Tumour evolution and cancer hallmarks

Question 1

What is cancer

Answer 1

The collective name given to a collection of related diseases. In all types of cancer some of the body’s cells begin to divide without stopping and are capable of spreading into surrounding tissues.

Question 2

How many mutations does it take to produce a cancer

Answer 2

1-10 driver mutations needed for each tumour, (tumour heterogeneity)

Question 3

What are the 6 original hallmarks of cancer?

Answer 3

1. Self sufficiency in growth factor signalling
2. Insensitivity to growth suppressing signals
3. Tissue invasion and metastasis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Evading apoptosis

Question 4

What are three common events that lead to an insensitivity to anti growth signalling?

Answer 4

1. Rb1, mutated in retinoblastoma and a number of other cancers
2. TP53 mutation or deletion is found in a wide variety of cancers
3. CDKN2A (p16) gene is mutated or deleted in many tumours

Question 5

How might a cell gain sustained proliferative signalling?

Answer 5

1. Cancer cells may begin to produce growth factor ligand themselves, responding via expression of cognate receptors. Results in autocrine proliferative signalling.
2. Cancer cells can send growth factor signals to the surrounding normal stroma. These cells respond by reciprocating and sending multiple growth factors to the cancer cell.
3. Elevation of mitogenic receptors at the cell surface. Renders the cell hyper-responsive to limited amounts of the ligand. Also can result in ligand independent firing of receptors.
4. Somatic mutations can activate additional downstream pathways.
5. Downregulation of negative feedback mechanisms. e.g Loss of intrinsic Ras GTPase activity which renders the Ras signal to always be on, many downstream targets.

Question 6

How do cancer cells evade apoptosis

Answer 6

p53 loss or mutation. Reduced expression of CD95/Fas receptor

Question 7

How does a cancer cell exhibit limitless replicative potential

Answer 7

By inhibiting the loss of telomeres at the ends of their chromosomes. Achieved by active expression of the telomerase gene. Or activation of homologous recombination mediated telomere repair.

Question 8

How many cycles of cell division can a normal cell undergo before telomere shortening induces cellular senescence or mitotic catastrophe

Answer 8

50 - 70 cycles

Question 9

What induces sustained angiogenesis

Answer 9

Hypoxia activated expression of VEGF.

Activation of angiogenic factors by aberrant Ras, myc or p53 signalling.

Question 10

What are the 4 additional hallmarks of cancer?

Answer 10

1. Deregulating cellular energetics
2. Avoiding immune destruction
3. Tumour promoting inflammation
4. Genome instability and mutation.