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EXMD504 > 12. Cancer Metabolism > Flashcards

12. Cancer Metabolism Flashcards

1
Q

how does metabolism differ in unicellular vs multicellular organisms?

A

unicellular –> metabolism dictated by abundance of nutrients

multicellular –> metabolism dictated by growth signals

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2
Q

what is the warburg effect?

A

preferential production of pyruvate and lactate even in aerobic conditions

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3
Q

what does lactate produce?

A

glycolytic intermediates that are building blocks for cancer cells to survive

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4
Q

what is the relationship btwn glycolysis and oxidative phosphorylation in cancer?

A

both are active in a specific balance

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5
Q

how does the type of metabolism change throughout a tumour?

A

depending on distance from blood supply there is a switch in metabolism due to diff access to nutrients, O2, pH

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6
Q

4 types of cancer model systems to study metabolism

A
  1. standard culture
  2. 3D culture
  3. tissue slice culture
  4. in vivo
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7
Q

metabolism in standard culture

A

relies more on glutamine, less on glucose

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8
Q

metabolism in 3D culture

A

relies more on glucose, less on glutamin

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9
Q

metabolism in slice culture

A

relies mostly on glucose

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10
Q

metabolism in in vivo model

A

almost entirely relies on glucose

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11
Q

from standard culture to mouse, what is the downside and upside?

A

increased physiological relevance

decreased tractability

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12
Q

how can we use cancer metabolism to detect tumour?

A

many tumour types potentiate glycolysis and require more glucose –> monitor glucose uptake with labelled glucose (FDG-PET)

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13
Q

when can we not use glucose metabolism to detect tumour?

A

prostate cancer does not rely on glucose metabolism –> can’t use FDG-PET

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14
Q

How can we image prostate cancer?

A

detect choline and acetate

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15
Q

is it fully impossible to use glucose metabolism to detect prostate cancer?

A

as disease progresses and patient receives therapies but disease returns, the cancer can become more dependent on glucose

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16
Q

how does a high fat diet affect prostate cancer?

A

high fat diet promotes aerobic glycolysis

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17
Q

experimental setup for high fat diet promoting aerobic glycolysis in prostate cancer

result and how we detect?

A

animals genetically engineered to express Myc in prostate fed high fat diet

metabolism in prostate switches to glycolysis –> see more lactate and G6P so glucose is more GLUCOSE AVID

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18
Q

how do cancer cells replicate their genome?

A

use nucleotides and glycolytic intermediates from warburg effect

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19
Q

what does PURINE nucleotide synthesis require?

A

requires folate cycle w folic acid

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20
Q

2 types of anticancer drugs that block purine nt synthesis

A
  1. drug that mimics metabolites
  2. drug that blocks PRPP amidotransferase
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21
Q

what drug targets pyrimidine nt synthesis?

A

5-FU targets TS to block conversion of uridine to thymidine

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22
Q

what is IDH?

A

normally makes a-KG

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23
Q

what does a-KG do?

A

cofactor for TET for DEmethylation of DNA and histones –> allows DNA to be active for factors to bind

interplay btwn metabolism and epigenetics

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24
Q

what does IDH mutant produce?

A

produces D-2-hydroxyglutarate –> ONCOMETABOLITE

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25
Q

what does D-2-hydroxyglutarate do?

A

reduces demethylation by TET to prevent factors from binding and DNA is inactive

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26
Q

describe IDH mutant causing loss of insulation

A

normally: area is demethylated so CTCF can bind and add TAD domains –> genes can be isolate so a specific gene can be associated with its enhancer

IDH mutant: area remains methylated so CTCF can bind and PREVENTS isolation of gene from different gene’s enhancer –> gene becomes incorrectly regulated by enhancer for diff gene

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27
Q

describe IDH mutant causing change of insulation

A

normally: loop is created by binding CTCF at demethylated sites so enhancer can be associated with far away gene

IDH mutant: CTCF cannot bind at methylated site so enhancer is too far from its gene

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28
Q

what is SAM?

A

methyl donor for methylation –> provided thru 1 carbon metabolism with folate cycle and methionine cycle

29
Q

what does epigenetic remodeling rely on?

A

epigenetic remodeling relies on metabolites

30
Q

what is metabolomics?

A

measures + interprets changes in small molecules in organisms

31
Q

why does the pH of tumour microenvironment change?

A

lactate is acidic so as metabolic waste accumulates, tumour microenvironment changes

32
Q

describe nutrient sharing in the tumour microenvironment

A

cancer cells can use glucose, make lactate, then other cells use the lactate

33
Q

describe the nutrient competition in the tumour microenvironment

A

diff metabolites and nutrients are differently used by diff cells –> leads to competition btwn cell types that shape interactions

34
Q

consequence of nutrient competition on Teff cells

A

glucose is depleted so there is less for Teff cells –> immune response is blocked

35
Q

consequence of nutrient competition on Treg cells

A

Trp is taken up by TAM and metabolized into Kyn –> attracts and increases prolfieration of Treg cells to repress immune response

36
Q

describe nutrient symbiosis in the tumour microenvironment

A

eventually reach steady state/symbiosis of interactions btwn cancer cells and microenvironment

37
Q

2 ways that high fat diet makes the immune system pro-tumourigenic

A
  1. high fat diet increases lactate –> recruits pro-tumourigenic macrophages
  2. high fat diet increases Treg cells in stroma of prostate tumours
38
Q

what is the consequence of the diet influencing tumour metabolism?

