Cancer genes and properties of cancer cells

Question 1

Cancer cells acquire key properties to cross each selection barrier. Name the 6 hallmarks of cancer cells.

Answer 1

1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Activating invasion and metastases
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Resisting cell death

Question 2

What is the concept of sustained proliferative signalling in cancer cells?

Answer 2

Autocrine growth stimulation is when a cell produces a growth factor to which it also responds to , resulting in continuous stimulation of proliferation, regardless of extracellular growth factors, even outside its normal environment.

Question 3

What is the concept of evading growth suppressors in cancer cells?

Answer 3

Normal cells proliferate in a culture until they reach a finite cell density, at which point they become quiescent. Tumour cells, however, continue to proliferate independent of cell density.

Question 4

What is the concept of resisting cell death in cancer cells?

Answer 4

Normally, when DNA damage is irreparable, p53 may induce apoptosis and trigger programmed cell death. Cancer cells evade this mechanism.

Question 5

DNA damage –> p53 increases –> two outcomes; if reparable due to reversible DNA damage (___ ____ _____) but if irreparable due to irreversible DNA damage (______)

Answer 5

cell cycle arrest

apoptosis e.g by increasing Fas

Question 6

What are telomeres?

Answer 6

Repeated DNA sequence that protect (cap) the end of chromosomes.

Question 7

What is the difference in telomere length and telomerase activity in embryonic stem cells and adult stem cells?

Answer 7

Embryonic stem cells:
- long telomeres
- telomerase active
Adult stem cells:
- short telomeres
- telomerase inactive or absent

Question 8

What is the concept of replicative immortality? (Hint: Telomeres)

Answer 8

• Telomeres are repeated DNA sequences that protect (cap) the end of chromosomes.
• During DNA replication, the leading strand replication results in complete copying of the 5’ - 3’ DNA stand.
• However, lagging strand replication is discontinuous and fails to copy the very end of each chromosome resulting in continuously shortening telomeres.
• Critically short telomeres threaten to damage the chromosome integrity.
• Cells are unable to divide and enter a state of replicative senescence (where they become inactive and die).
• Cancer/ stem cells can activate telomerase, which extends telomeres.

Question 9

What is the invasion-metastasis cascade?

Answer 9

1. Primary tumour formation
2. Localised invasion
3. Intravasion (interaction with platelets, lymphocytes and other blood components)
4. Transport through circulation
5. Arrest in microvessels of various organs
6. Extravasion
7. Micrometastasis formation
8. Colonisation (macrometastasis formation)

Question 10

Micrometastasis is often formed before _______ tumour is detected in some cancers e.g. ______, __________

Answer 10

primary
breast
melanomas

Question 11

What are the properties required for invasion and metastasis?

Answer 11

Cancer cells recruit other cells such as macrophages/ mast cells to secrete matrix metalloproteases to facilitate invasion of tissues and breakthrough basal lamina.

They are also anchorage-independent as they are unrestrained by their tissue interactions whereas normal cells are strictly adhesive and need to remain embedded in their tissue otherwise they may apoptose

Question 12

Cell to cell adhesion is impaired in cancer cells. What are the different types of junctions that are present in normal cells? Include function.

Answer 12

Tight junctions - seals neighbouring cells in an epithelial sheet to prevent leakage of molecules

Adherens junctions - joins actin bundles together

Desmosomes - joins intermediate filaments together

Gap junctions - forms channels allowing small water-soluble molecules and ions through from cell to cell

Hemidesmosomes - anchors intermediate filaments into basal lamina

Question 13

Adhesions molecules are often lost in cancer cells. What are these two molecules? What do they do? Where are they found? What happens as a consequence of them being lost in cancer cells?

Answer 13

Cadherins - Found in adheren junctions and desmosomes. Allow cell-to-cell attachment.
Integrins - allow anchorage of epithelial cells to basal lamina. Found in hemidesmosome.
Since they are lost in cancer cells, they can survive in unattached state and have increased mobility.

Question 14

Concept of inducing angiogenesis?

Answer 14

Primary tumour is present. It secretes angiogenic factors e.g VEGF towards blood vessel which causes it to form outgrowths towards tumour. This then supplies tumour with oxygen and nutrients. At the same time, tumour allows metastatic spread to occur. This whole process causes conversion of microscopic tumour to macroscopic tumour, which is clinically relevant.

