Principles Of Oncogenesis Flashcards
How can mutations occur which increase susceptibility to cancer?
Inherited (germline)
Acquired due to :
— random events
— environmental insults
What types of cancer are Boxers more susceptible to?
Lymphoma
MCT
(+others)
What types of cancer are Flat Coat Retrievers more susceptible to?
Soft tissue sarcomas
What types of cancer are Irish wolfhounds more susceptible to?
Osteosarcomas
What types of cancer are GSDs more susceptible to?
Haemangiosarcomas
How do normal cells become cancerous?
They undergo malignant transformation
What does it mean if a breed has a predisposition to cancer?
There are germ line polymorphism in these breeds
How can hormonal factors influence cancer development in females?
Oestrogen and progesterone (steroid hormones) linked to mammary tumours
How can hormonal factors influence cancer development in males
Androgens linked to prostate carcinomas and peri anal adenomas
What environmental factors can increase the risk of malignant transformation?
Exposure to carcinogens/mutagens
Exposure to mitogens
Exposure to biological agents (oncogenic pathogens)
What are mutagens?
Give examples
Induce mutations in DNA
Chemical agents (organic/inorganic)
Radionuclide
Radiation
What are mitogens?
How can they increase risk of cancer?
Stimulate cell proliferation
Therefore increased risk of random mutation (as increased risk of mistakes when there is an increased DNA copy rate)
What cancer type is associated with UV damage in white cats?
Squamous cell carcinoma
Give some examples of oncogenic pathogens.
Retroviruses (e.g. FeLV)
Poxviruses (e.g. BPV and equine sarcoids)
Helicobacter pylori - gastric carcinoma
What are equine sarcoids?
Cause?
Fibrosarcoma - locally invasive skin tumour
Caused by BPV - only genetically susceptible horses will develop
What are proto-oncogenes?
Genes whose normal function is to promote cell growth/ proliferation, or inhibit apoptosis
When might proto-oncogenes be beneficial during normal physiology?
How are they regulated?
Tissue growth/development, remodelling, or repair
Expression is tightly controlled
When do proto-oncogenes become oncogenes?
Loss of control following mutation
ACCELERATE PROLIFERATION
How can retroviruses be oncogenic?
Inject oncogenes into host cells resulting in malignant transformation
Give some categories of genes which are proto-oncogenes.
Genes for:
Growth Factors
GF-Rs
Signalling molecules
TFs
What are two key tumour suppressor genes?
What is their normal function?
p53 and Rb (retinoblastoma protein)
Act to prevent uncontrolled proliferation through cell cycle arrest or apoptosis
What needs to occur at a genetic level for oncogenesis to occur?
SIMULTANEOUS
Gain of function mutations in oncogenes
AND
Loss of function mutations in tumour suppressor genes
How many mutations must accumulate before a malignant cell can develop into a clinically significant tumour?
Usually 10-12
Outline the multi-stage model of malignant development
- Activation of oncogenes, mutations in tumour suppressor genes
- Cells proliferate
- Mutations inactivate DNA repair genes
- More genetic instability, more mutations accumulate, more malignant potential
What are the original hallmarks of cancer?
Sustaining proliferative signalling Evading growth suppressors Activating invasion and metastasis Enabling replicative immortality Inducing angiogenesis Resisting cell death
What was the goal of initial anti-cancer drugs?
Kill rapidly dividing cells
What is combination chemotherapy?
Attack the cancer on several biological fronts at the same time (targeting different ‘hallmarks’)
What are the advantages of combination chemotherapy?
Reduced dose of each agent required
Less adverse effects on healthy cells as the result of more targeted therapy
What is the major hallmark of cancer?
Sustaining proliferative signalling
What is required for sustaining proliferative signalling?
Cancer cells need to become independent of host regulatory mechanisms and become SELF SUFFICIENT
How can cancer cells become self sufficient?
