Principles of Oncogenesis Flashcards
Which breed is specifically predisposed to neoplasia? Which types?
Boxers - lymphoma, MCT and others
What neoplasia are flat coated retrievers predisposed to?
Soft tissue sarcoma
What neoplasia are irish wolf hounds predisposed to?
OSteosarcoma
What neoplasia are GSDs predisposed to?
Haemagniosarcoma
How may hormones impact neoplasias?
- male v female
- oestrogens and progesterones affect mammary tumours
- androgens drive prostate tumours and perianal adenoma
What is the difference between mutagens and mitogens?
- mutagens or carcinogens induce mutatiosn
- mitogens stimulate cell proliferation and increase the risk of a random mutation
Which viruses are assicated with neoplasia?
- retro virus eg. FeLV
- pox virus eg. BPV and equine sarcoids
Which bacteri are associated with neoplasia?
Helicobacter pylori and gastric ulcers -> carcinoma
How do proto-oncogenes differ to oncogenes?
- proto-oncogenes are normal and stimulate cell division
- oncogenes are abnorma and result from a loss of control following mutation (some viruses contain oncogenes in their genome)
What molecules are potentially oncogenic?
Any proteins in the normal cell growth control pathway
Give 2 tumour suppressor genes
p53 and Rb
- cell cycle arrest and programmed cell death
What kind of mutations must happen to oncogenes and tumour suppressor genes respetively to cause neoplasia?
- gain of function to oncogenes
- loss of function to tumour supressors
What are the 3 stages of the mutli stage model of neoplasia?
Initiation, promotion, progression
What are the 6 traditional “hallmarks” of cancer?
- ressiting cell death
- sustaining proliferative signalling
- evading growth supressors
- activating invasion and metastasis
- enabling replicative immortallity
- inducing angiogenesis
How many copies of the tumour suppressor genes must be mutated before their function is lost?
Both
How may neoplastic cells become self sufficient in sustained proliferative signalling?
- sectrecting endogenous growth factors -> autocrine/paracrine
- mutating growth factor receptors so they are active in the abscence of any ligand or overexpressed to make them more sensitive eg. KIT mutation in canine MCT
- mutating intracellular signalling pathways eg. activating mutations in Ras and Raf
How does the KIT gene mutation affect dogs?
- ^ severity of MCT diseaese with KIT mutation which allows receptor to autophoshorylate
- stem cell factor acts on KIT-R, and is required for mast cell survical
What mutation are bull mastiffs predisposed to?
p53 -> ^ risk lymphoid neoplasia
Hoiw does Rb work?
transduces growth-inhibitory signals that originate outside of cell
- can stop cell cycle progression
How does p53 work?
input from intrcellular operating systems
- can stop cell ccycle and trigger apoptosis
How does apoptosis ultimately occour?
Caspase cascade
What two pathways may lead to cell death and how do neoplastic cells avoid these pathways?
- Intrinsic and extrinsic pathways
- neoplastic cells downregulate “death receptors” to ignore extrinsic pathway
- upregulate Bcl-2 family [why??]
What is responsible for replicative senecence?
Telmomeres
What enzyme adds telomeres onto chromosomes? What type of enzyme is this?
- Telomerase
- a DNA polymerase
- absent in healthy tissue but upregulated in malignant cells
Eg. of an angiogenic factor
VEGF (vascular endothelial growth factor)
- supplies tumour with oxygen and nutrients and ^ risk metastasis
How may RTK inhibitors work on tumours other than MCTs?
inhibiting VEGF
How do neoplastic cells invade and metastasise?
- local invasion using matrix metalloproteinases
- intravasation -> nearby LNs or blood vessels by atering cel adhesion molecules to ^ metastatic potential eg. loss of E-cadherin by carcinoma cells.
- dissemination via lymphatics or haematogenous
- extravasation into other tissues
What are the 4 emerging hallmarks and enabling characteristcs?
Emerging hallmarks - deregulating cellular energetics - avoiding immune destrcution Enabling characteristics - genome instability and mutation - tumour promoting inflammation
How do neoplastic cells deregulate cellular energy metabolis?
- re-programme glucose metabolism
- use glycolysis only (cf. oxidative phosphorylation)
- upregulation of GLUT1 receptors for more efficient glucose uptake
Which cells are cpable of destroying neoplasia?
- antibody and CD8+ T killer cells (not-self antigen)
- NK cells (upregulated MHC)
How do neoplastic cells ensure genome instability and mutations occour at a high rate?
- ^ sensitivity to mutagenic agents
- breakdown of genome maintainance machinery
What paradoxical response of the body actually aids neopalstic growth?
Inflammation - provides growth factors, angiogenic cytokines and immunosupressive mediators
How do tumours evade the immune system?
- downreg immunogenic antigens
- kill infiltrating lymphocytes
- produce immunosupressive mediators
- induce tolerance
Which NSAIDs can be used therapeutically as anti-cancer?
- peroxicam (COX-2 blocker) for bladder cancer
- Aspriin for bowel cancer
What is oncept and oncept IL2?
- oncept canine melanoma vax
- oncept IL2 - immune modulator for injection iste fibrosarcoma
