Cancer Metabolism

rapidly proliferate

Cancers occur more often in tissues that…

exponential, better response to therapy, faster than primary tumours

Tumour growth is ________. Faster growth typically means ________, and metastases grow _______.

potentual doubling time if 100% cell survival, measured doubling time, rate of tumour cell death is 75-90%

V_pot (________) > V_D (________) because…

3-15%, CSCs, dedifferentiated cells

The growth fraction of tumours is _______ and consists of dividing cells like _______ or ______.

Mitochondria

_____ play a central role in tumour biology

TCA, acetyl-CoA, pyruvate, metabolic intermediates like NADH

The _____ cycle takes place within the mitochondria with ______ (from ______) as the input and _______ as the product.

ETC, NADH, TCA cycle, energy/ATP, oxygen dependent

The _____ in the mitochondria converts ______ from ______ to ______. This process is ______.

oxidative phosphorylation, aerobic glycolysis, much less efficient at making ATP but is faster, no oxygen

Differentiated tissues preferentially use ______ to produce ATP, while proliferative or tumour tissues typically use ______ which is _____ in comparison and requires ______.

glucose is converted to pyruvate via glycolysis in the cytoplasm > pyruvate in converted to acetyl-CoA in the mitochondria and acetyl-CoA enters TCA cycle > TCA makes NADH which fuels ETC > electrons from NADH are transferred to oxygen and ATP is generated

Glucose metabolism in healthy cells:

uncoupled from ETC, become the source of biosynthetic intermediates, Warburg effect

In cancer cells, the TCA cycle is _______ and components of the TCA cycle _______. This is referred to as the “_________.”

glucose is converted to pyruvate via glycolysis in the cytoplasm and pyruvate is converted to lactate > pyruvate in converted to acetyl-CoA in the mitochondria and acetyl-CoA enters TCA cycle > TCA cycle produces citrate, alpha-ketoglutarate, oxaloacetate, and malate which feed into tumour growth

Glucose metabolism in cancer cells:

lipids, amino acids, nucleotides

Citrate produced from uncoupled TCA in cancer cells is used to create _______, alpha-ketoglutarate produced is used to create _______, and oxaloacetate and malate are used to create _______.

used to make cell components

Because products from the TCA cycle are not entering the ETC in altered metabolism, they are ________ so that the TCA cycle can continue.

alternate energy sources, glucose, acetyl-CoA via aerobic glycolysis, glutamine, nucleotides via glutaminolysis, fatty acids and ketones, acetyl-CoA via beta oxidation, lactate, pyruvate via oxidation

Cancer cells, unlike most cells in the body, can use _______ such as ________ to make _______, ______ to make ______, _______ to make ______, and ______ to make _______.

direct glutamine conversion for nucleotide synthesis, conversion of glutamine to glutamate which can be used for glutathione synthesis and amino acid synthesis, and glutamate can be converted to alpha-ketoglutarate which is involved in histone and DNA methylation

Glutamine metabolism helps create components for new cells by:

FFA, cell components, uncoupling the TCA and ETC

Cancer cells can use _____ as another alternative fuel source. They enter to TCA cycle, providing _____, and also ________.

PI3K, increases inflammation, decreases glucose uptake in normal cells, increased circulating glucose, creating insulin resistance

Cancer cells can use FFAs to turn on _____ signalling, which directly ________ and _______ (leading to _______ and thus ______).

shuttling, change their metabolism, resource sharing, need glucose but make lactate, have glucose but can also use lactate

Cancer cells share lactate and glucose via _______. Not all cells in a tumour ________. Overall tumour growth is maximised by ________— hypoxic regions _______ and oxygenated regions ________.

take up lactate from hypoxic cells because it is a faster fuel source, take up glucose from oxphos in oxygenated cells

For resource sharing in cancer cells, oxygenated regions will ________ and hypoxic regions will ________.

farther from blood vessels, low oxygen and low glucose

Cells that are ________ and thus in areas of _______ are the ones that undergo the Warburg switch in a tumour.

diffuses towards blood vessels where there is lower lactate concentration, MCT4, MCT1, reverse Warburg effect

In a tumour, lactate _______. Lactate leaves the producing cell via ______ and is imported into the new cell via _____. This is referred to as “_________.”

