Principles of Oncogenesis

Question 1

Which breed is specifically predisposed to neoplasia? Which types?

Answer 1

Boxers - lymphoma, MCT and others

Question 2

What neoplasia are flat coated retrievers predisposed to?

Answer 2

Soft tissue sarcoma

Question 3

What neoplasia are irish wolf hounds predisposed to?

Answer 3

OSteosarcoma

Question 4

What neoplasia are GSDs predisposed to?

Answer 4

Haemagniosarcoma

Question 5

How may hormones impact neoplasias?

Answer 5

• male v female
• oestrogens and progesterones affect mammary tumours
• androgens drive prostate tumours and perianal adenoma

Question 6

What is the difference between mutagens and mitogens?

Answer 6

• mutagens or carcinogens induce mutatiosn

- mitogens stimulate cell proliferation and increase the risk of a random mutation

Question 7

Which viruses are assicated with neoplasia?

Answer 7

• retro virus eg. FeLV

- pox virus eg. BPV and equine sarcoids

Question 8

Which bacteri are associated with neoplasia?

Answer 8

Helicobacter pylori and gastric ulcers -> carcinoma

Question 9

How do proto-oncogenes differ to oncogenes?

Answer 9

• 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)

Question 10

What molecules are potentially oncogenic?

Answer 10

Any proteins in the normal cell growth control pathway

Question 11

Give 2 tumour suppressor genes

Answer 11

p53 and Rb

- cell cycle arrest and programmed cell death

Question 12

What kind of mutations must happen to oncogenes and tumour suppressor genes respetively to cause neoplasia?

Answer 12

• gain of function to oncogenes

- loss of function to tumour supressors

Question 13

What are the 3 stages of the mutli stage model of neoplasia?

Answer 13

Initiation, promotion, progression

Question 14

What are the 6 traditional “hallmarks” of cancer?

Answer 14

• ressiting cell death
• sustaining proliferative signalling
• evading growth supressors
• activating invasion and metastasis
• enabling replicative immortallity
• inducing angiogenesis

Question 15

How many copies of the tumour suppressor genes must be mutated before their function is lost?

Answer 15

Both

Question 16

How may neoplastic cells become self sufficient in sustained proliferative signalling?

Answer 16

• 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

Question 17

How does the KIT gene mutation affect dogs?

Answer 17

• ^ 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

Question 18

What mutation are bull mastiffs predisposed to?

Answer 18

p53 -> ^ risk lymphoid neoplasia

Question 19

Hoiw does Rb work?

Answer 19

transduces growth-inhibitory signals that originate outside of cell
- can stop cell cycle progression

Question 20

How does p53 work?

Answer 20

input from intrcellular operating systems

- can stop cell ccycle and trigger apoptosis

Question 21

How does apoptosis ultimately occour?

Answer 21

Caspase cascade

Question 22

What two pathways may lead to cell death and how do neoplastic cells avoid these pathways?

Answer 22

• Intrinsic and extrinsic pathways
• neoplastic cells downregulate “death receptors” to ignore extrinsic pathway
• upregulate Bcl-2 family [why??]

Question 23

What is responsible for replicative senecence?

Answer 23

Telmomeres

Question 24

What enzyme adds telomeres onto chromosomes? What type of enzyme is this?

Answer 24

• Telomerase
• a DNA polymerase
• absent in healthy tissue but upregulated in malignant cells

Question 25

Eg. of an angiogenic factor

Answer 25

VEGF (vascular endothelial growth factor)

- supplies tumour with oxygen and nutrients and ^ risk metastasis

Question 26

How may RTK inhibitors work on tumours other than MCTs?

Answer 26

inhibiting VEGF

Question 27

How do neoplastic cells invade and metastasise?

Answer 27

• 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

Question 28

What are the 4 emerging hallmarks and enabling characteristcs?

Answer 28

Emerging hallmarks 
- deregulating cellular energetics
- avoiding immune destrcution
Enabling characteristics
- genome instability and mutation 
- tumour promoting inflammation

Question 29

How do neoplastic cells deregulate cellular energy metabolis?

Answer 29

• re-programme glucose metabolism
• use glycolysis only (cf. oxidative phosphorylation)
• upregulation of GLUT1 receptors for more efficient glucose uptake

Question 30

Which cells are cpable of destroying neoplasia?

Answer 30

• antibody and CD8+ T killer cells (not-self antigen)

- NK cells (upregulated MHC)

Question 31

How do neoplastic cells ensure genome instability and mutations occour at a high rate?

Answer 31

• ^ sensitivity to mutagenic agents

- breakdown of genome maintainance machinery

Question 32

What paradoxical response of the body actually aids neopalstic growth?

Answer 32

Inflammation - provides growth factors, angiogenic cytokines and immunosupressive mediators

Question 33

How do tumours evade the immune system?

Answer 33

• downreg immunogenic antigens
• kill infiltrating lymphocytes
• produce immunosupressive mediators
• induce tolerance

Question 34

Which NSAIDs can be used therapeutically as anti-cancer?

Answer 34

• peroxicam (COX-2 blocker) for bladder cancer

- Aspriin for bowel cancer

Question 35

What is oncept and oncept IL2?

Answer 35

• oncept canine melanoma vax

- oncept IL2 - immune modulator for injection iste fibrosarcoma