Biology 2 How do Cancers Grow?

Question 1

What are the 6 hallmarks of cancer?

Answer 1

Sustained proliferative signalling 
Evading growth supressors 
Activating invasion and metastases
Enabling replicative immortality
Inducing angiogenesis 
Resisting cell death

Question 2

What are telomeres?

Answer 2

The repetitive regions at the end of chromosomes, each time a cell divides, the telomere gets shorter (unless telomerase is active to restore them).

Question 3

What is telomerase?

Answer 3

It is not normally active in cells apart from in germ cells and stem cells.
Around 90% of malignant cells express telomerase. This enables telomeres to be restored and cell division to continue unrestricted.

Question 4

What is senescence and when does it occur?

Answer 4

cellular old age - occurs when telomeres have reduced to an inactive size/been used up after X no. of cell divisions.

Question 5

What happens if p53 is lost?

Answer 5

If normal cell checkpoints are lost or disrupted then cell division continues until the cell reaches “crisis”.
In some cases cells escape crisis by activating telomerase or by alternative telomere lengthening (ATL) –> this is a way in which cancer cells become immortal as according to hallmarks of cancer.

Question 6

Which of the 6 Hallmarks of Cancer are relevant in this lecture?

Answer 6

Replicative immortality

Question 7

How is replicative immortality ensured?

Answer 7

Telomerase or Alternative Telomerase Lengthening to allow cell division to continue (for example in absence of p53).

Question 8

What is ATL?

Answer 8

Alternative telomerase lengthening
In cells that don’t express telomerase, recombination or fusion between the ends of different chromosomes occurs. The cells that survive ATL then have chromosome rearrangements (fused, deletions, amplifications)
Some of these changes may be oncogenic

Question 9

How do cells know what to do?

Answer 9

How do they know how to divide, grow, rest, die, differentiate, move etc
They sense the environment and respond accordingly from stimuli transduced to nuclei which can lead to changes in gene expression etc
Receive chemical messages (growth factors, mitogens, cytokines, hormones). If this foes wrong it can lead to uncontrolled proliferation and cell survival.

Question 10

Name two oncogenes

Answer 10

MYC and RAS

Question 11

Name two tumour suppressors

Answer 11

p53 and Rb

Question 12

What is the effect of Myc and Ras on the cell cycle?

Answer 12

Inhibits checkpoints in the cell cycle that are regulated by p53 and Rb. These checkpoints would normally repair any damages to DNA or abnormalities etc or programme cell death (apoptosis) but without them, damaged DNA etc goes on to proliferate.

Question 13

Three S’s of receptors

Answer 13

Specificity (ligand-protein and protein-protein)
Signal amplification
Signal convergence

Question 14

What types of receptors are there?

Answer 14

Receptor tyrosine kinases, (RTKs i.e. EGFR, VEGFR)
Steroid hormone receptors (nuclear receptors) e.g. estrogen receptor.
G-protein coupled receptors - despite being common drug target, not many anti-cancers use this as a target.

Question 15

What is EGFR?

Answer 15

Epidermal growth factor receptor, senses growth signals and leads to an increase in proteins needed for cell division.

Question 16

What is the EGFR signalling pathway and what does it lead to?

Answer 16

Two proteins bind to the EGF receptor and activates RAS (oncogene). This leads to downstream signaling to RAF–> MEK and switches on genes for proliferation via EKR (kinase transcription factor).
PI3K is also activated and leads to AKT; normally this leads to cell apoptosis, p53 or protein synthesis. In cancer cells, apoptosis and TP53 is downreglated and protein synthesis/cell division proliferates.

Question 17

EGFR mutations

Answer 17

Cancers are caused by mutations and EGFR is frequently mutated in cancer;
changes in DNA, protein sequence, protein function. In this mutation EGFR is permanently activated, as if bound to EGF which causes the cell to divide.

Question 18

Which drugs target the EGFR and how do they work?

Answer 18

Cetuximab is an antibody that binds to the receptor and blocks it
Erlotinib and Gefitinib look like ATP and stop EGFR activation by blocking functional ATP.

Question 19

How do Erlotinib and Gefitinib fair against mutant EGFR?

Answer 19

The same EGFR mutations that promote cancer also make EGFR more sensitive to erlotinib and gefitinib. A patient’s cancer DNA sequence is determined to decide which drug is used - personalised medicine example.

Question 20

What is the mechanism behind tyrosine kinase inhibitors?

Answer 20

Competitive inhibition of ATP binding

Question 21

What are steroid hormone receptors?

Answer 21

Steroid hormones are derived from cholesterol (a lipid membrane component). They can diffuse into cells so there is no need for cell surface receptors.

Steroid hormone receptors are part of the same nuclear receptor superfamily. They are transcription factors that become activated by steroid hormones e.g. estrogen receptor, androgen receptor, progesterone receptor, retinoic acid receptor.

Question 22

What is an estrogen receptor and how is it activated?

Answer 22

An exmaple of a type I steroid hormone receptor that is activated in the cytoplasm. Estradiol is the ligand that diffuses into the cell. Binds to the receptor, displacing associated chaperone proteins e.g. HSP90. The ER dimerizes and migrates to the nucleus. ER dimer associates with co-activators or co-repressors to modify transcription of target genes.

Question 23

What kind of drug is tamoxifen?

Answer 23

It is a pro-drug
Metabolised to active metabolite CYP2D6
Binds to the ER with much higher affinity than estrogen
It is therefore an estrogen antagonist (with some unexpected agonism).
Known as a selective-ER-modifier (SERM)

Question 24

What is Fulvestrant?

Answer 24

A pure anti-estrogen (without the agonism that is associated with Tamoxifen).
Prevents dimerisation and therefore activation of ER
Known as a selective-ER-down regulator (SERD)