Question 15

What are the hallmarks of cancer cells that are found in normal stem cells?

Answer 15

Proliferation
Motility
Replicative immortality

Question 16

Cancer stem cells are cells that

Answer 16

have their differentiation pathway blocked.

Question 17

What are the emerging hallmarks and enabling characteristics?

Answer 17

Emerging:

• deregulation of cellular energetics via metabolic switch to glycolysis
• avoid immune destruction via secretion of immuno suppressive factors

Enabling:

• Growth instability and mutation
• Tumour promoting inflammation

Question 18

How does tumour promoting inflammation occur? In terms of necrosis..

Answer 18

Necrosis in hypoxic core of tumour cell. Leads to activation of TAMS - Tumour associated macrophages. TAMS release growth, survival and angiogenic factos (IL1, 6, VEGF, TNF) that support tumour promotion and progression.

Question 19

Cancer cells show what kind of phenotype?

Answer 19

Mutator-phenotype

Question 20

What will happen if a cell has optimum genetic instability and if a cell has too much genetic instability?

Answer 20

Optimum genetic instability will favour further mutations, allowing the cell to pass successive ‘selection barriers’ . However, this also makes cancer cells hypersensitive to DNA-damaging chemo

Question 21

Currently, the cancer gene census lists how many genes for which mutations have been casually implicated in cancer?

Answer 21

488 genes

Question 22

We traditionally distinguish two types of genes. These are?

Answer 22

Oncogenes

Tumour suppressors

Question 23

What are oncogenes

Answer 23

These are genes that drive abnormal cell proliferation. They may represent the overactive form of normal cellular genes (proto-oncogenes), OR may enter the cell as part of a virus

Question 24

Tumour suppressors are..

Answer 24

Genes that normally inhibit cell proliferation and tumour development. In tumours, these are often lost or inactivated. This usually requires 2 mutations.

Question 25

Dominant mutation (___ of function) in proto-oncogenes results in

Answer 25

creation of oncogenes. This activation will allow cell survival and proliferation

Question 26

Recessive mutation (___ of function) is seen in? How many mutations required?

Answer 26

tumour suppressor genes.

no effect of mutation in one gene copy. Two inactivating mutations functionally eliminate the tumour suppressor gene.

Question 27

What are the three ways in which a proto-oncogene can be made overactive to convert it into an oncogene? What is the outcome?

Answer 27

Deletion or point mutation - hyperactive protein produced in normal amounts.

Gene amplification - normal protein overproduced

Chromosomal rearrangement e.g. translocation

Question 28

What are all the functions of proto-oncogenes?

Answer 28

Autocrine growth stimulation - produce growth factors. Act on growth factor receptors e.g. ErbB1 acts on EGFR/ Erb2 acts on Her2-neu.
This activates intracellular signalling pathway which may act on Regulatory GTPase pathways e.g oncogenic K-Ras, Cytoplasmic kinases e.g CDKs or Anti-apoptopic factors e.f. Bcl-2. These activate transcription factors such as MYC.
The proto-oncogenes are associated with invasion, metastasis and angiogenesis e.g VEGF and VEGFR

Question 29

What are the targets of anticancer therapies?

Answer 29

GF
GFR
TF
Anti-apoptotic factors
Intracellular signalling pathways
Cell cycle machinery

Question 30

Inactivation of tumour suppressors can occur through three ways: deletion, ___ _____ and _______ ___ (gene not mutated but switched off). Once one copy is lost, the second copy is…..
This is called ‘___ __ __________’

Answer 30

point mutation
epigenetic changes
often deleted
loss of heterozygosity

Question 31

What kinds of genes are tumour suppressors? The are 3 types. State their function also.

Answer 31

Caretakers: Promote genome stability and control mutation rate e.g. checkpoint genes and DNA repair genes. Their loss increase the mutation rate and thus promotes progresison e.g. p53 and BRCA genes
Gate keepers: Monitor cell division and death e.g. Rb and pro-apoptotic genes
Landscapers: Control cellular micro-environment e.g. cadherins and integrins

Question 32

Rb mutations can be hereditary or

Answer 32

non hereditary. Both copies of Rb need to be mutated for tumour formation. Sometimes one mutation can be inherited and the second acquired.