Neoplasia 3

Question 1

What are the 3 categories of Growth receptors, what are some examples of growth receptors and what may happen if they do not function correctly?

Answer 1

3 categories
- Receptors with intrinsic tyrosine kinase activity.
- 7 transmembrane G protein-coupled receptors.
- Receptors without intrinsic tyrosine kinase activity.
C-KIT - Gastrointestinal stromal tumours.
Ras - colon, lung etc…
Braf - melanomas (50%). Vemurafanib

Question 2

What is Myc?

Answer 2

One of the last points in the sequence.
Myc is a nuclear transcription factor that promotes growth - DNA replication etc.
Common in lymphoma, neuroblastoma, small cell carcinoma of the lung.
Burkitt lymphoma (t;14). Myc translocation which is diagnostic.

Question 3

What is P13K?

Answer 3

Most commonly mutated kinase in cancer.
Limited success in trials (may change).
Targeted at haematological malignancies (e.g. chronic lymphocytic leukaemia).
May be used in combination with receptor inhibitors.

Question 4

What are Tumour suppressors and why do cells with malignant ambitions want to remove them?

Answer 4

Stop growth.

Cells with malignant ambitions must remove them to survive and proliferate.

Question 5

What is the role of Tumour suppressor genes?

Answer 5

Tumour suppressor genes produce lots of proteins that inhibit the cell cycle.
If there is a little p at the start of a gene name it is most likely a tumour suppressor gene.
e.g. p53
VHL - von-Hippel Lindau
Can be a syndrome. Renal cancers.
Loss of VHL increases levels of angiogenic growth factors.

Question 6

What are the roles of p53?

Answer 6

Most commonly mutated protein across all cancers.
Various roles in the cell cycle.
Cell cycle arrest - senses DNA abnormalities at G1 and pauses cell cycle. Increases levels of p21 which is a CDK inhibitor.
CDK activated by cyclins.
Remember phosphorylation of Rb.
Induces apoptosis - if DNA repaired, p53 restarts the cell cycle. If repair not possible p53 initiates apoptosis - if DNA repaired, p53 restarts the cell cycle. If repair not possible p53 initiates apoptosis (via BA pathway).

Question 7

What is the role of PTEN?

Answer 7

Increases transcription of p27.
p27 blocks CDKs and cell cycle progression.
Remember CDK are activated by cyclins.
Inhibits P13K/AKT pathway we saw earlier.
Without PTEN and therefore p27 cells can proliferate in an uncontrolled fashion.

Question 8

What prevents your cells from replicating an unlimited number of times?

Answer 8

Telomeres prevent you from replicating an unlimited number of times.

Question 9

Why do normal cells not have Unlimited replicative potential. What do malignant cells do to overcome this?

Answer 9

Remember cells can only divide a limited number of times.
Telomeres - TTAGGG repeats.
Certain cells express telomerase to renew the length of telomeres - stem cells.
In malignancy, there is often a mutation that reactivates telomerase.

Question 10

What cells undergo apoptosis?

Answer 10

Faulty cells are removed through apoptosis.
Avoid death.
Bax/Bak etc.

Question 11

What is Bcl-2?

Answer 11

Bcl-2 anti apoptotic molecule.
Binds Bax/Bak to stop holes being punched in mitochondria.
Follicular lymphoma - common lymphoma.
Translocation t(14;18).
Switches on Bcl-2.
No cell suicide.

Question 12

Because cancers grow fast and so there is an increased demand for oxygen, what must successful cancers do?

Answer 12

Without a blood supply cancers can only grow so much.
A common feature of malignancy is necrosis.
“successful” cancers must create their own blood supply.
The development of new blood vessels is called angiogenesis.

Question 13

What ways can the body repair damage?

Answer 13

Mutation is common.
Normally we can repair damaged DNA in cells.
Recall p53 etc.
We encounter NER already - xeroderma pigmentosa and skin cancer.
Many other mechanisms for DNA repair.

Question 14

What is BRCA?

Answer 14

Complex genes and proteins.
Breast, ovarian and pancreatic tumours.
Complex roles in ER and AR regulation.
Also has a role in DNA repair and cell cycle arrest at G1/S phase.

Question 15

What are Mismatch repair proteins?

