Intro to photocarcinogenesis Flashcards
Define what cancer is
An accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body by invasion and/or distant metastasis via the blood and lymphatic system
What does the emergence of a cancer cell involve ?
- Cancer cells originate from a single cell
- Genetic mutations contribute to the emergence of cancer cell
- There is then a series of mutations which accumulate in successive generations in a process known as colonal evolution
- Eventually a cell accumulates enough mutations to become cancerous
The emergence of cancer follows linear clonal succession rather than Dynamic clonal diversification - T/F?
False
The emergence of cancer follows dynamic clonal diversification rather than linear clonal succession
What are the 6 main hallmarks of cancer ?
- Sustaining proliferative signalling
- Evading growth surppressors
- Activating invasion and metastases
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
Define what a proto-oncogene is and what they do
They are normal genes which stimulate cell proliferation, promote survival (anti-apoptotic) and/or overcome cell senescence
What does a proto-oncogene become when it becomes mutated ?
An oncogene
What are oncogenes and what do they do ?
An over-active form of a gene that positively regulates cell division. Drives tumour formation when activity or copy number is increased e.g. Ras, Raf, growth factor receptors
What are tumour suppressors and what do they do ?
- They control the cell cycle (cell cycle arrest) and signal cell senescence or programmed cell death (apoptosis).
- Prevents the formation of a tumour when functioning normally (brake) e.g. Rb, TP53
Describe what cell senesence is, what it is triggered/regulated by & what is needed to be done in realtion to this for cancer development ?
- This is an irreversible arrest of cell proliferation, is a major barrier to the development of many cancers.
- Triggers for senescence include telomer shortening (replicative senescence) and oncogenic stress (overactivation of proliferation)
- Two important regulators of cell senescence are the p53 pathway and the p16-RB pathway
- To overcome senescence cancers cells usually must activate telomerase as well as block p53/p16-RB pathways
Appreciate the pic explaining the idea of oncogenic signalling
Appreciate the pic explaining the inactivation of a tumour suppressor - specifically p53
What are the 2 main conditions mentioned that are linked with a genetic predisposition for developing skin cancer ?
Albinism and Xeroderma pigmentosum (XP- genes are involved in the repair of damaged DNA) XP has a 2000 fold risk of developing skin cancer before age 20
What are some of the causes of immune suppression which increases the risk of skin cancer ?
Autoimmune conditions:
- UC and chrons both increase the risk of malignant melanomas
Immunosuppressants:
- e.g. azathioprine, cyclosporine, adalimumab
Organ transplant recipients
How does UVB damage the skin ?
Causes direct DNA damage - 1000x’s more damaging than UVA
How does UVA damage the skin ?
Causes indirect oxidative damage - penetrates more deeply than UVB
Bar specifically the mechanisms and skin damage of UVA and UVB what is the other way in which UV radiation also plays a role in the development of skin cancer ?
UV induced immunosuppression
What is the characteristic type of DNA damage caused by UV radiation ?
Pyrimidine dimers:
They are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions. Ultraviolet light induces the formation of covalent linkages by reactions localized on the C=C double bonds.
What are the 2 major types of UVB induced DNA lesions ?
- Cyclobutane pyrimidine dimers (CPDs)
- Pyrimidine–pyrimidone (6–4) photo-products
How are UVB induced DNA lesions formed ?
Both are formed by covalent bonding between adjacent pyrimidines on the same DNA strand
Recall which bases in DNA are classified as purines and which are classified as pyrimidines
- Purines - A&G
- Pyrimidines - T,C&U
How is UVB induced lesions repaired ?
By nucleotide excision repair (NER):
- Recognition of the damaged DNA
- Cleavage of the damaged DNA on either side of the photoproduct
- DNA polymerase fills in the gap, using the undamaged strand as a template
- DNA ligase seals the ends
What is meant by error prone DNA repair ? (hint to do with DNA polymerase)
- In most cases, polymerase will insert the correct bases (A-A)
- Beacuse polymerase is error prone, it may not correctly “guess” the structure of the lesion and instead insert G-G opposite the thymidine dimer
Describe what happens during Indirect DNA damage by UVA
- UVA causes indirect DNA damage via oxidation of DNA bases, especially deoxyguanosine to form 8-oxo-deoxyguanosine:
- 8-oxo-dG can mispair with deoxyadenosine rather than forming a normal base pair with deoxycytosine.
- If 8-oxo-dG is not removed, when DNA is replicated, dA rather than dC can be incorporated causing GC → AT point mutations
How are 8-oxo-dG lesions (UVA induced lesions) repaired ?
Mainly repaired by base excision repair (BER)
- Recognition of the chemically altered base causing slight helix distortion
- Cleavage of the altered base from the deoxyribose by DNA glycosylase
- Base-free deoxyribose cleaved away by endonuclease
- Single nucleotide gap filled by DNA polymerase β
- DNA ligase seals the ends