Metabolic symbiosis, condition all cells in their surroundings to support tumour growth, competing for the same nutrients

_______ extends through the entire tumour microenvironment— cancer cells _________ and all cells in the TME are _______.

substrates added to histones are generated via metabolic pathways, nucleotides are generated by metabolic pathways and their levels affect DNA repair capacity of cells, and metabolic processes regulate redox balance which relates to oxidative DNA damage accumulation

Cancer cell metabolism is highly linked to DNA damage repair because…

purine synthesis, glutamine and glycine, pyrimidine synthesis, aspartate

The pentose phosphate pathway conducts ________ fueled by _______ and _______ fueled by _______.

ATM activates PPP, increased glucose consumption, ROS can inactivate many glycolytic enzymes, genes that decrease expression of glycolysis genes and increases genes for ETC and mitochondrial stability, resistant to low glucose

DNA damage repair can lead to metabolic rewiring of cancer cells: _______ which requires ________, __________, p53 regulates _________, and KRAS mutant cancers are _________.

metabolic flexibility

KRAS mutations promote ________ in cancer cells.

Oxygen

____ is the most important regulator of metabolism in cancer.

increased signalling, increased proliferation, increased stress response, increased stress tolerance via antioxidants, antioxidants to be overwhelmed, moderate ROS

Low dose ROS causes _______ and thus ________. Moderate dose ROS causes _______ and thus _______. High dose ROS causes __________. Cancer cells are happiest at…

HIF1a, degraded by VHL and hydrolases, stabilised and can dimerise with HIF1b in the nucleus and recruit cofactors

_______ is the oxygen-sensing transcription factor. In the presence of oxygen it is __________, and in the absence of oxygen it is __________.

regulated metabolic adaptation to hypoxia

HIF1 regulates transcription of over 200 genes involved in…

activates HIF1, inhibits mTOR, and activates autophagy

Hypoxia regulates 3 key pathways involved in cancer promotion:

increase in glucose transporters, increase in glycolytic enzymes

Metabolic adaptions to hypoxia include ______ and ______.

glycolysis, oxidative phosphorylation

Oncogenes favour _______ while tumour suppressors favour _______.

inhibits, downregulating glucose importers, upregulating inhibitory enzymes, downregulating glycolysis converting enzyme

p53 ______ aerobic glycolysis by ________, _______, and _______.

inhibits, suppressing autophagy, blocking formation of the autophagy complex

mTOR _____ aerobic glycolysis by _______ via _________.

promotes, generating degradation products to feed into TCA cycle

Autophagy ______ aerobic glycolysis by __________.

rarely mutated, expression of genes invovled in energy production, turn enzymes on, turn enzymes off

Metabolic enzyme genes are _______. Regulation is by controlling _________, thus expression of key converting enzymes is changed— oncogenes tend to _______ while tumour suppressors _______.

Pyruvate kinase isoform change, M1 form that is efficient at shuttling pyruvate to mitochondria is switched to M2 form which is slow and inefficient, backlog of TCA intermediates that can be shuttled to biosynthetic pathways

______ initiates the metabolic switch to aerobic glycolysis, wherein _________. This leads to…

hypertrophy and hyperplasia of adipocytes, inflammatory macrophage recruitment, and angiogenesis

Cell imbalances in obesity that promote cancer:

insulin insensitivity, leptin dysregulation, and free fatty acid increase

Metabolic imbalances in obesity that promote cancer:

adipokine secretion

________ in obesity causes inflammatory imbalance that promote cancer.

loss of regulatory T cells, infiltration by inflammatory macrophages, secretion of pro-inflammatory cytokines, TNF and IL6, increase STAT3 and NFkB signalling

Obese adipose tissue is characterised by ______, ______, and _______ such as ________ that ________. This leads to inflammation.

increases glucose storage by increasing IGF1, insulin receptor downregulation

In normal cells, insulin _________. This function is lost during cancer due to…

increased, increased circulating insulin and maintained insulin receptors, increased IGF1

In cancer cells, there is ______ insulin signalling due to _________, and there is ______.

