Transmissible Cancer Flashcards
Mutations which cause cancer often occur in which genes?
Genes encoding:
- Oncogenes
- Tumour suppressor proteins
What are examples of oncogenes?
Ras, Myc, RTK
Example of a tumour suppressor protein?
P53
What is the role of P5S?
- Cell cycle checkpoint
- DNA repair
- Induction of apoptosis if DNA cannot be repaired
- Increased cell adhesion to reduce tumour metastasis
How many copies of P53 are required to prevent formation of cancers?
A single copy of P53 is enough to prevent excessive tumour formation
Main characteristics of cancer cella/
- Can rapidly proliferate
- Can prevent induction of apoptosis
- Can prevent cell cycle arrest
- Can develop their own blood supply= angiogenesis
- Can spread to invade other locations of the body via metastasising
- Can rapidly develop mutations
- Can evade immune detection
How do cancers develop?
- Neoplastic progression: mutations arise e.g. in tumour suppressor genes
- There is clonal expansion. Rapid excessive proliferation and selection
- The tumour cells move to different parts of the body (metastasis) or can even invade other individuals (transmissible tumours)
Where do many tumours tend to metastasise?
- Liver
- Bone marrow
- Lung
Why do many tumour cells metastasise to certain locations?
Due to the overexpression of CXCR4 on the surface of tumour cells, causes them to move to locations expressing high levels of CXCL12 ligand
What is required for cancers to be transmissible?
- Require a means of transmission
- Require an ability to evade immune detection
What prevent transmissible cancers in humans?
- MHC variation between individuals. Very good ability of our immune systems to discriminate self from non-self
- No route of direct transmission
Which species can transmissible cancers be observed in?
Tasmanian devils
Syrian hamsters
Canines
Marine bivalves
Tasmanian devils were found in Australia up until?
500 years ago
Tasmanian devils now have a restricted distribution where?
Mainland tasmania
What is DFTD?
Devil Facial Tumour Disease
When was DFTD first recognised?
1996
DFTD has spread through?
85% of the population
DFTD causes death within?
6 months
Death is caused by?
Organ failure
Metastasis
Starvation
We expect the natural population to go extinct within the next?
20-30 years
How did they recognise this was not caused by a virus but through allograft transmission?
Identical karyotypes between the tumours
What was the common karyotype compared to normal cells?
Normal cells: 14 chromosomes
Tumour cells: 13 chromosomes and non sex chromosomes
What is the karyotype?
The number and appearance of chromosomes in a eukaryotic nucleus
What else showed that the tumours were of the same origin?
Microsatellite analysis showed that the tumours from different devils were more closely related to eachother than they are to other devils
What is the original origin of these cells?
From a female devil
20 years ago
Schwann cell origin
How did they know the tumour cells are of neural cell origin?
Transcriptome of the tumour cells was very similar to the transcriptome of schwann cells
Where does DFTD cause tumours?
On the face
How is DFTD transmissible?
Biting during feeding and sex
How does DFTD evade immune detection?
- Has the same MHC alleles as the devils
- Devils show low MHC diversity, probably due to the population bottle neck and due to high levels of inbreeding in fragmented populations
Why did they believe DFTD would not spread from Eastern to Northwestern populations?
As they showed varying MHC alleles
More MHC diversity
Skin allografts were rapidly rejected between the two populations
Did the northwestern devils catch DFTD?
Yes
How did the northwestern devils catch DFTD if skin allografts were rejected?
The DFTD was mutating to develop immune evasion techniques
What methods of immune evasion?
Down regulation of MHC-I to avoid T cell detection (reduced expression of genes associated with antigen processing and expression e.g. TAP1 and TAP2)
Reduced recognition by NK cells
Why was the DFTD observed in the Northwestern populations less virulent?
It was strain 2 which is less virulent and tetraploid
There are different strains of DFTD, different karyotypic strains
Why was strain 2 less virulent?
Tetraploid which means it grows slower as it takes longer to replicate its DNA
As the tumours grow slower the devils live for longer and virulence is reduced
Why is lower virulence associated with directly transmitted diseases unsurprising?
As for directly transmitted diseases there is a transmission-mortality tradeoff. Lower virulence is selected for and expected as it is more likely to be transmitted
What is DFT2?
A second transmissible neoplastic cell line which was discovered
DFT2 origin?
Male devil
DFT1 origin?
Female devil
Discovered of DFT2 showed that?
Multiple transmissible tumours can arise
How can we prevent the extinction of devils?
- Creating captive bred insurance populations
- Developing a vaccine
- Culling of infected devils
Why might we think that DFTD will evolve to become non-harmful?
Due to CTVT in canines, this has almost no virulence
What transmissible tumours were seen in laboratory syrian hamster populations?
Contagious reticulum cell sarcoma
Contagious reticulum cell sarcoma was spread via?
Mosquitos
Social contact
CTVT?
Canine Transmissible Venereal Cancer
CTVT is what type of cancer?
Histiocytic tumour
Where do the tumours grow?
Genitalia
Origin?
Wolf
~11,000 years ago
CTVT spreads via?
Sexual transmission
How does CTVT overcome host immunity?
Developed immune evasion mechanisms:
- Down regulation of MHC
- Production of immunosupressive cytokines
Is CTVT virulent?
Not very virulent
Self-limiting
Regressive
Does CTVT metastasise?
Only in immunosuppressed canines
CTVT is very responsive to?
Chemotherapy
Transmissible cancer in bivalves is?
Haemic cancer
Haemic cancer?
Haemocytes
Leukaemia like
What cancer is CTVT?
Histiocytic tumour
What transmissible cancer is present in bivalves?
Haemic neoplasm
Hamocytes, leukaemia like
How are haemic neoplasms transmitted?
In the water
Via filter feeding
How are they not rejected?
Do not believe they have MHC
Immune systems have yet to be fully characterised
In bivalves the tumours can spread from?
One species to another
Example of spread from one species to another?
Spread from pallet clam to a golden carpet shell clam
The pallet clams are resistant to the?
Haemic neoplasm
Transmissible cancers only occur in humans in which cases?
- Immune suppression due to organ transplant
- From mother to child during development: Placental transmission
In order for placental transmission?
- Mother must have homozygotic HLA loci
- Developing immune system may be tolerized by early exposure
- Deletion of different HLA loci