By:
Making their own growth factors
Altering their receptors
Mutating their signalling molecules
How do growth factors produced by cancer cells act?
give an example
Autocrine and paracrine - drive their own proliferation
Epidermal growth factor (EGF)
How can the receptors of cancer cells be altered to allow them to become self sufficient?
Activating mutations so that receptor is always switched on
- even in absence of ligand
Overexpression of receptors
- respond to relatively low levels of ligand
What is the receptor for stem cell factor?
KIT
What happens when Stem Cell factor binds to KIT?
Receptor tyrosine kinase.
Dimerisation of KIT receptors and transphosphorylation resulting in activation of cell signalling pathways for survival and proliferation
How can a mutation affect the function of KIT?
Mutation in the Juxtamembrane region allows for autophosphorylation and cell signalling for survival and proliferation
IN THE ABSENCE OF LIGAND
- oncogenic -
What is a KIT mutation associated with?
Aggressive mast cell tumours
More likely to be resistant to chemo and relapse
Name to drugs which are RTK inhibitors?
Masitinib (masivet)
Toceranib (Palladia)
How can mutation of signalling molecules result in sustaining proliferative signalling?
Activating mutations switch on proliferation in absence of receptor ligation.
Eg. Ras, Raf (in MAPK pathway involved in cellular proliferation)
(When proteins in the MAPK pathway are mutated, they can be stuck in the ‘on’ or ‘off’ position)
What are two growth suppressor genes?
How can these change to bring about proliferation?
p53, and Rb (Retinoblastoma protein)
Loss of function
Which breed is known to have a germline p53 mutation?
What is the result of this?
Bull Mastiff
predisposed to lymphoid neoplasia e.g. lymphoma
In apoptosis, what are the intrinsic and extrinsic pathways?
Intrinsic:
DNA damage -> p53 -> caspase cascade -> apoptosis
Extrinsic: Death receptor (e.g. Fas ligand) -> caspase cascade -> apoptosis
How does radiotherapy result in apoptosis of cells?
Exploits the intrinsic pathway.
DNA damage results in p53 signalling and caspase cascade
How can cancer cells evolve to avoid apoptosis?
Downregulation of death receptors
Blocking P53 signalling
How do cancer cells avoid senescence?
Telomerase adds new telomeres
— often unregulated in cancer cells
(In normal cells telomeres become eroded after each cell division, and once they have been critically shortened, the cell undergoes apoptosis)
Why is angiogenesis important for tumour support?
Why else may it be beneficial/
Once it reaches a critical size it needs a dedicated blood supply for oxygen and nutrients.
Also convenient for metastasis - can travel via blood to other sites
How do tumour cells induce angiogenesis?
Secrete angiogenic factors
Vascular Endothelial Growth Factor (VEGF)
Why are receptor tyrosine kinase inhibitors effective in reducing angiogenesis?
Give examples of these
VEGF receptor is a RTK.
Masitinib
Toceranib
How are cancer cells adapted to invade local tissues?
Produce matrix metalloproteinases to disrupt surrounding tissue and allow entry.
How are cancer cells adapted to allow metastasis?
Alteration in cell adhesion molecules to detach and migrate
E.g. E-cadherin downregulation in canine mammary tissues
What are the ‘emerging hallmarks’ of cancer?
Deregulation of cellular energetics
Avoiding immune destruction
What are the ‘enabling characteristics’ of cancer cells?
Genome instability and mutation
Tumour-promoting inflammation
How can the immune system detect malignant cells?
Recognition of ‘altered self’ antigen
Altered expression of MHC
How can the immune system respond to malignant cells?
Antibody-mediated attack against surface antigens
CD8 killer T cell destruction
NK cell attack
How can malignant cells evade the immune response?
Downregulate immunogenic antigens
Produce immunosuppressive mediators
Induce tolerance
Kill tumour infiltrating lymphocytes
How might inflammatory cells paradoxically enhance malignancy?
Immunosuppressive cytokines
Growth factors
Angiogenic mediators
