Introduction to Photocarcinogenesis Flashcards
What is cancer?
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
Progression of genetic damage in cancer development?
Cancers originate from a single cell and gather genetic mutations (give it a growth advantage)
A series of mutations accumulate in successive generation in a process called CLONAL EXPANSION
Eventually, enough mutations result in a cancerous cell
Mutations in relation to morphology?
A single mutation can make the difference between skin being morphologically normal or abnormal (hyperplastic, dysplastic or neoplastic)
Why are tumour populations not homogenous?
Cancer cells are genetically unstable and so there are MULTIPLE PARALLEL CLONAL EXPANSIONS (branched, not linear, expansion), so tumour populations are HETEROGENOUS
Hallmarks of cancer?
Sustaining proliferative signalling
Resisting cell death - cancer cells reactivate telomerase, allowing them to replication beyond their normal lifespan
Inducing angiogenesis - for sustenance
Evading growth suppressors
Achieving invasion and metastases
Enabling replicative immortality
Enabling characteristics of cancer cells?
Genome instability and mutation
Tumour promoting inflammation - use growth factors provided by recruited cells as sustenance
Emerging hallmarks of cancer cells?
Deregulating cellular energetics
Avoiding immune destruction
Difference between proto-oncogenes and oncogenes?
Proto-oncogene - normal, not yet mutated, form of an oncogene
Oncogene - 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 is a tumour suppressor gene?
Inactive or non-functional form of a gene that negatively regulates cell division, e.g: p53, Retinoblastoma gene; when functioning normally, prevents the formation of a tumour
How does normal Ras signalling work?
When growth factor is present:
- Growth factor binds to the receptor and Ras is switched on, when it binds GTP
- Raf drives cell division and proliferation
When no growth factor is present:
- Growth factor receptor is unoccupied, Ras binds GDP and is off; there is no division or proliferation
How does oncogenic Ras signalling work?
Even when there is no growth factor present:
- Mutant Ras is always on and binds GTP
- There is cell division and proliferation
How does the functional p53 tumour suppressor gene work?
- DNA damage activates p53, which binds DNA
- Cdk and G/S cyclin are inhibited by Cdk inhibitor and the cell cycle progression is halted
- Cell halts at the G1 checkpoint
- DNA repair is activated
- Apoptosis is triggered, if repair is impossible
Net effect: CELLS DO NOT PASS ON DAMAGED DNA
How does the non-functional tumour suppressor gene work?
- DNA damage occurs but p53 cannot binds DNA
- Cdk and G/S cyclin are not inhibited by Cdk inhibitor and thus none of the previous normal effects occur
Net effect: DAMAGED DNA (mutations) PASSED ON
Types of skin cancers?
Malignant melanoma - most serious form
Non-melanoma (NMSC) - most skin cancer:
Basal Cell Carcinoma (BCC)
Squamous Cell Carcinoma (SCC)
Skin cancer risk factors?
UV radiation
Genetic risk factors
Age
Chemical exposure
Immune suppression
Examples of how the dose and pattern of sunlight exposure are important in determining the type of skin cancer?
ADD TABLE
How does skin type affect skin cancer risk?
Fitzpatrick type I-VI
Fair-skinned with light-coloured hair and eye - more likely to burn rather than tan
Genetic conditions that increase risk of skin cancer?
Albinism - no melanin produced so there is no UV protection
Xeroderma pigmentosum
Describe xeroderma pigmentosum
XP-assoc. genes are involved in repair of DNA damage; 2000-fold increase in skin cancer risk before the age of 20
Examples of chemicals that increase the risk of skin cancer?
Coal tar pitch
Soot
Creosote (wood preservative)
Petroleum products, e.g: mineral oil or motor oil
Shale oils
Arsenic
Examples of autoimmune conditions that increase of malignant melanoma?
Ulcerative colitis
Crohn’s disease - increases risk more than UC
Examples of immunosuppressants?
Azathioprine, cyclosporine, adalimumab
How does organ transplant increase the risk of skin cancer?
