Principles of Oncogenesis

Question 1

What is neoplasia usually the interaction between?

Answer 1

Environmental and genetic factors

Question 2

List some biologic agents that are oncogenic pathogens

Answer 2

Retroviruses (FeLV) - express oncogenes
Poxviruses (BPV and equine sarcoids)
Others (Helicobacter pylori and gastric carcinoma)

Question 3

List examples of environmental carcinogens

Answer 3

Chemical
Radionucleic
Radiation

Question 4

What is a mitogen?

Answer 4

Causes cell proliferation

Question 5

Define oncogene

Answer 5

contribute to formation of a cancer when inappropriately activated

Question 6

What does activating/gain of function mutation of proto-oncogenes cause?

Answer 6

promote proliferation, inhibit apoptosis or both

Question 7

Name 2 tumour suppressor genes

Answer 7

Rb and p53
Normally act to prevent cells proliferating out of control
For function to be lost, both copies of the gene need to be mutated/deleted/silenced

Rb - transduces growth-inhibitory signals that originate largely outside the cell and determines whetherh or not cell cycle progression should proceed.

p53 - receives input from intracellular operating systems, such that if cell viability is suboptimal, it calls a halt to cell cycle progression, until such time as these new conditions have been normalised. Can also trigger apoptosis.

Question 8

What can increase susceptibility to malignant transformation?

Answer 8

insertion, deletion, chromosomal rearrangement or missense mutation of:
oncogenes or tumour suppressor genes

Question 9

What is the multi-step carcinogenesis model?

Answer 9

Initiation
Promotion
Progression

These depend on accumulation of several different mutations (usually at least 10-12). Thus, cumulative mutations in several oncogenes and tumour suppressor genes are required before a clinically significant tumour can develop.

Question 10

What are the Hallmarks of Cancer (Hanahan and Weinberg)? 6

Answer 10

Sustaining proliferative signalling
Evading growth suppressors
Activating invasion and metastases
Enabling replicative immorality
Inducing angiogenesis
Resisting cell death

Question 11

What tumours do the sex hormones predispose to?

Answer 11

Oestrogen/progesterone - mammary tumours

Androgens - prostatic carcinoma and perianal adenoma

Question 12

List some common breed predispositions

Answer 12

Boxers - lymphoma, MCT, others
Flat coated retrievers - STS
Irish Wolfhound - OSA
GSD - HSA

Question 13

How can sustaining proliferative signalling be achieved by tumour cells? 3

Answer 13

Secretion of endogenous growth factors
Mutation of growth factor receptors
Mutation of intracellular signalling molecules

Question 14

Outline MCT and KIT mutations.

How does this affect novel treatment?

Answer 14

N.b. KIT is a RTK

Mast cells normally rely on stem cell factor (SCF) to survive and this acts through the KIT pathway. In these tumours, there is a mutation in the juxtamembrane portion of the RTK-R meaning that the KIT pathway is constitutively active.

NOVEL TREATMENT: RTK inhibitors include:
Toceranib and Masitibib
(Secondary effect of also inhibiting angiogenesis)

Question 15

How can tumour cells resist cell death? 2

Answer 15

EXTRINSIC PATHWAY - receives and processes EC death-inducing signals

INTRINSIC PATHWAY - sensing and integrating variety of singals of intracellular membrane

Each culminates in the activation of the Caspase cascade –> apoptosis.

Many cancer cells downregulate death receptors or upregulate members of the Bcl-2 family to this end. This can also provide some resistance to cytotoxic anti-cancer drugs

Question 16

Define combination chemotherapy

Answer 16

Modern treatment technique

Attack the cancer on several biological fronts simultaneously

Question 17

How do tumour cells enable replicative immortality?

Answer 17

Telomerase is upregulated in the vast majority of malignant cells –> immortality. THis is a specialised DNA polymerase that adds telomere repeat segments to the ends of DNA

Question 18

How do tumours induce angiogenesis?

Answer 18

Many tumours secrete angiogenic factors (VEGF)

Question 19

How do tumour cells invade tissues and metastasise? 2

Answer 19

Produce MMPs

Alter cell adhesion molecules to detach and migrate (e.g. loss of E-cadherin by carcinoma cells)

Question 20

Name 2 emerging hallmarks of cancer

Answer 20

Deregulating cellular energetic/reprogramming energy metabolism

Evading immune detection

Question 21

How do tumour cells alter their energy metabolism?

Answer 21

Re-programme their glucose metabolism (limiting metabolism largely to glycolysis rather than mitochondrial oxidative phosphorylation which is achieved in a number of ways such as upregulating GLUT1 transports for more efficient glucose uptake)

Question 22

How do tumour cells evade immune destruction?

Answer 22

WHAT?
Avoid immunosurveillance
Downregulate immune effector mechanisms
Induce immunological tolerance

HOW?
downregulating immunogenic Ags
Kill tumour-infiltrating WBCs
Produce immunosuppressive mediators
Induce tolerance

Question 23

What are the 2 new enabling characteristics of cancer?

Answer 23

Genome instability and mutation

Tumour-promoting inflammation

Question 24

How do tumour cells become genetically unstable? 3

Answer 24

increased sensitivity to mutagenic agents

breakdown in one or several components of the genome maintenance machinery

both

Question 25

Does inflammation aid or hinder inflammation?

Answer 25

Infiltrating inflammatory cells enhance tumourigenesis. Thus inflammation may paradoxically enhance the malignant potential of the tumour by supplying bioactive molecules (GFs, angiogenic mediators and immunosuppressive cytokines)

Question 26

List 2 examples of where anti-inflammatory drugs have been used against cancer.

Answer 26

COX-2 inhibitors -decrease risk of bladder cancer

ASPIRIN - prevent bowel cancer