A

diet influences tumour metabolism which affects the tumour microenvironment to cause diff cell interactions

39
Q

describe the 1914 study on the relationship btwn tumour types and nutrients

A

some tumours were not affected by nutrients, some were affected by nutrients

40
Q

why is it difficult to isolate 1 variable in the relationship btwn diet and cancer

A

tumour involves thousands of players, microbiome, etc. that are all affectedby age and metabolic rate

lots of associations btwn diet and cancer but hard to find causality

41
Q

describe how genetic alterations affect prostate tumour response to diet with PTEN and PTP1B

conclusion
- how can you further develop the tumour?

A

prostate cancer has loss of PTEN
- leads to increased PIP3 which activates phospho-Akt
- high fat diet had no effect on this

high fat diet only increased prostate cancer if PTP1B is lost
- PTP1B is negative regulator of IGF-1R

THEREFORE, with PTEN loss, there is a certain threshold of disease progression if you feed more –> beyond this, it is resistant to high fat diet
- further develop the tumour by de-repressing the system

42
Q

how does calorie restriction affect prostate cancer vs KRAS cancer model?

significance?

A

prostate cancer (PIP3): calorie restriction didn’t affect proliferation and didn’t slow down progression of cancer

KRAS model: calorie restriction reduced proliferation

THEREFORE, there is genetic basis that determines whether disease is affect by diet

43
Q

what is the master TF in prostate cancer?

A

Myc overexpression

44
Q

describe the experiment with high fat diet on overexpressed Myc in prostate cancer

A

saw changes in metabolites BEFORE visual changes in tumour pathology

45
Q

what occurs before visual changes in tumour?

A

metabolic, epigenetic, and transcriptional reprogramming occur before changes in tumour

46
Q

what were the results when looking at functional capacity after surgery with pre-surgery exercise and nutrition rehab?

A

measuring quality of life –> patients were in better shape with the rehab

47
Q

how does radiation work?

A

causes replication-independent DOUBLE STRAND BREAKS that kill non-replicating cells

48
Q

what can cause cells to be resistant to radiation? (2)

A
  1. production of nucleotides
  2. control of ROS
49
Q

what is resistance to radiation linked to?

A

the production of nt and control of ROS are both linked to folate and methionine pathways

50
Q

what is dietary methionine for?

A

methionine cycle

51
Q

methionine restriction + radiation VS methionine restriction + no radiation

conclusion

A

Met restriction + no radiation –> no impact on tumour growth

Met restriction + radiation –> reduced tumour growth

THEREFORE, Met restriction alone doesn’t help but can potentiate the radiation treatment

52
Q

what type of drug is 5-FU and how does 5-FU help cancer?

downsides to 5-FU?

A

antimetabolite drug

inhibits TS –> prevents incorporation of its metabolites into RNA and DNA, leading to DNA damage

has many side effects

53
Q

experiment to test methionine restriction + 5-FU

conclusion

A

Mice given tolerable dose so tumour won’t respond (on purpose)

Met restriction + 5-FU increases 5-FU restriction

even at dose of 5-FU known to be ineffective, Met restriction will give an effect

54
Q

what does methotrexate inhibit? (4)

A

inhibits synthesis of:
1. DNA
2. RNA
3. thymidylates
4. proteins

55
Q

how did researchers try to potentiate methotrexate treatment?

A

did CRISPR screen to see sensitivity of methotrexate by removing diff genes –> see which genes are important for cell survival, oncogenes, tumour suppressor, etc.

56
Q

what gene was found to increase sensitivity to methotrexate?

A

FTCD

57
Q

what is FTCD?

A

Breaks down histidine in 2 steps

58
Q

why does FTCD increase sensitivity to methotrexate?

how can we use this for better methotrexate treatment?

A

one of the steps of FTCD uses THF from the folate cycle –> target of methotrexate

if you feed histidine to tumour, will force its catabolism so it uses up THF and depletes the THF pool –> increasing sensitivity to methotrexate

59
Q

what do PI3K inhibitors do? (3)

A

blocks:
1. proliferation
2. cell survival
3. angiogenesis

60
Q

are PI3K inhibitors successful?

A

worked in vitro but NOT in vivo

61
Q

why did PI3K inhibitors not work in vivo?

A

after treatment, there is flare of insulin the bloodstream to increase glucose uptake in tumour

62
Q

what mitigated the excess insulin released and glucose taken up after PI3K inhibitor treatment?

A

metformin worked but best effect was with ketogenic diet

63
Q

why was there an increase in insulin following PI3K inhibitor treatment? and the 6 steps for insulin release?

A

PI3K pathway is also in liver cells

  1. inhibit PI3K in liver
  2. glycogen stores breakdown
  3. increased glucose in blood
  4. increased insulin
  5. insulin acts on insulin receptor and feeds into PI3K pathway to activate it
  6. causes INCOMPLETE blockage of PI3K
64
Q

how did the ketogenic help with the PI3K side effects?

A

ketogenic diet blocked breakdown of glycogen store

65
Q

what happens with ketogenic diet + PI3K inhibitor?

A

FULL blockade of PI3K

66
Q

role of PD1 checkpoint inhibitor

A

allows T cells to attack tumour

67
Q

what affects PD1 checkpoint inhibitor efficacy?

A

obesity –> associated with higher tumour growth and exhaustion of T cells –> therefore MORE responsive to PD1 inhibitor

68
Q

why was it odd that patients who were more obese responded better to PD1 inhibitors?

A

they had worse tumour progression, but could be rescued more easily

EXMD504 (12 decks)

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