Non-melanoma (~30x) skin cancer risk is massively increased, esp. SCC
Malignant melanoma risk is more than doubled
Types of UV radiation?
UVA and UVB - involved with sunburn, ageing and skin cancer
UVA causes INDIRECT oxidative damage and penetrates the skin more deeply
UVB causes DIRECT DNA damage
UVC - shortest wavelength
Types of DNA damage?
Altered or missing base
Incorrect base
PYRIMIDINE DIMER (UV SIGNATURE)
Insertion/deletion
Strand break
Cross-linking
2 major types of UVB induced DNA lesions?
Cyclobutane pyrimidine dimers (CPDs)
Pyrimidine-pyrimidone (6-4) photo-products
Both are formed by covalent bonding between adjacent pyrimidines on the same DNA strand
How can UVB induced DNA lesions be repaired?
CPDs and 6-4 PPs are relatively stable and are removed by NUCLEOTIDE EXCISION REPAIR (NER)
Steps of 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
How does error prone DNA repair cause mutations?
Unrepaired UB-induced photoproducts interfere with base pairing during DNA replication, leading to mutations
In most cases, polymerase inserts the correct bases (A-A); however, because polymerase is error prone, it may not correctly “guess” the lesion structure and may insert G-G opposite the thymidine dimer
Describe indirect DNA damage by UVA
Causes indirect DNA damage via oxidation of DNA bases, esp. deoxyguanosine to form 8-oxo-deoxyguanosine
How does 8-oxo-deoxyguanosine cause mutations?
Can MISPAIR with deoxyadenosine, rather than forming a normal base pair with deoxycytosine
If 8-oxo-deoxyguanosine is not removed, when the DNA is replicated,deoxyaadenosine is incorporated, causing GC to AT point mutations
Method by which 8-oxo-deoxyguanosine lesions be repaired?
Oxidised bases are mainly repaired by BASE EXCISION REPAIR (BER)
Steps of 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
Summary of UVB induced DNA damage?
UVB leads to DIRECT DNA damage:
Cyclobutane pyrimidine dimers (CPDs) OR pyrimidine–pyrimidone (6–4) photo-products
Repaired by nucleotide excision repair (NER)
TT → CC UV signature mutation
Summary of UVA induced DNA damage?
UVA causes indirect DNA damage:
Oxidation of deoxyguanosine forming 8-oxo-deoxyguanosine
Repaired by base excision repair (BER)
C → A point mutation
How does UV induced DNA damage cause immunosuppression?
Depletion of Langerhans cells in the skin and reduced ability to present antigens
Generation of UV induced regulatory T (Treg) cells with immune suppressive activity
Secretion of anti-inflammatory cytokines, e.g: IL-10 by macrophages and keratinocytes
Important mutations in BCC development?
In PTCH1, which is a key component of the Hedgehog signalling pathway
This should normally activate certain transcription factors, leading to induction of cell proliferation gene and angiogenesis activators
Which drug used in BCC treatment exploits Hedgehog signalling?
Vismodegib - binds to Smoothened to
block hedgehog signalling and prevent
cell cycle activation and angiogenesis
Important mutations in malignant melanoma development?
Mutations in Ras/Raf/MAPK signalling pathways are common in melanomas:
Over half of melanomas have an activating B-Raf mutation
Which drugs target mutated form of B-raf?
Vemurafenib and Dabrafenib
Which drugs target MEK?
Tramatenib
Which two genes have been linked to familial melanoma?
CDKN2A - encodes two proteins (p16 and p14) and prevents cells from replicating when they contain damaged DNA, by activating G1/S
CDK4 (cyclin-dependent kinase 4) - permits cell cycle progression by phosphorylation of Retinoblastoma protein
What do mutations do in familial melanoma?
Inactivating mutations in p16 permit cell division in the presence of unrepaired DNA
Activating mutations in CDK4 accelerated the cell cycle
Name of drugs, their targets and functions?
Table 2
How are B-raf inhibitors used and why?
Used in combo with Trametinib, as resistance to them is rapid (6-7 months)
