’s no family association