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BVetMed3 POS - Principles Of Oncology > Principles Of Oncogenesis > Flashcards

Principles Of Oncogenesis Flashcards

1
Q

How can mutations occur which increase susceptibility to cancer?

A

Inherited (germline)
Acquired due to :
— random events
— environmental insults

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2
Q

What types of cancer are Boxers more susceptible to?

A

Lymphoma
MCT
(+others)

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3
Q

What types of cancer are Flat Coat Retrievers more susceptible to?

A

Soft tissue sarcomas

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4
Q

What types of cancer are Irish wolfhounds more susceptible to?

A

Osteosarcomas

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5
Q

What types of cancer are GSDs more susceptible to?

A

Haemangiosarcomas

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6
Q

How do normal cells become cancerous?

A

They undergo malignant transformation

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7
Q

What does it mean if a breed has a predisposition to cancer?

A

There are germ line polymorphism in these breeds

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8
Q

How can hormonal factors influence cancer development in females?

A

Oestrogen and progesterone (steroid hormones) linked to mammary tumours

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9
Q

How can hormonal factors influence cancer development in males

A

Androgens linked to prostate carcinomas and peri anal adenomas

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10
Q

What environmental factors can increase the risk of malignant transformation?

A

Exposure to carcinogens/mutagens
Exposure to mitogens
Exposure to biological agents (oncogenic pathogens)

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11
Q

What are mutagens?

Give examples

A

Induce mutations in DNA

Chemical agents (organic/inorganic)
Radionuclide
Radiation

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12
Q

What are mitogens?

How can they increase risk of cancer?

A

Stimulate cell proliferation

Therefore increased risk of random mutation (as increased risk of mistakes when there is an increased DNA copy rate)

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13
Q

What cancer type is associated with UV damage in white cats?

A

Squamous cell carcinoma

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14
Q

Give some examples of oncogenic pathogens.

A

Retroviruses (e.g. FeLV)
Poxviruses (e.g. BPV and equine sarcoids)
Helicobacter pylori - gastric carcinoma

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15
Q

What are equine sarcoids?

Cause?

A

Fibrosarcoma - locally invasive skin tumour

Caused by BPV - only genetically susceptible horses will develop

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16
Q

What are proto-oncogenes?

A

Genes whose normal function is to promote cell growth/ proliferation, or inhibit apoptosis

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17
Q

When might proto-oncogenes be beneficial during normal physiology?

How are they regulated?

A

Tissue growth/development, remodelling, or repair

Expression is tightly controlled

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18
Q

When do proto-oncogenes become oncogenes?

A

Loss of control following mutation

ACCELERATE PROLIFERATION

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19
Q

How can retroviruses be oncogenic?

A

Inject oncogenes into host cells resulting in malignant transformation

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20
Q

Give some categories of genes which are proto-oncogenes.

A

Genes for:

Growth Factors
GF-Rs
Signalling molecules
TFs

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21
Q

What are two key tumour suppressor genes?

What is their normal function?

A

p53 and Rb (retinoblastoma protein)

Act to prevent uncontrolled proliferation through cell cycle arrest or apoptosis

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22
Q

What needs to occur at a genetic level for oncogenesis to occur?

A

SIMULTANEOUS
Gain of function mutations in oncogenes
AND
Loss of function mutations in tumour suppressor genes

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23
Q

How many mutations must accumulate before a malignant cell can develop into a clinically significant tumour?

A

Usually 10-12

24
Q

Outline the multi-stage model of malignant development

A
  1. Activation of oncogenes, mutations in tumour suppressor genes
  2. Cells proliferate
  3. Mutations inactivate DNA repair genes
  4. More genetic instability, more mutations accumulate, more malignant potential
25
Q

What are the original hallmarks of cancer?

A 
Sustaining proliferative signalling 
Evading growth suppressors 
Activating invasion and metastasis 
Enabling replicative immortality 
Inducing angiogenesis 
Resisting cell death
26
Q

What was the goal of initial anti-cancer drugs?

A

Kill rapidly dividing cells

27
Q

What is combination chemotherapy?

A

Attack the cancer on several biological fronts at the same time (targeting different ‘hallmarks’)

28
Q

What are the advantages of combination chemotherapy?

