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cancer > 27. tumour metabolism > Flashcards

27. tumour metabolism Flashcards

1
Q

what are the hallmarks of cancer?

A
  • self sufficient in growth signals
  • insensitivity to anti-growth signals
  • tissue invasion and metastasis
  • limitless replication potential
  • sustained angiogenesis
  • evade apoptosis
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2
Q

what four hallmarks were added in 2011?

A
  • avoiding immune destruction
  • genome instability and mutation
  • tumour promoting inflammation
  • deregulation of cellular energetics
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3
Q

what is an important driver of cancer?

A

altered cellular metabolism

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4
Q

metabolic phenotype can promote carcinogenic, what can this also be a consequence of?

A

rapid growth and/or hypoxia

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5
Q

what can be exploited therapeutically in terms of metabolism?

A

metabolic dependence of cancer cell

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6
Q

what can be used to facilitate discovery of new cancer biomarkers and drug targets?

A

metabolic profiling

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7
Q

what did Otto Warburg’s observe?

A

observed that cancer cells exhibit glycolysis to lactate (fermentation) and reduce mitochondrial respiration even in the presence of sufficient oxygen

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8
Q

what was Otto Warburg sure to be true?

A

that cancer cells arose from some defects in respiration - this is only true in some circumstances

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9
Q

name 5 common metabolic phenotypes associated with cancer cells

A
  1. increased glycolysis and lactate production
  2. increase in glutamine uptake and metabolism
  3. increase acid production and export
  4. increase lipid synthesis
  5. increase nc synthesis and folate dependency
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10
Q

common metabolic phenotypes associated with cancer cells are hallmarks of rapidly dividing cells. what are they the consequence of?

A

the fact that tumour cells are dividing rapidly and therefore hypermetabolic

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11
Q

describe PET imaging

A

> radiolabelled glucose analogue, fluoro-deoxyglucose
taken up by fast metabolisng cells
P by hexokinase and retained by tissue with high metabolic activity

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12
Q

what does PET imaging allow?

A

detection of distal metastasis i.e. surgery will not be curative

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13
Q

what can PET Imaging be used to monitor?

A

monitor therapy - impairing tumour cells will impair their metabolism

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14
Q

name a chemotherapy that targets highly metaboling cells?

A

anti-metabolites, these are targeted at inhibiting nucleotide and DNA synthesis
e.g. 5-fluorouracil
when incorporated this causes chain termination, blocks replication and lead to cell death

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15
Q

what are some hormone dependent cancers treated with?

A

anti-oestrogen and anti-androgens

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16
Q

glycolysis to lactate is energy inefficient compared to what? but what does it allow?

A

mitochondrial oxidation of pyruvate

>but it does allow glycolysis to occur more rapidly

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17
Q

what can be used for anabolism in rapidly dividing cells? (give 2 examples)

A

glycolytic intermediates
e.g. intermediates of glycolysis can form amino acids
>glucose-6-phosphate can enter oxidative pentose phosphate pathway to make NADPH

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18
Q

name one major drive form metabolic reprogramming cancer cells?

A

> cells need to tolerate lack of oxygen (hypoxia) and switch to glycolysis

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19
Q

what do cancer cells need to do in order to survive, promote invasion and metastasise?

A

export acid
>this gives them survival advantage over other cells - they can adapt and survive in these conditions as they are genomically unstable
>low pH degrades some ECM

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20
Q

in terms of cells cycle check points, what does having high glycolytic rate mean?

A

high production of some metabolic intermediates will allow for the cell cycle check points to be cleared - this promotes growth and survival

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21
Q

how do this metabolic reprogramming of cancer cells come about?

A

they are driven by the action of oncogenes or the loss of tumour suppressers

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22
Q

name a target gene of p53, and what is it?

A

TIGAR

>a metabolic enzyme that catalyses conversion of fructose-2-6-bisphosphate to fructose-6-phosphate

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23
Q

what does frustose-6-phosphate do?

A

this affects phosphofructokinase by allosteric interactions decreasing its activity

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24
Q

what does fructose-2-6-bisphosphate do?

A

this is an activator of phosphofructokinase

>TIGAR reduces its levels and so phosphofructokinase activity is decreased

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25
Q

what affect does p53 have on the glycolytic rate?

A

> it makes TIGAR
this increases fructose-6-phosphate levels
this allosterically reduces phosphofructokinase activity
glycolic rate reduced

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26
Q

what does p53 supresses and promote?

A

supresses glycolysis and promotes respiration

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27
Q

what level of DNA damage does TIGAR get expressed?

A

low levels, after high levels of DNA p53 carries out pro-apoptotic function

28
Q

what can p53 also respond to ?

A

metabolic stress

29
Q

name 4 oncogenes that have been linked with metabolism

A

Myc
Ras
HIF-1
Akt

30
Q

in what way to oncogenes and tumour supresses generally regulate glycolysis

A

tumour suppressers inhibit glycolysis and oncogenes promote it

31
Q

what is the last enzyme in glycolysis? and name an isoforms

A

pyruvate kinase

M2

32
Q

in what form of the m2-pyruvate kinase isoform is there maximum glycolytic rate?

A

when M2 is a tetramer

33
Q

what form of M2-pyruvate kinase is found in tumours and why is this?

A

tumour specific isoform of M2-pyruvate kinase is found as a dimer, this has lower affinity to its substrate phosphoenolpyruvate, lowering glycolytic flux = accumulation of glycolytic intermediated that can be used for growth

34
Q

how is glutamine used in lipid synthesis

A

> pyruvate enters TCA in mt
citrate generate in TCA cycle exported in cytosol for lipid synthesis as acetyl-coA
this removes substrate from TCA and so glutamine enters TCA cycle as alpha ketoglutarate to maintain flux

35
Q

what is anaplerosis

A

the act of replenishing TCA cycle intermediates that have been extracted for biosynthesis

36
Q

what occurs under conditions of hypoxia or mitochondria miss-function? and why does this occurs?

