parasitic cancers Flashcards
1
Q
cancer transmission
A
- can spread throughout whole body, eventually killing host
- shouldn’t be able to transmit to another host
- can’t survive outside the body
- can’t evade immune recognition of non-self
- but has been shown in a few cases to be directly transmitted
2
Q
DFTD
A
- devil facial tumour disease
- tasmanian devils appeared with facial tumours
- prevents eating
- death from starvation
- 50% of total populaiton wiped out in 10 years
- apparently caused by virus
3
Q
viruses and cancer
A
- viruses known to initiate cancer
- HPV
- induces transcription of specific genes
- induces gene mutations
- feline lymphosarcoma
- apparently similar to DFTD
4
Q
DFTD karyotyping
A
- of devil tumour cells
- exactly the same karyotype in all samples
- 13 chromosomes with no XY
- usually 14 with XY
- should be impossible
- cancer is accumulation of different random mutation events
- hypothesised tumour as allograft
- transmitted as a tumour
- reproduction independent from host
- essentially a parasite
5
Q
microsatellite analysis of DFTD
A
- to investigate closeness of DNA
- normal devil cells unrelated to tumour cells
- tumour cells from different devils apparently similar to each other
6
Q
microRNA expression profiling of DFTD
A
- only X chromosome sequences found in tumour cells
- originated from female
- similar to neural cell expression profile
- schwann cell markers
- therefore, at some point, female grew tumour in schwann cell
- managed to transfer to other devils and kill them
7
Q
tasmanian devil biting behaviour
A
- tend to bite on snout
- tumours generally found on motuh
- ulcerated tumour elaks into buccal cavity
- upon biting tumour cells directly injected into the next devil
- never exposed to the environment
8
Q
immune system evasion of DFTD
A
- no immune suppression of devils
- but small populations → inbred
- devils so similar that tumour cells not recognised as non-self
- also downregulation of MHC
- not too much - other systems would kill host
- enough to reduce immunodetection
9
Q
tasmanian devil MHC genes
A
- in particular peptide binding domain
- allows range of antigens to be presented
- humans have up to 7 aas at each position
- devils have 1 or 2
- genetically similar devils → easy for tumour cells to avoid presentation on MHC
10
Q
DFTD allografts
A
- transplant skin from eastern devil to north-western devil
- different populations → genetically diverse
- should reject it but didn’t
- now spread to this NW population
- MHC downregulation?
11
Q
DFTD strains
A
- some more easily transmitted than others
- if tetraploid → slower replication → slower growth → kill devil slower
- decreased virulence → increased transmission
12
Q
DFT2
A
- DFTD found with traces of Y chromosome
- same situation originating in male devil
- different MHC loci and distinct karyotype
13
Q
resistance to DFTD
A
- some surviving devils may have resistance
- some genes more frequent in surviving devils
- has been dramatic change in allele frequencies
- usually in genes associated with resistance to other types of cancer
- selection in host population for disease resistance
14
Q
current status of DFTD
A
- no longer individualised cancer
- clonally reproducing highly virulent parasite
- transmitted due to extreme aggression and inbreeding
- may be evolving to become less virulent
- tetraploidy
- immune evasion
15
Q
syrian hamsters
A
- used to study very virulent cancers
- 3 original hamsters used to create genetically similar population
- transplant cancers between hamsters before first one dies so you continue to study same cancer
- each transplant → appear faster and increased blood titres
- selection for highly aggressive cancer
- successful ones established
- contagious reticulum cell sarcoma
- after 12 transplants, cancer jumped from hamster to hamster on its own through social activities
16
Q
mosquito feeding on syrian hamsters
A
- fed on cage of hamsters with tumours
- then fed on healthy hamsters
- cancer was still transferred
- both external survival and immune evasion have been overcome here
17
Q
transmissible cancers in dogs
A
- canine transmissible venereal tumour
- sexually transmitted
- has been around for a long time
- small tumours on genitals that don’t invade host
- stabilise at certain size
- often disappear on their own
- can metastasise in immunocompromised dogs
- possibly virus? → microsatellite analysis
18
Q
CTVT microsatellite analysis
A
- if a virus like HPV, tumour cells appear similar to dog they came from
- however tumours were more similar to each other
- → direct neoplastic transfer
- also clustered with wolves, not dogs
- originated in wolves/early ancestors of dogs
19
Q
CTVT full genome sequencing
A
- originated ~11,000 years ago
- two tumours analysed
- split off 500 years ago
20
Q
CTVT chromosomes
A
- very different to dog cells
- 78 chromosomes in dogs, 57-59 in tumour cells
- many structural rearrangements
- deletions, duplications, ranslocation
- nearly 1 million nucelotide substitutions
- over 2000 genes disrupted
- mostly immune related
- MHC downregulation
- apoptosis genes
- redundant immune evasion pathways
21
Q
CTVT adaptation
A
- highly adapted to immune evasion
- non-invasive with no strong immune response trigerred
- mutations in immune genes
- self-limiting (small size then regression)
- low virulence for transmission
- similar to DFTD but more highly sophisticated
- much older so more adaptation
- dogs are more genetically diverse so needs to be
22
Q
transmissible human cancers
A
- no evidence of serial neoplastic cells in humans
- Chester Southam - macerated tumours injected into humans
- established in immunosuppressed individuals
- stem cell therapy with iPSCs
23
Q
iPSC treatment
A
- need to knockout p53 and treat with high expression TFs e.g. c-myc to create iPSCs
- select for high proliferation levels, activaiton of proto-oncogenes, deactivation of tumour suppressors and transformation
- tumorigenic processes → iPSCs prone to tumour formaiton
- derived from host cells → no detection by immune system
- control is vital
