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Flashcards in Lecture 1 Deck (45):
1

What are the 8 (previously 6) commonly acquired traits of cancer causing cells?

1) Self-sufficiency in growth signals

2) Insensitivity to growth-inhibitory signals

3) Tissue invasion and metastasis capability

4) Limitless replicative potential

5) Sustained angiogenesis

6) Evasion of programmed cell death

7) Reprogramming of energy metabolism

8) Evading immune system

2

Name two enabling events

Loss of genome surveillance and checkpoint control Destabilisation of nuclear organisation

3

Why are there so many ways to acquire the same trait?

Mutation of several pathways leads to same consequence for the cell In each pathway mutation of several different genes or proteins can have same effect

4

What three measures are used in classifying cancers? Why is this not the best way?

Site of origin

Cell type

Age of onset

Does not look at molecular level

5

Why do stem cells require fewer mutations on average to become a cancer cell?

Already have unlimited proliferative ability

6

Why are most tumours described as heterogeneous?

Made up of both neoplastic and pre-neoplastic cell populations

7

How can two independent cancers come from the same origin?

Same starting mutation but different mutation later on lead to them being separated by healthy tissue which has not developed the caner causing mutation

8

What do normal cells require to move from quiescence to profilerence?

Mitotic signal; paracrine or endocrine 

9

What are the steps from a mutation to fully invasive cancer

1) Cell acquires genetic mutation - which promotes or allows proliferation 2) Hyperplasia 3) Dysplasia 4) In situ cancer 5) Invasive Cancer - with its own blood supply

10

How are external signals transmitted into the cell?

Transmembrane Receptors- which then dimerize and phosphoryalte each others tyrosine domains and start an signal transuction pathway

11

What types of singalling molecules are involved in mitotic signalling?

1) Diffusbale growth factors

2) Extracellular matrix components

3) Cell-to-cell ahgesion/interaction moleclues

12

How can oncognenes hijack these signal pathways?

Mimicking normal growth signaling

Code forconstitutively active (ligand independent receptors)

Disrupt signal transduction

13

What are oncogenes?

Gain of function mutations in genes that promote cell proliferation

Dominant mutations

14

What are tumour supressor genes?

Loss of function mutations in a genes that restrain cell proliferation or guard the genome

Recessive mutations (often underlie familial cancers)

15

Outline 2 examples of how cancer cells can de-regulate and acquire self-suffiency in growth signals

Example 1: the ErbB2/Her2/Neu

Overexpression of receptor = hypersensitivity to ligand. Acitvates intracellular kinase which has complex set of effects on both apoptosis and proliferation

Example 2: RAS

An intra-cellular switch protein which can be permanently on due to mutation. When GDP is bound the protein is inactive whereas GTP bound RAS is active. The swtiching between the two have effects on the shape of the entire protein, with active RAS being able to bind down-stream proteins in cell signalling pathways. in non-cancer cells RAS will hydrolyse GTP to switch off; this is dependent on RAS-GAP, inserting an argiunine side chain directly into the active site, which work with threonine and glutamine, of the RAS itself, to promote GTP hydrolysis. 

 

16

What is herceptin?

Monocolonal antibody that blocks Her2 receptor and extends life in breast cancer patients

Howvere, the life extension is only for months and the quality of life is severed inpacted

17

What percentage of all cancers have RAS mutations?

25%

18

What are viral oncogenes?

Some viruses have acquired proto-oncogenes which they will pass onto host cells; conferring a growth advantage to the cell, helping to propagate the virus but causing cancer in the host.

 

19

What is heterotypic signalling?

Signalling between cancerous and non-cancerous neighbours.

Neighbours may co-evolve with tumour cells to sustain their growth

20

What happens during apoptosis and how long will it take?

-Disruption of cell membranes

-Structural filaments broken down

-Chromosomes degraded

- Debris is phagocytosed

The process will take approximately 24hours

21

What are the two types of trigger for apoptosis?

Extrinsic singal - Respond to signalling imblances of survival signals and death signals

Intrinsic Signals - Respond to DNA damage and hypoxia

22

How do these tirggers lead to apoptosis?