A

Reduced dose of each agent required

Less adverse effects on healthy cells as the result of more targeted therapy

29
Q

What is the major hallmark of cancer?

A

Sustaining proliferative signalling

30
Q

What is required for sustaining proliferative signalling?

A

Cancer cells need to become independent of host regulatory mechanisms and become SELF SUFFICIENT

31
Q

How can cancer cells become self sufficient?

A

By:

Making their own growth factors

Altering their receptors

Mutating their signalling molecules

32
Q

How do growth factors produced by cancer cells act?

give an example

A

Autocrine and paracrine - drive their own proliferation

Epidermal growth factor (EGF)

33
Q

How can the receptors of cancer cells be altered to allow them to become self sufficient?

A

Activating mutations so that receptor is always switched on
- even in absence of ligand

Overexpression of receptors
- respond to relatively low levels of ligand

34
Q

What is the receptor for stem cell factor?

A

KIT

35
Q

What happens when Stem Cell factor binds to KIT?

A

Receptor tyrosine kinase.

Dimerisation of KIT receptors and transphosphorylation resulting in activation of cell signalling pathways for survival and proliferation

36
Q

How can a mutation affect the function of KIT?

A

Mutation in the Juxtamembrane region allows for autophosphorylation and cell signalling for survival and proliferation
IN THE ABSENCE OF LIGAND

  • oncogenic -
37
Q

What is a KIT mutation associated with?

A

Aggressive mast cell tumours

More likely to be resistant to chemo and relapse

38
Q

Name to drugs which are RTK inhibitors?

A

Masitinib (masivet)

Toceranib (Palladia)

39
Q

How can mutation of signalling molecules result in sustaining proliferative signalling?

A

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)

40
Q

What are two growth suppressor genes?

How can these change to bring about proliferation?

A

p53, and Rb (Retinoblastoma protein)

Loss of function

41
Q

Which breed is known to have a germline p53 mutation?

What is the result of this?

A

Bull Mastiff

predisposed to lymphoid neoplasia e.g. lymphoma

42
Q

In apoptosis, what are the intrinsic and extrinsic pathways?

A

Intrinsic:
DNA damage -> p53 -> caspase cascade -> apoptosis

Extrinsic:
Death receptor (e.g. Fas ligand) -> caspase cascade -> apoptosis
43
Q

How does radiotherapy result in apoptosis of cells?

A

Exploits the intrinsic pathway.

DNA damage results in p53 signalling and caspase cascade

44
Q

How can cancer cells evolve to avoid apoptosis?

A

Downregulation of death receptors

Blocking P53 signalling

45
Q

How do cancer cells avoid senescence?

A

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)

46
Q

Why is angiogenesis important for tumour support?

Why else may it be beneficial/

A

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

47
Q

How do tumour cells induce angiogenesis?

A

Secrete angiogenic factors

Vascular Endothelial Growth Factor (VEGF)

48
Q

Why are receptor tyrosine kinase inhibitors effective in reducing angiogenesis?

Give examples of these

A

VEGF receptor is a RTK.

Masitinib
Toceranib

49
Q

How are cancer cells adapted to invade local tissues?

A

Produce matrix metalloproteinases to disrupt surrounding tissue and allow entry.

50
Q

How are cancer cells adapted to allow metastasis?

A

Alteration in cell adhesion molecules to detach and migrate

E.g. E-cadherin downregulation in canine mammary tissues

51
Q

What are the ‘emerging hallmarks’ of cancer?

A

Deregulation of cellular energetics

Avoiding immune destruction

52
Q

What are the ‘enabling characteristics’ of cancer cells?

A

Genome instability and mutation

Tumour-promoting inflammation

53
Q

How can the immune system detect malignant cells?

A

Recognition of ‘altered self’ antigen

Altered expression of MHC

54
Q

How can the immune system respond to malignant cells?

A

Antibody-mediated attack against surface antigens

CD8 killer T cell destruction

NK cell attack

55
Q

How can malignant cells evade the immune response?

A

Downregulate immunogenic antigens

Produce immunosuppressive mediators

Induce tolerance

Kill tumour infiltrating lymphocytes

56
Q

How might inflammatory cells paradoxically enhance malignancy?

A

Immunosuppressive cytokines

Growth factors

Angiogenic mediators

BVetMed3 POS - Principles Of Oncology (5 decks)

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