Cancer cell biology

Question 1

What factors can impact a cell?

Answer 1

Genetics
Environment
Regulators ( hormones, cytokines, growth factors ect)
Architectural constraints

Question 2

Describe clonal evolution and what it leads to?

Answer 2

Contributes to heterogeneity
Stepwise accumulation of mutations
Cells develop mutations and undergo rounds of mutation and proliferation
Selection pressures will allow the survival of certain cell clones so these will increase in size

Question 3

What is inter tumour heterogeneity?
What is intra tumour heterogeneity?
What are the implications of heterogeneity?

Answer 3

Differences in the cells between tumours of different individuals
Differences in the cell clones of individual tumours

Cancers in the elderly are often very mutationally complex so are often incurable or very hard to treat

Question 4

Describe the effect of cancerous stem cells and why they only give rise to a small % of the total cell population

Answer 4

Cancerous stem cells give rise to stem cell and non stem cell = transient amplifying cells
Transient amplifying cells always out number the cancer stem cells

Question 5

What are the requirements of anti cancer drugs?

Answer 5

High therapeutic index

Selective toxicity: Target the cancerous cells over human cells

Question 6

How can cancer treatments target mutations to kill the cancer tumour?

Answer 6

Tumours cells mutate, change phenotype and become more dangerous
Selection causes survival of cancer cells with more advantageous and beneficial mutations
Some mutations would be dangerous to the cell if a beneficial mutation had not come prior to this
Cancer drugs can target mutations prior to the beneficial mutation -> cancer cell death

Question 7

Describe the principal of oncogene addiction and how it is used in cancer treatment

Answer 7

Oncogenic pathways become activated and remain dominant
Epigenetic and genetic changes can silence the parallel proliferation pathways
Cancer cells become dependent on the oncogenic pathways for survival
Drugs can target the oncogenic pathways to cause death

Question 8

Describe synthetic leathality

Answer 8

Normal cells: 1 gene is silenced by drug leaves remaining gene to compensate for remaining function

Cancer cells: 1 gene is mutated, leaves the other gene sensitive to inhibition by drugs

Question 9

How do we screen for synthetic lethality?

Answer 9

Isogenic cells = identical except for the presence of absence of a cancerous mutation
Different chemical/genetic factors ( perturbants) are added to see if any are cytotoxic to the cell

Question 10

Example of BRCA1/BRAC2 + PARP inhibition

Answer 10

BRCA1/2 proteins are involved in double stranded DNA repair
PARP - Single stranded DNA repair via base excision repair
BRCA mutation -> non functional protein so DNA cannot be repaired by this pathway
PARP inhibitors block other pathway so cancer cells have no mechanism of DNA repair so will die

Question 11

What is a marker of sensitivity to PARP inhibition?

Answer 11

Lack of RAD51 foci ( caused by BRCA1/2 mutations)

• RAD 51 foci will form when cells are exposed to DNA damgage
• Those with RAD51 foci are resistant to PARP inhibitors

Question 12

Describe the philadelphia chromosome

What conditions is it associated with?

Answer 12

Translocation between the ends of chromosome 9 ( ABL) and chromosome 22 ( BCR)

Forms the transgene = BCR-ABL encoding for the chimeric BCR-ABL protein

This protein allows for growth and survival via tyrosine kinase signalling

Associated with Acute lymphoblastic leukaemia and chronic myeloid leukaemia

Question 13

What translocation is associated with acute pro myelocytic leukaemia ?

Answer 13

Translocation between chromosome 15 + 17 to produce the PML-RARalpha fusion oncoprotein

Question 14

Describe the function of RAR?

Describe the effects of the fusion oncoprotein?

Answer 14

RAR is a transcriptional regulator, binds to response elements as a heterodimer with RXRS.
Binding of retinoic acid ligand allows for co regulatory exchange and activates gene transcription

PML-RARalpha fusion oncoprotein does not require RA to bind to response elements is binds as a homodimer. Does not respond to physiological levels of RA so no co regulatory exchange or gene transcription.

Therapeutic RA allows for co regulatory exchange

Question 15

What may be a therapeutic target of PML-RARalpha?

Answer 15

• RA binds to RARalpha and induces a conformational change to recruit the proteosome
• Aresenic trioxide binds to PML part of fusion oncoprotein leading to degradation

Question 16

What are PROTACS?

Answer 16

Proteolysis targeting chimeras
Bifunctional molecules made of 2 active domains joined by a linker to remove proteins

1 protein engages with E3 ligase and other will bind to the target protein
Recruitment of E3 ligase to target protein causes ubiquitination + degradation by proteosome