MCB Lecture 65 Neoplasia II

Question 0

Conventional cancer therapies are effective against …

Answer 0

The tumour cells, not the cancer stem cells or progenitors

Question 1

Describe the paradigm of cancer

Answer 1

Normal cell
-hit-
Cancer stem cell
-more hits-
Progenitor cells
Tumour

Question 2

What is a ‘hit’?

Answer 2

This is genetic or epigenetic changes to the Cell

Question 3

What is the effect on a cell of a ‘hit’?

Answer 3

Increased self renewal potential

Question 4

What are the four genetic events that result in cancer?

Answer 4

1. Activation of a proto oncogene
2. Deactivation of a tumour suppressor gene
3. Replication despite DNA damage
4. Inhibition of apoptosis or senescence

Question 5

Describe proto-oncogene activation causing cancer

Answer 5

Eg. KRAS

When a proto oncogene is activated, the cell undergoes increased proliferation

Question 6

Why does mutation of KRAS result in cancer?

Answer 6

Constitutively active proliferation pathways such as MAPK

Question 7

Describe mutation in tumour supressor genes resulting in cancer

Answer 7

Eg. APC or Rb

When APC is mutated, beta catenin is not marked for breakdown.
Beta catenin stabilises and switches on genes that result in proliferation

Question 8

Which tumour suppressor genes mutate commonly to form cancer?

Answer 8

APC and Retinoblastoma

Question 9

What does SNPs of APC cause?

Answer 9

Adenomatous polyposis

1000s of polyps in the small intestines
One polyp then may undergo malignant transformation, resulting in cancer

Question 10

What is the function of APC?

Answer 10

It is an integral part of the beta catenin destruction complex

Question 11

Describe replication causing genomic instability

Which gene in commonly involved?

Answer 11

p53

If DNA is replicated despite genomic instability, mutations in the cells are perputuated, possible resulting in cancer

Question 12

Describe the function of p53 in healthy and cancerous cells

Answer 12

Healthy:
When there is DNA damage, three things will occur:
- try to repair the damage
- G1 arrest
- apoptosis

p53 mutation:
When there is DNA damage, p53 isn’t able to effect all these changes that would stop the perpetuation of the mutated DNA and mutation survives in the cell population

Question 13

Homozygous loss of … is seen in almost every type of cancer

Answer 13

p53

Question 14

Describe how inhibition of apoptosis or senescence results in cancer

Which genes are involved?

Answer 14

p53, Fas receptor, bcl-2, bcl-xL

If there is a mutation in any of these genes, apoptosis can not occur

Question 15

Which epigenetic events result in cancer?

Answer 15

DNA methylation

Histone tail modification

Question 16

Where does DNA methylation occur?

Answer 16

On the cysteine of CpG islands in the promoter region

Question 17

What is the outcome of DNA methylation?

Answer 17

That DNA is bulky and thus is not transcribed: is silenced

Question 18

What patterns of methylation are seen in cancer?

What does this result in ?

Answer 18

Genome wide demethylation

CpG island hypermethylation (promoters of tumour suppressor genes)

Question 19

Describe how histone tail modifications result in cancer

Answer 19

The histone tails can be acetylated or methylated on lysine residues resulting in either silencing or activation

This results in activation of proto oncogenes or silencing of tumour suppressor genes

Question 20

Epigenetic modifications are …

Thus they are a … for the cell

Answer 20

Reversible

Selective advantage

Question 21

Describe the selective pressures that cancer cells face

Answer 21

Hypoxia
Low nutrients
Natural barriers to tissues

Question 22

How is diversity generated in cancer cell populations?

Answer 22

Consecutive rounds of mitosis, mutation

Question 23

Natural selection of cancer cells results in …

Answer 23

More aggressive cells

Question 24

Describe the mechanism of invasion and dissemination of cancer cells What are the genetic requirements for this to occur?

Answer 24

They must break down the tissue in which they are, then migrate in the blood stream, and then adhere to another tissue Requirements: - Lose Adherens junctions - Proteolytic enzymes - Evasion of immune systems - Angiogenesis - Colonising the new site: GF etc

Question 25

Describe the 'vogelgram model' of tumour progression using the example of adenoma formation

Answer 25

``` Normal epithelium - hit - Hyper-proliferative epithelium, Mucosa at risk Early adenoma Intermediate adenoma Late adenoma Malignant adenoma/ carcinoma Metastasis ```

Question 26

What criticism is there for the vogelgram model?

Answer 26

Too simplistic However, it is ok for colorectal cancer

Question 27

What is the parallel model of tumour progression?

Answer 27

There is a population of heterogeneous progenitor cells From this population, some will go on to form the bulk of the tumour in the tissue Conventional treatments target these cells. Further down the track, other cells from the progenitor population, with different mutations, form tumours. There are now multiple tumours in the tissue, all with different mutations and resistances. We can't treat all the tumour with the same treatment

Question 28

What are the conventional cancer treatments?

Answer 28

Chemotherapy Radiotherapy Surgery

Question 29

Describe conventional treatment with the example of colorectal cancer

Answer 29

``` Early stage: surgery to remove the adenoma Late stage (metastasis has occurred) : surgery, chemotherapy and radiotherapy - COMBINATION THERAPY ```

Question 30

How does colorectal cancer arise?

Answer 30

Adenomas in the gut undergo malignant transformation and become metastatic

Question 31

What happens in colorectal cancer metastasis

Answer 31

The cancerous cells spread to the liver

Question 32

How does chemotherapy work?

Answer 32

It targets rapidly dividing cells will poor selectivity

Question 33

How does radiotherapy work?

Answer 33

It kills malignant cells with radiation

Question 34

What is problematic with the conventional cancer treatments?

Answer 34

They are coarse and kill healthy cells as well

Question 35

What is required to proceed from hyper-proliferative epithelium to early, intermediate and late adenoma?

Answer 35

Accumulation of mutation: such as mutations in APC, beta catenin, KRAS

Question 36

What is required to transform from late adenoma to carcinoma and metastasis?

Answer 36

Mutation in p53