CSIM 1.6 Neoplasia 3

Question 1

What is transformation?

What is carcinogenesis?

Answer 1

The cellular changes that enable a cell to form a tumour, carcinogenesis is the molecular process underlying this

Question 2

What are the three types of cells with regard to replication

Which of these are most likely to develop neoplasms?

Answer 2

Permanent cells
Quiescent cells
Continuously cycling cells

Continuously cycling cells

Question 3

What are cyclins?

Answer 3

Cyclin-dependent kinases (CDK) - these fluctuate in a cyclical manner and have difference concentrations in different parts of the cell cycle

Question 4

What happens to cyclins in cancer?

Answer 4

They become abnormally activated due to transformation of cyclin genes into oncogenes

Question 5

What is retinoblastoma protein?

Answer 5

A protein which is a negative regulator of the cell cycle: binds to transcription factors which regulate the genes controlling cyclin levels throughout the cell cycle

It is therefore a tumour suppressor gene

Question 6

What behavioural differences are seen in tumour cells?

Answer 6

• Loss of contact inhibition (most epithelial cells’ division is inhibited when they come into contact with other cells in the layer)
  
  • Reduced cohesion
  • Reduced GF requirement
  • Immortal (no hayflick limit)

Question 7

What is ‘tumour clonality’?

Answer 7

Genetic hypothesis of cancer which states that a tumour mass arises from a single progenitor cell which has incurred repeated genetic damage, therefore most tumours are MONOCLONAL (but still heterogeneous when detectable)

Question 8

What is the evidence for tumour monoclonality?

Answer 8

In women, where one of their two X-chromosomes (let’s say Xa and Xb) is always deactivated randomly, yet all tumours always have only Xa OR Xb chomosomes active

This is tested for by looking at glucose-6-phosphate dehydrogenase isoenzymes, of which there are many variants, all X-linked

Question 9

What factors determine the growth rate of tumours

Answer 9

Cell production speed
Cell loss:
  •  Shedding
  •  Lack of cohesion
  •  Differentiation
  •  Reversion to G0

Question 10

What is ‘growth fraction’?

What are the implications of a high and low growth fraction

Answer 10

The proportion of cells which remain in the proliferating pool

High = rapid course and growth of tumour

Low = slower growth

Question 11

Which growth fraction tumours are often more easily treated?

Answer 11

High growth factor tumours, as chemotherapy is targeted at rapidly dividing cells, and these fast tumours have less time to mutate in more harmful ways

Question 12

What host factors can affect hormone growth?

Answer 12

• Hormones

* Vascular supply

Question 13

The growth of which cancers is affected by host hormones? Which hormones affect each

Answer 13

Breast cancer
  •  Oestrogen
Prostate cancer
  •  Androgens
Uterine leimyosomas 
  •  Oestrogen
Endometrial cancer
  •  Oestrogen

Question 14

Which tumours require vascularisation for further growth?

What does this vascularisation allow the tumours to do?

Answer 14

Those over 1-2mm

• Gain oxygen and nutrients
• Metastasise

Question 15

Through which process can tumours generate their own blood vessels? How do they do this?

Answer 15

Tumour angiogenesis:
• Tumour cells and infiltrating inflammatory cells make angiogenic growth factors
> VEGF
> bFGF

Question 16

Describe what is meant by tumour heterogeneity

Answer 16

Tumours form ‘subclones’ as different cells within the tumour which are genetically unstable acquire different mutations

Question 17

How many cells are there in the following tumours, and how many divisions is needed to reach each?

1) 1g tumour
2) 1kg tumour

Answer 17

1) 10^9 cells, 30 divisions

2) 10^12 cells, 10 further divisions (after 1g tumour)

Question 18

What may occur due to mutations resulting from genetic instability in some subclones

Answer 18

Apoptosis of cells with mutations which make cellular survival inviable (IMG 28)

Question 19

What is the implication of heterogeneity?

Answer 19

Any given treatment is unlikely to treat all subclones of a tumour

Question 20

What do mutations leading to tumours do?

Describe if a mutation in each is dominant or recessive

Answer 20

Activate growth-promoting oncogenes
• Mutations dominant over the normal allele

Inactivate tumour suppressor genes
• Recessive - mutations in both alleles needed for this inactivations

Alterations in genes regulating apoptosis
• Can be recessive or dominant

Changes in DNA repair genes can also occur
• Recessive

Question 21

What viral oncogenes are introduced by cancer-causing retroviruses?

Answer 21

Retroviral transformation gene

Question 22

Where do viral oncogones come from/ how are the developed by the virua?

Answer 22

When a virus infects a host cell, and inserts its DNA into a gene, some of the host’s DNA is incorporated into the protein product, and thus the genetic information of the daughter viruses. If this gene happens to be an oncogene, these viruses may infect another cell and ‘deliver’ that oncogene, thus spreading it around

This is an issue, as cellular oncogenes are usually very tightly controlled, however this process may activate them inappropriately

Question 23

What do cellular oncogenes normally do?

Answer 23

Regulate normal growth and differentiation (but can become inappropriately ‘activated’)

Question 24

Why are cellular oncogene mutations dominant?

Answer 24

They ADD a function (through their inappropriate activation), so only one copy needs to be present