Feed into the mitochondria and cause the release of cytochrome C; activating caspases

23

Which familly contains most pro- and anti-apoptotic factors?

Bcl-2 family

24

How was Bcl-2 discovered?

Bcl-2 was identified as one half of a chromosomal translocation in B-cell lymphoma that results in Bcl-2 up-regulation and increased anti-apoptotic activity

25

What effect does a loss of p53 mutation have?

Mutant cells are not able to die in response to DNA damage

seen in ~50% of tumours

26

What initially determines the maximum size of a tumour? How is this overcome?

Diffusion limits - all cells must be ~100µm from a capillary

Can be overcome by a tumour developing a blood supply

27

Outline an example of the angiogenic switch

Hypoxia Induced Factor (HIF)

Under normal oxygen conditions HIF is hydroxylated (at proline and asparagine), this is recognised by Cul2 (an E3 ligase) which will target the protein for proteolysis. This hydorxylation of asparagine also blocks binding of transcriptional activators.

Under hypoxic conditions, unphosphorylated HIF is stabilised and coactivators(p300/CBP) can binf cuasing transcription of target genes. 

28

What three factors are essential for angiogenesis?

Vascular Endothelial Growth Factor (VEGF)

Fibroblast Growth Factors (FGFs)

Transforming Growth Factors (TGFs)

29

What is the Warburg Effect?

The observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.

30

Why do cancer cells convert glucose to lactate regardless of whether oxygen is present? 

Aerobic glycolysis allows diversion of glycolytic intermediates into biosynthetic pathways required for assembling new cells.

31

What are the emerging links between metabolism and growth control?

Proliferation signaling regulates pathways that incorporate nutrients into biomass (Eg PI3K)

Cancer-associated mutations favour these pathways and enable nutrient manufacture over efficient ATP production

32

How has cancer's tendency to use aerobic glycolysis been targeted for tumour treatment?

Inihibitor of PI3 kinase (Sunitinib) shown to stop glucose uptake by tumours

Shown using flourescent glucose analogue and PET scan - where tumour in liver no longer taking up the flourescent analgue after treatment with Sunitinib 

Study did not show if the inhibitor was capable of stopping tumour growth and if it did extend life

33

What is immune surveillance?

Ability of immune system to recognise tumour cells and kill them 

34

What factor can tumour cells use to stop natural killer proliferation?

TGF-ß

35

What is immune escape?

What is immune privelage?

Ability of cancer cells to evade detection or killing

Tumours develop the ability to modulate immune function

36

Give an example of a type of immune escape used by cancer cells

Resistnace to Fas mediated apoptosis 

  • Down-regulation or mutation of Fas receptor
  • Abnormalities in signal transduction proteins
  • Down regulation of caspase 1, Bax or Bak
  • Upregulation of Bcl2

 

37

Give an example of a type of immune privilege employed  cancer cells

Cancer cells can express Fas-L and kill Fas sensitive tumour-infiltrating lymphocytes 

38

Give an example of the search and destory capability of the immune system 

Pigmentation is gradually lost around an abnormal melanocytic mole as abnormal melanocytes are destroyed. Those in surrounding area are also killed generating a distinctive halo. Likely to be happening all over the body to pre-malignant lesions that are:

i)different enough to be recognised, but

ii)not advanced enough to have acquired evasive strategies

39

What are the steps between normal cell divisions and immortalisation?

1)  Cell divisions (~60-70 for most mammalian cells)

2) Senescence (Alive but not dividing) 

3) Crisis (Cell recieving signals to divide from onocgene; usually cleads to cell death but some cells become immortal)

4) Immortalization (Cell develops ability to proliferate forever - only 1 in 107

40

What is the end replication problem?

During cell division DNA polymerase can only add nucleotides onto the 3' end so the lagging template strand gets shorter 

41

How can this problem be overcome?

Telomerase: a protein-RNA complex which can extend chromosome ends to allow replication of genome

42

How can this lead to immortalisation?

A mutation that causes over expression of telomerase can lead to a cell being able to divide indefinitely 

This is seen in 85-90% of cancers.

43

What is thought to be a consequence of passage through crisis?

Altered karotypes due to random fusion and repair by non-homologous end joining

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