12. Cancer Metabolism Flashcards
how does metabolism differ in unicellular vs multicellular organisms?
unicellular –> metabolism dictated by abundance of nutrients
multicellular –> metabolism dictated by growth signals
what is the warburg effect?
preferential production of pyruvate and lactate even in aerobic conditions
what does lactate produce?
glycolytic intermediates that are building blocks for cancer cells to survive
what is the relationship btwn glycolysis and oxidative phosphorylation in cancer?
both are active in a specific balance
how does the type of metabolism change throughout a tumour?
depending on distance from blood supply there is a switch in metabolism due to diff access to nutrients, O2, pH
4 types of cancer model systems to study metabolism
- standard culture
- 3D culture
- tissue slice culture
- in vivo
metabolism in standard culture
relies more on glutamine, less on glucose
metabolism in 3D culture
relies more on glucose, less on glutamin
metabolism in slice culture
relies mostly on glucose
metabolism in in vivo model
almost entirely relies on glucose
from standard culture to mouse, what is the downside and upside?
increased physiological relevance
decreased tractability
how can we use cancer metabolism to detect tumour?
many tumour types potentiate glycolysis and require more glucose –> monitor glucose uptake with labelled glucose (FDG-PET)
when can we not use glucose metabolism to detect tumour?
prostate cancer does not rely on glucose metabolism –> can’t use FDG-PET
How can we image prostate cancer?
detect choline and acetate
is it fully impossible to use glucose metabolism to detect prostate cancer?
as disease progresses and patient receives therapies but disease returns, the cancer can become more dependent on glucose
how does a high fat diet affect prostate cancer?
high fat diet promotes aerobic glycolysis
experimental setup for high fat diet promoting aerobic glycolysis in prostate cancer
result and how we detect?
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
how do cancer cells replicate their genome?
use nucleotides and glycolytic intermediates from warburg effect
what does PURINE nucleotide synthesis require?
requires folate cycle w folic acid
2 types of anticancer drugs that block purine nt synthesis
- drug that mimics metabolites
- drug that blocks PRPP amidotransferase
what drug targets pyrimidine nt synthesis?
5-FU targets TS to block conversion of uridine to thymidine
what is IDH?
normally makes a-KG
what does a-KG do?
cofactor for TET for DEmethylation of DNA and histones –> allows DNA to be active for factors to bind
interplay btwn metabolism and epigenetics
what does IDH mutant produce?
produces D-2-hydroxyglutarate –> ONCOMETABOLITE
what does D-2-hydroxyglutarate do?
reduces demethylation by TET to prevent factors from binding and DNA is inactive
describe IDH mutant causing loss of insulation
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
describe IDH mutant causing change of insulation
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
what is SAM?
methyl donor for methylation –> provided thru 1 carbon metabolism with folate cycle and methionine cycle
what does epigenetic remodeling rely on?
epigenetic remodeling relies on metabolites
what is metabolomics?
measures + interprets changes in small molecules in organisms
why does the pH of tumour microenvironment change?
lactate is acidic so as metabolic waste accumulates, tumour microenvironment changes
describe nutrient sharing in the tumour microenvironment
cancer cells can use glucose, make lactate, then other cells use the lactate
describe the nutrient competition in the tumour microenvironment
diff metabolites and nutrients are differently used by diff cells –> leads to competition btwn cell types that shape interactions
consequence of nutrient competition on Teff cells
glucose is depleted so there is less for Teff cells –> immune response is blocked
consequence of nutrient competition on Treg cells
Trp is taken up by TAM and metabolized into Kyn –> attracts and increases prolfieration of Treg cells to repress immune response
describe nutrient symbiosis in the tumour microenvironment
eventually reach steady state/symbiosis of interactions btwn cancer cells and microenvironment
2 ways that high fat diet makes the immune system pro-tumourigenic
- high fat diet increases lactate –> recruits pro-tumourigenic macrophages
- high fat diet increases Treg cells in stroma of prostate tumours
what is the consequence of the diet influencing tumour metabolism?
diet influences tumour metabolism which affects the tumour microenvironment to cause diff cell interactions
describe the 1914 study on the relationship btwn tumour types and nutrients
some tumours were not affected by nutrients, some were affected by nutrients
why is it difficult to isolate 1 variable in the relationship btwn diet and cancer
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
describe how genetic alterations affect prostate tumour response to diet with PTEN and PTP1B
conclusion
- how can you further develop the tumour?
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
how does calorie restriction affect prostate cancer vs KRAS cancer model?
significance?
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
what is the master TF in prostate cancer?
Myc overexpression
describe the experiment with high fat diet on overexpressed Myc in prostate cancer
saw changes in metabolites BEFORE visual changes in tumour pathology
what occurs before visual changes in tumour?
metabolic, epigenetic, and transcriptional reprogramming occur before changes in tumour
what were the results when looking at functional capacity after surgery with pre-surgery exercise and nutrition rehab?
measuring quality of life –> patients were in better shape with the rehab
how does radiation work?
causes replication-independent DOUBLE STRAND BREAKS that kill non-replicating cells
what can cause cells to be resistant to radiation? (2)
- production of nucleotides
- control of ROS
what is resistance to radiation linked to?
the production of nt and control of ROS are both linked to folate and methionine pathways
what is dietary methionine for?
methionine cycle
methionine restriction + radiation VS methionine restriction + no radiation
conclusion
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
what type of drug is 5-FU and how does 5-FU help cancer?
downsides to 5-FU?
antimetabolite drug
inhibits TS –> prevents incorporation of its metabolites into RNA and DNA, leading to DNA damage
has many side effects
experiment to test methionine restriction + 5-FU
conclusion
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
what does methotrexate inhibit? (4)
inhibits synthesis of:
1. DNA
2. RNA
3. thymidylates
4. proteins
how did researchers try to potentiate methotrexate treatment?
did CRISPR screen to see sensitivity of methotrexate by removing diff genes –> see which genes are important for cell survival, oncogenes, tumour suppressor, etc.
what gene was found to increase sensitivity to methotrexate?
FTCD
what is FTCD?
Breaks down histidine in 2 steps
why does FTCD increase sensitivity to methotrexate?
how can we use this for better methotrexate treatment?
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
what do PI3K inhibitors do? (3)
blocks:
1. proliferation
2. cell survival
3. angiogenesis
are PI3K inhibitors successful?
worked in vitro but NOT in vivo
why did PI3K inhibitors not work in vivo?
after treatment, there is flare of insulin the bloodstream to increase glucose uptake in tumour
what mitigated the excess insulin released and glucose taken up after PI3K inhibitor treatment?
metformin worked but best effect was with ketogenic diet
why was there an increase in insulin following PI3K inhibitor treatment? and the 6 steps for insulin release?
PI3K pathway is also in liver cells
- inhibit PI3K in liver
- glycogen stores breakdown
- increased glucose in blood
- increased insulin
- insulin acts on insulin receptor and feeds into PI3K pathway to activate it
- causes INCOMPLETE blockage of PI3K
how did the ketogenic help with the PI3K side effects?
ketogenic diet blocked breakdown of glycogen store
what happens with ketogenic diet + PI3K inhibitor?
FULL blockade of PI3K
role of PD1 checkpoint inhibitor
allows T cells to attack tumour
what affects PD1 checkpoint inhibitor efficacy?
obesity –> associated with higher tumour growth and exhaustion of T cells –> therefore MORE responsive to PD1 inhibitor
why was it odd that patients who were more obese responded better to PD1 inhibitors?
they had worse tumour progression, but could be rescued more easily
