Principles of Oncogenesis

Question 1

What does neoplastic disease often occur as a result of?

Answer 1

Interactions between genetics and environmental factors

Inherited genetic mutations

Exposure to environmental carcinogens can induce mutations

Question 2

What are environmental mitogen?

Answer 2

Stimulate cell proliferation and promote oncogenesis but done stimulate mutation

Question 3

What are oncogenes?

Answer 3

Genes which when inappropriately activated, contribute to the formation of a tumour.

In normal cells they are tightly controlled, but mutation can result in loss of regulation.

Question 4

What are proto-oncogenes?

Answer 4

Genes whose normal function is to promote cell growth/proliferation/inhibition of apoptosis

Important for tissue development, remodelling and repair

Expression = usually tightly controlled

Question 5

When does an oncogene become a proto-oncogene?

Answer 5

Loss of control of oncogene gene expression following mutation.

Leads to accelerated proliferation.

Question 6

How do some viruses induce malignant transformation, give an example…

Answer 6

Express oncogenes that deliberately induce malignant transformation after infection of host

e.g. retroviruses (FeLV)

Question 7

What are tumour suppressor genes? Give examples…

Answer 7

Produce proteins that normally act to prevent cells from proliferating out of control.

eg. Rb, p53

For tumour suppressor function to be lost, both copies of the gene need to be mutated, deleted, silenced.

Question 8

What induces dysregulation gene expression?

Answer 8

Chromosomal rearrangements e.g. c-myc

Question 9

What is required for a clinically significant tumour to develop?

Answer 9

Accumulation of several different mutations (at least 10-12)

Need cumulative mutations in several oncogenes and tumour suppressor genes

Question 10

Which dog breeds are predisposed to which cancers?

Answer 10

Boxers
- Lymphoma, MCT

Flat coat retrievers
- Soft tissue sarcoma

Irish wolfhound
- Osteosarc

GSD
- Haemangiosarcoma

Question 11

What are the hallmarks of cancer?

Answer 11

1. Sustaining proliferative signaling
2. Evading growth suppressors
3. Activating invasion and metastasis
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Resisting cell death

Question 12

How can malignant cells of cancer become self sufficient in terms of growth signals?

Answer 12

1) Secretion of endogenous growth factors that act in autocrine/paracrine manner
2) Mutation of growth factor receptors
3) Mutation of intracellular signalling molecules eg. Ras and Rad activates MAPK pathway

Question 13

Give example of growth factor receptor mutation…

Answer 13

KIT receptor mutation in canine mast cell tumour means receptor activation without ligand

Leads to more aggressive form of disease

Question 14

What cancer treatment can we use to overcome mutation of growth factor receptors?

Answer 14

Receptor tyrosine kinase inhibitors to inhibit signalling.

Question 15

How do Rb proteins work?

Answer 15

Transduces growth inhibitory signals that originate outside of the cell and determines whether or not cell cycle progression should proceed

Question 16

How does p53 work?

Answer 16

Recieves input from intracellular operating systems. If cell viability is suboptimal, it halts cell cycle progression.

In the face of overwhelming cell damage, p53 can actively trigger apoptosis.

Question 17

What are the 2 major circuits for apoptosis?

Answer 17

1) Extrinsic pathway = receiving and processing extracellular death inducing signals (death receptors induce caspase cascade)
2) Intrinsic pathway = sensing and integrating variety of signals of intracellular origin (induces caspase cascade)

Cancer cells can inhibit action of death receptors and p53 driven intrinsic pathways. Means we need higher levels of cytotoxic drug.

Question 18

What is replicative senescence?

Answer 18

Normally cells are only able to replicate a limited number of times before becoming non viable

Telomeres protect the end of chromosomes

Erosion of telomeres occurs with every division

Once they become critically shortened = no more mitosis and apoptosis

Question 19

What is telomerase? How present is it in healthy tissues?

Answer 19

Specialised DNA polymerase that adds telomere repeat segments to ends of DNA.

Almost absent in healthy tissue cells, but unregulated in vast majority of malignant cells.

Question 20

Cancer treatment for tackling malignant cells ability to enable replicative immortality…

Answer 20

Telomerase inhibitors in clinical trials at the moment.

Question 21

What is a tumour at risk of once it reaches a critical size?

Answer 21

Hypoxia-induced cellular necrosis.

Therefore requires a dedicated blood supply in order to continue growing.

Question 22

How do tumours induce angiogenesis?

Answer 22

Secrete angiogenic factors eg. Vascular Endothelial Growth Factor.

Acts on adjacent vascular endothelial cells to stimulate development of new blood vessels into tumour.

Supplies it with oxygen and nutrients.

Question 23

Cancer treatment to target tumour’s ability to induce angiogenesis…

Answer 23

VEGF receptor is a receptor tyrosine kinase, so inhibitors have place in preventing tumour angiogenesis

If it cannot go through angiogenesis, tumour is small and benign

Question 24

What does metastasis usually start with?

Answer 24

Local invasion then intravasation by cancer cells into nearby lymph/blood vessels.

They disseminate via lymphatic or haematogenous routes.

Question 25

What are matrix metalliproteinases?

Answer 25

Enzymes produced by tumour cells which disrupt local tissues allowing invasion by cancer cells.

Question 26

What changes can cancer cells make to cell adhesions?

Answer 26

Influence the expression of cell adhesion molecules

Alters ability of cells to attach to each other and the ECM

Can enhance metastasis

eg. E-cadherin loss allows mammary carcinoma cells to travel around the body

Question 27

Describe how dysregulation of cellular energy can allow malignant cells to survive…

Answer 27

Cancer cells re-programme glucose metabolism and therefore energy production

Limit metabolism to glycolysis

Upregulate GLUT1 transporters for more efficient uptake of glucose into malignant cells

Question 28

Describe how malignant cells evade immune destruction

Answer 28

Downregulate immune effector mechanisms or induce immunological tolerance

Can kill tumour infiltrating lymphocytes and produce immunosuppressive agents

Question 29

Cancer treatments to target cancer cell immune evasion…

Answer 29

Monoclonal antibodies

Anticancer vaccines

Question 30

How do cencer cells increase the rate of mutation?

Answer 30

Increased sensitivity to mutagenic agents through breakdown in one or several components of genome maintenance machinery/both.

Question 31

How can migration of immune cells into tumours be counterproductive?

Answer 31

Infiltraying cells can enhance tumorigenesis

Supplying bioactive molecules
+ Growth factors
+ Angiogenic cytokines
+ Immunosuppressive mediators

Question 32

How do anti-inflammatory drugs target tumour promoting inflammation?

Answer 32

COX-2 inhibitors/aspirin can be helpful in treating certain types of cancer by preventing inflammation.

Question 33

Examples of cancer treatments targeting each hallmark of cancer….

Answer 33

Sustaining proliferative signaling = EGFR inhibitors

Evading growth suppressors = Cyclin-dependent kinase inhibitors

Avoiding immune destruction = Immune activating anti-CTLA4 MAb

Enabling replicative immortality = Telomerase inhibitors

Tumour promoting inflammation = Selective anti-inflammatory drugs

Activating invasion and metastasis = Inhibitors of HGF/c-Met

Inducing angiogenesis = Inhibitors of VEGF signaling

Genome instability and mutation = PARP inhibitors

Resisting cell death = Pro-apoptotic BH3 mimetics

Deregulating cellular energetics = Aerobic glycolysis inhibitors