A

reductive carboxylation

>little C enters TCA and so de novo lipid synthesis needs to occur by another method in order to obtain citrate

37
Q

how does reductive carboxylation occur?

A

> in the cytosol, glutamine is converted citrate
this is converted to acetyl-CoA without passing through TCA cycle
this can be used as precursor for fatty acid synthesis

38
Q

what upregulates glutamine catabolism emzynes?

A

c-Myc

39
Q

can defect in metabolism can promote cancer?

A

sometimes, genetic polymorphism alteration in kerb cycle enzymes can promote cancer

40
Q

name an enzymes that are tumour suppressers

A

succinate dehydrogenase (SDH)

41
Q

what leads to an accumulation of succinate? and what affect does this have?

A

loss of function mutations in succinate dehydrogenase
>succinate inhibits HIF propyl hydrolase
>HIF cannot be hydroxylsted and so is stabilised even in normoxia
>this leads to upregulation of glycolysis and angiogenesis

42
Q

what types of cancer are people with succinate dehydrogenase mutations susceptible to?

A

head and neck paragangliomas

43
Q

what two things lead to low pH in cnacer cells?

A

lactate from glycolysis and high rates of respiration leading to CO2 production

44
Q

what does acidosis in cancer cells can lead to? and what may this lead to?

A

necrosis

>potential therapeutic opportunity

45
Q

what do cancer cells upregulate in order to maintain cellular pH?

A

lactate transporters

46
Q

when extracellular pH drops below optimum, what may this result in?

A

> cytotoxic T cell inhibition

>promote invasion

47
Q

what does the acidic environment also select for?

A

motile cells that can eventually breach the basement membrane

48
Q

when oxygen is low, what two options do cancer cells have?

A

adapt to glycolytic lifestyle or die

49
Q

what two things does the acidic environment disrupt in terms of other cells?

A

inhibit immune cells and disrupts the function or surrounding cells

50
Q

why can K-ras mutations give a cell a better advantage under low glucose conditions?

A

this upregulates glucose transporters and metabolic enzymes

51
Q

what is metabolomics profiling?

A

characterising the metabolite composition of biological samples using technology that measure many molecules in a single analysis
e.g. NMR and mass spec

52
Q

what does NMR exploit?

A

magnetic properties of atoms nuclei

53
Q

how does MS work?

A

vaporises a molecule, gives it a charge, applies a magnetic field and measure the time it takes for it to be detected

54
Q

molecular profiling was done on lots of different cancer cells lines, what did they do and what did this show?

A

> they looked at culture medium to see what cells were taking up and releasing
glycine and phosphocholine appearing in medium correlated with growth rate
prolife mRNA to show glycine synthesis enzymes correlated with growth rate
glycine synthesis essential for rapid growth

55
Q

how was the molecular profiling work done on cancer cell lines correlated to patients?

A

> look at enzyme that catalyses serine to glycine

>patients with high levels of this enzyme relapse more quickly with breast cancer

56
Q

in terms of metbolomics, what is associated with malignant transformation ?

A

altered choline metabolism

>high peaks in NMR spectrum seen in all solid tumours and is a sign of rapid proliferating in tissue

57
Q

what can levels of choline in a tissue detected by MRS provides a biomarker for?

A

transformation
staging
response to therapy

58
Q

how is choline kinase implicated in cancer?

A

it is upregulated

59
Q

a certain point mutations is frequently seen in what enzyme in kidney, brain and bone cancer? how was metabolomics used to determines its function in krebs cycle?

A 
isocitrate dehydrogenase (IDH) 
>metabolomics used for functional genomics
>compared cells with and without mutation for kerb cycle intermediates 
>massive difference in 2-hydroxyglutartate levels
60
Q

what type of mutation did metabolomics identify in isositrate dehydrogenase?

A

gain of function mutation - faster back reaction that forward
IDH converts isocirate to aKG
oncogenic IDH converts aKG to 2-hydroxyglutarate

61
Q

what is 2-hydroxyglutarate produced by oncogenic IDH?

A

an oncometabolite
this activates HIF and inhibits DNMT and HMT
>this is direct cause on cancer progression

62
Q

tumour suppresser are harder to drug as a deletion mutation has resulted in the loss of a protein, how can we get around this? and what is this process called?

A

loss of TS means cells become more dependent on other pathways - these can be selectively targeted and wont affect other tissue
>this process is called synthetic lethality

63
Q

how does synthetic lethality work?

A

hitting an enzyme/gene that is synthetically lethal in the context of the loss of a tumour suppresser

64
Q

loss of fumerate dehydrogenase can lead to accumulation of succinate in cells, what would happen if cells could not remove this and how can we target this? what are these cells synethically dependent on?

A

this would be toxic to cells.
>cell shunts metabolites into haem synthesis, haem is broken down by haem oxygenase
>haem oxygenase (KO out in cells with KO FD will result in cell death)

65
Q

give 2 example of how diet can affect cancer

A
  • strong correlation between fat intake and breast cancer

- correlation between colorectal cancer and red meat consumption

66
Q

obesity is associated with breast cancer and many other cancers, why is this?

A

> increased GF production leads to insulin resistance
fat cells release oestrogen - this drives hormone dependent cancer and promotes tumour development (in certain tissue e.g. breast - proliferation and inhibit apoptosis)

cancer (24 decks)

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