Brain Tumours and Cancer Stem Cells

Question 1

Are all brain tumours malignant?

Answer 1

No, but they are likely to be life threatening due to they location.

Question 2

Are brain tumours more common in children or adults?

Answer 2

Children

Question 3

What are the cells of the central nervous system?

Answer 3

Glial cells and Neuronal cells

Question 4

What are Gliomas?

Answer 4

Gliomas are tumours that originate from the glial cells of the brain. Astrocytomas and Oligodendrocytomas.

Question 5

Why do adults not usually develop neuronal tumours?

Answer 5

By adulthood most of the neurons with the brain are developed, there is no longer a pool of dividing progenitor required for tumour formation. Tumours come for proliferating tissues.

Question 6

In adults what cells are the primary source for brain tumours?

Answer 6

Glial cells. These are still dividing. Astrocystomas come from astrocytes, oligodendrocytomas come from oligodendrocytes.

Question 7

How are neuronal tumours named?

Answer 7

Some by morphology but others from the location in which they are found.

Question 8

Where is the most common site for neuronal tumours?

Answer 8

In the cerebellum at the back of the brain.

Question 9

Why is radiotherapy more damaging for children than adults?

Answer 9

Radiotherapy destroys all the dividing cells, adults have fewer neuronal cells and thus damage is reduced. Growth in children is stunted from the point of treatment.

Question 10

Why is chemotherapy ineffective for the treatment of brain tumours?

Answer 10

The blood-brain barrier is a difficult obstacle to overcome.

Question 11

What is the most common brain tumour of children?

Answer 11

Medulloblastoma

Question 12

What classes of tumour are there?

Answer 12

Classical Tumour (big nuclei, not much cytoplasm)

Nodular Tumour Desmoplastic

Large cell version

Question 13

What is Turcot’s syndrome?

Answer 13

Turcot syndrome is a cancer syndrome associated with biallelic DNA mismatch repair mutations. It predisposes individuals to colon cancer and certain brain tumours.

Question 14

What is Gorlin’s syndrome?

Answer 14

Gorlin’s syndrome predisposes individuals to develop non-melanoma skin cancer (BCC, basal cell carcinoma) and brain tumours.

Question 15

What two syndromes, with different genetic pathways can lead to similar brain tumours?

Answer 15

Turcot and Gorlin’s syndrome.

Question 16

How does Turcot syndrome affect the colon?

Answer 16

In the colon FAP (familial adenomatous polyposis) occurs.

Question 17

What method of inheritance does Turcot syndrome show?

Answer 17

Autosomal Dominant

Question 18

Why can Turcot syndrome be thought of as two syndromes?

Answer 18

APC (Adenomatous polyposis coli), in the Wnt pathway, mutations results in predisposition to colon cancer and medulloblastoma.

MMR (Mismatch repair) mutations results in predisposition to colon cancer and glioblastoma.

Question 19

If β-catenin and TCF are activated what occurs?

Answer 19

They drive the expression of genes that promote cell proliferation.

Question 20

Without a signal how does β-catenin function within the cell?

Answer 20

β-catenin is involved in a destruction complex. β-catenin is phosphorylated and degraded, it doesn’t go to the nucleus and is not involved in proliferation.

Question 21

If a wnt signal activates β-catenin what occurs?

Answer 21

β-catenin builds up and activates genes and proliferation.

Question 22

What does a mutation in APC result in?

Answer 22

Mutations in APC prevent the degradation of β-catenin. Even in the absence of the signal, the β-catenin is not degraded, it goes to the nucleus and drives cell proliferation.

Question 23

How do mutations in the wnt pathway lead to cancer?

Answer 23

β-catenin is stabilised/activated, this associates with Tcf/Lef and activates gene expression including c-Myc.

This leads to irregular proliferation and cell control within the brain and the colon.

Question 24

What inheritance pattern does Gorlin’s syndrome exhibit?

Answer 24

Autosomal Dominant

Question 25

What is the receptor for Shh?

Answer 25

Shh (Sonic hedgehog) binds to its receptor Ptch

Question 26

What happens to the Wnt/β-catenin pathway in the absence of wnt and β-catenin?

Answer 26

When wnt is absent, β-catenin is bound by a 'destruction complex' which induces protein kinases CK1γ and GSK-3β. The protein kinases phosphorylate β-catenin, targeting it for ubiquitination and degradation in the proteasome. When β-catenin is absent, transcriptional co-receptors bind to TCF transription factors which prevents the expression of certain genes.

Question 27

What happens to the Wnt/β-catenin pathway in the presence of wnt and β-catenin?

Answer 27

The wnt protein binds to the transmembrane receptor **Frizzled**. This causes a signal to be transmitted across the membrane by Frizzled and **LRP**, activating them. Activation of Frizzled and LRP causes protein kinases **CK1γ** and **GSK-3β** to associate with the membrane. The protein kinases then phosphorylate the tail of the activated LRP. Next, the intracellular signalling protein **D****ishevelled**and the protein**Axin** are recruited to the cytoplasmic tails of LRP and Frizzled. This prevents the formation of the destruction complex, meaning β-catenin accumulates in the cytoplasm. β-catenin the moves into the nucleus. β-catenin binds to TCF, displacing the co-receptors. This enables the target genes to be expressed

Question 28

What is the role of **shh**?

Answer 28

**Shh** (Sonic hedgehog) is a key factor needed for the proliferation of granule neuron precursors of the cerebellum during normal development. Shh binds to **PTCH**, derepressing **Smo**. Smo releases **Gli** to the nucleus to act as a transcriptional activator.

Question 29

What are the effects of a mutation in the **PTCH** receptor?

Answer 29

Mutations in **PTCH** stop the receptor inhibiting **Smo**. Therefore **Shh** is no longer needed to bind to PTCH. Smo is de-repressed and stimulates growth (normally Shh stops PTCH from inhibiting Smo). Smo can signal regardless of PTCH as it is no longer repressed by it. The mutation has stopped PTCH from inhibiting Smo. The growth pathway is activated, granules form (root of proliferative disease). ***Gli*** **TF** levels increase within the nucleus.

Question 30

What does **SUFU** do?

Answer 30

SUFU takes the key receptor, **GLI** out of the pathway, switching proliferation off. This SUFU mutation is found in 12% of patients.

Question 31

What did experiments on **PTCH1+/1** heterozygote mice show?

Answer 31

3-7% of the PTCH1+/- heterozygote mice developed tumours.

Question 32

What did experiments on **PTCH1+/1** heterozygote mice crossed with **p53-/-** show?

Answer 32

All **PTCH1+/1** **p53-/-** spontaneously develop tumours. This shows that simply disrupting the **Shh** pathway is SUFFICIENT to predispose these animals to develop the granule brain tumour of the cerebellum: MB.

Question 33

How do **wnt** and **shh** tumours differ anatomically?

Answer 33

**Shh** tumours tend to be away from the brain stem. **Wnt** tumours tend to be right up against the brain stem.

Question 34

Why are **wnt** tumours not cerebellum tumours?

Answer 34

They are brainstem tumours that push their way into the cerebellum. **_Experiment:_** Target mutated B-catenin to cerebellum = No tumours Target mutated B-catenin to the brainstem = Disrupted migration, proliferation in dorsal brain tumours. When p53 is knocked out 15% of mice developed **classic medulloblastoma** after 290 days.