Molecular Pathology of Tumours

Question 1

What is the multi step process that leads to metastasis?

Answer 1

Normal
I
V
Dysplasia - some loss of stratification - immature cells escape from basal layer
I
V
Carcinoma in situ - total loss of stratification, immature cells throughout basement membrane are intact
I
V
Invasion - Erosion of basement membrane, tumour gains access to vascular channels
I
V
(Cells escape from tumour via lymphatics etc)
I
V
Metastasis - secondary tumour (in lymph node etc)

Question 2

If tumour cells have a clonal origin, how do different kinds of tumour cell (nonantigenic, invasive, etc) exist in the same tumour?

Answer 2

Some cell lines of the clone will have variants, which will form their own cell lines

Question 3

What happens in oncogene activation and tumour suppressor gene inactivation?

Answer 3

Neoplasia

Question 4

What are oncogenes?

Answer 4

• Drivers of neoplastic behaviour

* Proto-oncogenes undergo a single mutation event to create oncogenes

Question 5

What kind of genes/genetic events have the potential to become oncogenic?

Answer 5

Coding sequences

Gene amplification

Chromosome rearrangement

Question 6

What can oncogenes do?

Answer 6

• Growth factor – sis, fibrosarcoma
• Growth factor receptor - HER2, breast cancer
• Signal transducer – ras, colon cancer
• Transcription factor - myc, Burkitt’s lymphoma

Question 7

How do oncogenes work?

Answer 7

A Direct stimulation of cell cycle dependent transcription
B Increased/activation of growth factor receptors
C Increased growth factor
D Interference with intracellular signalling

Question 8

What is a dominant mutation?

Answer 8

A mutation that causes a gain of function

Question 9

What is a recessive mutation?

Answer 9

A mutation that causes loss of function

Question 10

How are tumour suppressor genes inactivated?

Answer 10

Both copies of the tumour suppressor genes have to be mutated in two separate events on each chromosome

Question 11

What hypothesis posits to explain the cause of retinoblastoma?

Answer 11

Knudson’s two hit hypothesis

Question 12

Why does mutating Rb drive carcinogenesis?

Answer 12

Inactive Rb does not end to E2F on the DNA thus activating the protein. This will then cause the activation of the expression of the S-phase of the cell cycle

Question 13

What do gatekeepers do?

Answer 13

• Inhibit proliferation or promote the death of cells, especially those with DNA damage
• Send negative signals to the cell

Question 14

What do caretakers do?

Answer 14

• Maintain integrity of the genome by promoting DNA repair
• Nucleotide excision repair
• Mismatch repair
• DNA double strand break repair

Question 15

Name a gatekeeper

Answer 15

p53

Question 16

What does gatekeeper p53 do to a cell that has been mutated?

Answer 16

If active, it will repair the mutation or cause apoptotic cell death

Question 17

How often is p53 mutated?

Answer 17

p53 is frequently mutated in a wide range of different tumours

Most notably cancers of the ovary and oesophagus

Question 18

What does p53 do in the face of a lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia or blockage of transcription?

Answer 18

Cell cycle arrest leading to senescence or return to proliferation

DNA repair

Block of angiogenesis

Apoptosis

Question 19

What impact does a variation of the rate of apoptosis have on homeostasis and what does it balance?

Answer 19

Normal cell division and decreased apoptosis creates a tumour just as increased cell division and normal apoptosis does.

Question 20

What tumours are BCL-2 linked to?

Answer 20

Follicular lymphoma - Leads to overproduction of antibodies

Question 21

What limits ability to replicate?

Answer 21

The generational reduction in telomeric DNA

Question 22

What does introduction of telomerase to cells in culture do?

Answer 22

Immortalise them - ‘Immortal life of Henrietta Lacks’

Question 23

What is the angiogenesis signalling cascade?

Answer 23

Cancer cell releases VEGF (or bFGF)

This binds to receptor protein on endothelial cell surface

It is then passed through relay proteins to nucleus

Genes are activated in cell nucleus

Proteins stimulate new endothelial cell growth

Question 24

How can one recognise a blood network affected by tumours?

Answer 24

It has no, or only residual, structure found in the arterioles -> capillaries -> venules of a normal mature network

Is just a big mess inappropriate to location

Question 25

How do tumour cells in the bloodstream/lymphatics form a metastasis?

Answer 25

Cells released into the bloodstream will travel to a site where they will adhere to the vessel wall
Only 1 in 1000 will survive to form metastasis

They will then escape from the blood vessel and enter whatever structure the vessel supplies to form a micrometastasis

They will then proliferate and colonise to form a full blown metastasis

Question 26

How do tumour cells penetrate the basal lamina?

Answer 26

A. Loosening of intercellular junctions
- Tumor cells detach from each other because of reduced adhesiveness

B. Attachment
- Cells then attach to the basement membrane via the laminin receptors

C. Degradation
- Cells secrete proteolytic enzymes, including type IV collagenase and plasminogen activator

D. Migration
- Degradation of the basement membrane and tumor cell migration follow.

Question 27

What are the ‘7 deadly sins’ of tumour growth?

Answer 27

•Self-sufficiency in growth signals 
•Insensitivity to growth-inhibitory
signals
•Evasion of apoptosis
•Defects in DNA repair
•Limitless replicative potential •Sustained angiogenesis
•Ability to invade and metastasise