Cell And Molecular Biology Of Cancer

Question 1

What kind of triggers can increase likelihood of mutations

Answer 1

Radiation
Chemicals
Infectious agents
Hereditary

Question 2

What are the 8 hallmarks of a malignant cancerous cell

Answer 2

Self sufficiency in growth signals (oncogenes)
Insensitivity to antigrowth signals (tumour suppressors)
Evasion of apoptosis
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis
Reprogramming of energy metabolism
Evasion of immune destruction

• cell must be proliferative/able to divide otherwise cannot form cancer
  All above underlain by genomic instability and inflammation

Question 3

Challenges the cell cycle needs to ensure happen

Answer 3

Replication of the genetic information with high fidelity

Distribution of the chromosomes equally between daughter cells

Question 4

What are the phases of the cell cycle and what happens in each one?

Answer 4

Mitosis = segregation of chromosomes —> division to produce 2 daughter cells

G1 = increase in cell contents including the machinery for DNA replication

S = DNA replication occurs = two sister chromatids attached by a centromere

G2 = cell prepares for division and checks for errors in replication

G1, S and G2 are all interphase

G0 = cells in arrest, no need to divide or if are terminally differentiated such as cardiomyocytes or neurons

Question 5

Cancer cells do not divide faster than normal cells in proliferating tissues. What characterises them…

Answer 5

Is the ability to escape control of cell division

Question 6

Examples of how long the cell cycle takes in different tissues

Answer 6

Intestinal epithelial and BM precursors take 12 hours

Skin cells = 5 days

Liver cells = 1 year

Cancer cells 12-24 hours

Question 7

Control mechanisms have to ensure what 3 three things with regard to the cell cycle

Answer 7

1) making sure processes happen in the right order (cyclin and CDK’s are produced and eliminated in an ordered manner during the cycle and signal the different stages)

2) deciding whether cells divide at all
Checkpoint pathways monitor. Progression of cell cycle is controlled at transition points

3) being able to respond to signals (both external and internal
External = GF’s
Internal = quality control eg has DNA fully repaired and replicated

Question 8

What are the regulators of cyclin and CDK’s (cyclin dependent kinases)

Answer 8

CDK inhibitors
Cdc25 phosphatases

Question 9

Examples of transition points in the cell cycle and what checkpoints control them

Answer 9

G0 —> G1 = bringing arrested cells into division eg when needs more cells in tissue damage. Driven by growth factor

G1–> S = restriction/start point. Cell verifies environment is favourable, whether cell has grown and if DNA is ready to replicate. (DNA DAMAGE CHECKPOINT)

G2 —> M = check whether DNA has replicated properly (DNA DAMAGE CHECKPOINT)

M —> G1 called metaphase anaphase transition = cell verifies chromosomes aligned properly (MITOTIC SPINDLE ASSEMBLY CHECKPOINT)

Question 10

Pathway of external signalling

Answer 10

Growth factors activate membrane receptors
These activate signalling proteins
Modulation of transcription factors and expression of particular genes that activate the cell cycle to initiate proliferation

Question 11

DNA damage response (internal signalling pathway)

Answer 11

When damage in single or doubled strands is detected ATM and ATR are activated

Both activate downstream to 1) arrest the cell cycle and 2) activate DNA repair machinery

• p53 plays crucial role here

Question 12

Definition of oncogenes

Answer 12

Genes whose presence can trigger the development of cancer

Question 13

Definition of tumour suppressor genes

Answer 13

Genes whose loss or inactivation can trigger the development of cancer

Question 14

The mutations in oncogenes cause pathways to be…

Answer 14

Switched on inappropriately leading to excessive cell proliferation and/or promotion of cell survival

Leads to production of excessive amounts of normal protein or abnormal protein that is hyperactive

Question 15

Normal role of tumour suppressor genes

Answer 15

Provide negative control of cell division or activate apoptosis

Mutation of both alleles is required to promote cancer however in some cases one may be inherited so leaves only 1 to mutate to cause cancer

Question 16

2 classes of TSG’s, their role and examples

Answer 16

Gatekeeper genes = loss of these directly opens the gates to excessive cell proliferation
Eg p53 involved in DNA damage checkpoint
RB = controls the G1–> S restriction point

Caretakers = (maintain genetic stability) not directly involved in cell proliferation but instead in DNA repair and chromosome sorting
Eg BRCA 1 and 2 (DNA repair). Inactivated in most hereditary forms of breast cancer

Question 17

Pathophysiology of retinoblastoma

Answer 17

Causes multiple tumours in both eyes of children

In a arrested cell active RB is bound to the transcription factor E2F. Growth factors give signal to proliferate that makes G1-CDK complex phosphorylate RB inactivating it so now the transcription factor can be released allowing transcription and translation of the gene. Allows production of proteins required for S phase. This is what happens normally. In retinoblastoma the Rb protein is not produced or is faulty so does not bind/inhibit E2F allowing for gene expression and cell division

Question 18

How does p53 normally work to inhibit the cell cycle, induce repair and apoptosis

Answer 18

P53 is a protein produced by a gene. In circumstances of DNA damage ATM is activated and this phosphorylates p53 to prevent it from being degraded when it binds to mdm2.

P53 can now act as a transcription factor at other genes. Eg to produce p21 which inactivates CDK so now CDK will not be able to phosphorylate RB which means it cannot dissociate from E2F. Gene not expressed that produces proteins required for S phase of cell cycle

P53 can also induce production of repair proteins

p53 can activate transcription of PUMA (p53 unregulated modulator of apoptosis) that inhibits Bcl-2 which is an inhibitor of apoptosis. This allows apoptosis to proceed when repair is not possible

When mutations arise and p53 is not produced or is faulty the subsequent proteins that negatively regulate the cell cycle are also not produced allowed excessive proliferation

Question 19

Example of how HPV causes cervical cancer

Answer 19

Viruses DNA may integrate in the DNA of basal epithelial cells of the cervix. Virus genome encodes two oncogenic proteins E6 + E7

E6 = binds to p53 even when it is phosphorylated and promotes it’s degradation not allowing it to accumulate in circumstances of DNA damage. Cell will not arrest or undergo apoptosis.

E7 binds to RB thus not allowing it to bind to E2F. = E2F will act at gene as a TF to produce proteins for S phase of cell cycle

Question 20

Mutation of a single gene is insufficient in causing cancer. Normally how many mutations are required that contribute to the sequential accumulations of mutations over the years that lead to cancer

Eg colorectal cancer

Answer 20

5-6

1) loss of TSG APC (adenomatous polyposis coli) —> may form polyps and further mutations may occur putting the mucosa at risk

2) mutation of the proto-oncogene K-RAS = formation of adenomas

3) subsequent mutation of DCC and p53 —> carcinoma

4) further mutations facilitate invasion and metastasis