Answer 15

Family of proteins responsible for identifying faults in the code - mismatched sequences.
MLH1
Others - MHL3, MSH2, MSH3, PMS1, PMS2.
Abnormal in Lynch syndrome.
Commonly develop colorectal carcinomas.

Question 16

what is Lynch Syndrome?

Answer 16

3% of all colorectal cancers.
Prevelance 1:440
We can look for faulty protein expression using immunohistochemistry.
Look for frequency of mismatched sequences by analysing microsatellites - segments of repeated DNA code specific to an individual.
If the microsatellites are full of errors his is called microsatellite instability and indicates the proteins aren’t working.
The cost of screening is less.
The cost of surgery, chemotherapy, post op care, clinics etc. is large.

Question 17

Why is it that sometimes our bodies react to our own malignancy and what can happen if the body does?

Answer 17

We do react to our own malignancy.
Malignant cells may express “foreign” proteins or expose proteins to the immune system that aren’t normally exposed.
Cancers with a pronounced inflammatory response do better.
Some melanomas even regress!

Question 18

What is PD-L1 and why can it be targeted for treatment?

Answer 18

Programmed death - Ligand 1.
Inhibits T-cell proliferation (apoptosis).
Thought to be important in pregnancy etc.
Tumours can over express PD-L1 and avoid the immune system.
As of now - all lung cancers are tested for PD-L1. Soon lots of other malignancies.
Can block PD-L1 as a form of target treatment.

Question 19

Why it is a complex process for the malignant cells within tumour to survive?

Answer 19

You have to be able to chew up surrounding tissue and survive. Which is difficult.
Increase expression of matrix metalloproteins (MMP).
Cells can chew their way through surrounding tissues and blood vessels.

Question 20

What must happen before a tumour becomes metastatic. What is the process when a tumour is actually becoming metastatic?

Answer 20

Many, many steps first.
Must grow uncontrollably and survive.
Avoid our own immune system.
Chew basement membrane, extend through connective tissues.
Break through vessel walls.
Enter through vessel wall.
Survive in the vessel.
Aggregate and adhere to vessel wall.
Get back through vessel wall.
Anchor in a new organ.
Develop a new vascular system and survive and grow.

Question 21

Are all malignancies the same?

Answer 21

The order is always consistent.
One abnormality may occur before another.
Not all malignancies have an abnormality in every category.
(If you are a metastatic disease, you have to have an abnormality in the last category).

Question 22

What is the Lineage Promiscuity of malignant cells?

Answer 22

Given the faulty repair mechanism and lack of apoptosis, each daught cell develops new mutations with each division and so on.
Sub-clones and sub-clones of sub-clones.
Not all sub-clones will possess the ability to become malignant.

Question 23

What are Sub clones and why does allow recurrence to occur?

Answer 23

Important concept in treatment resistance.
Chemotherapy and targeted therapies may work against certain but no all clones.
Recurrence occurs when a clone has a survival advantage that measn it isn’t effected by a specific treatment.
Can mean that second and third line treatment options are limited.

Question 24

What are most cancers beginning to be treated with?

Answer 24

Most cancers are beginning to be treated with specific drugs targeting abnormalities in these groups.

Question 25

Why have we earnt the most from inherited forms of malignancy?

Answer 25

If people with mutations in these genes get cancer they must be important genes in the development of cancer.
Cancer also requires initiators and promotors.

Question 26

The aim of cancer cells is to get big and grow and not stop. What do they need to do, to allow this?

Answer 26

Avoid normal homeostatic controls and permit a permanent green light. This is called sustained growth signals.

Question 27

What are Wnt/APC/beta catenin?

Answer 27

APC mutations are one of the earliest mutations in colorectal cancer.
Can occur as a germline mutation causing an inherited condition - Familial Adenomatous Polyposis and Gardener’s syndrome.

Question 28

what can you use to target angiogenesis and stop a cancer form growing?

Answer 28

VEGF - vascular endothelial growth factor is frequently up-regulated in some malignancies.
A useful target for treatment.
If you block the receptor you block angiogenesis and stop the cancer from growing.

Question 29

Is cancer clonal?

Answer 29

Cancer is not clonal.
Single parent, yes.
All cells identical, no.