Principles of Oncogenesis

Question 1

What does exposure to enviromental carcinogens do to cells?

Answer 1

Can lead to malignant transformations

Question 2

What does exposure to enviromental mitogens do to cells?

Answer 2

Can stimulate cell proliferation

Question 3

Before a clinically significant tumour is seen, what needs to happen?

Answer 3

Accumulation of several mutations (usually 10-12).

Question 4

What are the 6 original “Hallmarks of Cancer”?

Answer 4

Sustained proliferative signalling, evading growth supressors, activating invasion and metastasis, Enabling replicative immortality, inducing angiogenesis, resisting cell death.

Question 5

What are the emerging Hallmarks of cancer? (2)

Answer 5

Deregulating cellular energetics, avoiding immune destruction.

Question 6

What are the enabling characteristics of cancer? (2)

Answer 6

Genome instability and mutation, tumour-promoting inflammation

Question 7

By what mechanisms can cancer have sustained proliferative signalling?

Answer 7

They can become self sufficient in terms of growth signals. They can secrete their own growth factors, mutate GF receptors so they are always active or activated at low levels, or they can activate mutations in proto-oncogenes.

Question 8

Can you think of one example where a mutation in a receptor can lead to sustained proliferative signalling in cancer?

Answer 8

Stem cell factor acts through the C-kit receptor, which has tyrosine kinase activity. KIT mutations are present in 30-50% of mast cell tumours.

Question 9

How does the anti-oncogene (tumour supressor gene) Rb work?

Answer 9

It transuces growth-inhibitory signals that originate largely outside the cell and determines whether or not cell cycle progression should procede.

Question 10

How does the anti-oncogene (tumour supressor gene) p53 work?

Answer 10

Receives input from intracelluar operating systems, e.g. if the cell viability is sub-optimal, and calls a halt to cell cycle progress until conditions have been normalised. p53 can actively trigger apoptosis.

Question 11

By what mechanisms can cancer evade growth suppressors (e.g. Rb, p53)?

Answer 11

Cancer cells with defects in Rb or p53 are more likely to undergo uncontrolled proliferation.

Question 12

By what mechanisms can cancer resist cell death?

Answer 12

A counterbalance between pro-survival and pro-apoptotic molecules will allow cancer cells to resist apoptosis. E.g. by downregulating death receptors and upregulating Bcl-2 family.

Question 13

How does apoptosis work?

Answer 13

The regulators of apoptosis can be divided into two circuits, extrinsic and intrinsic. Each leads to activation of the Caspase cascade, which leads to apoptosis.

Question 14

By what mechanisms can cancer enable replicative immortality?

Answer 14

Most malignant cancer cells have telomerase, which adds telomere repeat segments to the ends of DNA, which allows the cell to keep dividing.

Question 15

By what mechanisms can cancer induce angiogenesis?

Answer 15

Tumour cells often secrete angiogenic factors, such as Vascular endothelial growth factor (VEGF), which stimulates development of new BV.

Question 16

By what mechanisms can cancer activate invasion and metastasis?

Answer 16

Tumour cells can produce enzymes (matrix metalloproteinases) to disrupt local tissues allowing invasion. They can also express or not express cell adhesion molecules, which allows them to adhere or detach and invade/metastasize.

Question 17

By what mechanisms can cancer deregulate cellular energetics?

Answer 17

They reprogramme glucose metabolism, by limiting metabolism to glycolysis, to fuel high levels of proliferation. They can upregulate GLUT1 transporters.

Question 18

By what mechanisms can cancer evade immune destruction?

Answer 18

Downregulate immune effector mechanisms, and induce immunological tolerance/immunosuppression.

Question 19

Why is genome instability and mutation an enabling characteristic of cancer?

Answer 19

There needs to be a succession of mutations. Usually DNA would resolve defects, but cancer cells often increase the rate of mutation, by increasing sensitivity to mutagenic substances, or breakdown in maintenance.

Question 20

Why is tumour-promiting inflammation an enabling characteristic of cancer?

Answer 20

A significant infiltration of inflammatory cells may actually be counterproductive, as it actually enhances tumourgenesis. Production of growth factors, angiogenic cytokines and immunosuppressors may help tumour.