ER stress and inflammation as insulin signalling is blocked by stress pathways, mitochondrial dysfunction as insulin signalling is blocked by PKC, and lipotoxicity as excess fatty acids in the blood alter ER stress/mitochondria/inflammation

Obesity-induced insulin insensitivity can be caused by…

Adiponectin

Growth suppressive adipokine that is needed to respond to glucose

inhibited/decreased, decreased glucose uptake in normal cells, increased glucose uptake in cancer cells, proliferation, apoptosis, angiogenesis, and inflammation

Adiponectin is ______ by obesity and cancer, leading to…

Leptin

Growth promoting adipokine

increased, increased glucose uptake and thus increased JAK/PI3K/MAPK signalling, proliferation, angiogenesis, inflammation, decreased apoptosis, and increased estradiol

Leptin is ______ by obesity and cancer, leading to…

eat, stop eating

Ghrelin signals to _______ while leptin signals to ______.

decreased appetite and increased growth, there is increased leptin and increased leptin resistance

In a healthy system, increased leptin production causes _______, but in obesity and cancer…

inhibit glucose release thus causing decreased gluconeogenesis and glycogenolysis, there is increased insulin resistance leading to release of new and stored glucose

In a healthy system, insulin functions to __________, but in obesity and cancer…

glucose and FFA uptake to increase energy stores, increased insulin resistance leads to release of stored glucose and FFAs

In a healthy system, insulin induces __________, but in obesity and cancer…

decrease circulating glucose

In a healthy system, leptin and insulin activity function to…

increased circulating glucose

In obesity and cancer, disrupted leptin and insulin activity causes…

increased aromatase expression within the adipocyte thus increased estrogen, increased insulin in circulation that sequesters SHBG carrier proteins leading to increased hormone availability, and increased androgen production in ovarian and adrenal cells

Obesity increases production and bioavailability of steroid hormones by 3 major mechanisms:

decrease apoptosis and increase proliferation

Hormone action in cancers tend to…

protein degradation, releases glutamine, used by the tumour for protein synthesis or feed into the TCA cycle, glucose release, lactate promotes glucose release so the glucose can be used to fuel muscle which produces lactate, role of muscle is replaced by the tumour, futile cycling

Insulin resistance leads to ______ in muscles which _______ that can be _______. Lactate released from the tumour promotes ______ by the liver. The normal cycle is _______, but _______. This process is referred to as “________.”

uncoupling of oxidative phosphorylation creates a proton leak that generates heat without ATP

Systemic energy imbalance can be caused by mitochondrial ATP synthesis dysfunction because…

cancer catabolism, decreased protein synthesis because of lack of amino acids in muscle, increased protein degradation

Muscle wasting results from ______ due to _______ and ______.

increased amino acid oxidation and increased amino acid export

There is decreased protein synthesis because of lack of amino acids in the muscle due to…

myofibril myosin and actin, decreased IGF1 signalling/increased myostatin/pro-inflammatory cytokines, ubiquitination and autophagy

There is increased protein degradation in cancer , especially _______, induced by ________ and conducted by _______.

myocyte, many mitochondria, mitochondrial proton gradient is uncoupled from ATP generation, generate heat

Brown fat cells, derived from the ______ lineage, contain ______ wherein ______. This functions to _______.

adipocyte, intermediate mitochondria numbers, not present at baseline, white fat cells induced in obesity and cancer to brown

Beige fat cells, derived from the _____ lineage, contain ______. These cells are _______ and are instead ______.

FFAs uncouple mitochondrial proton gradient and heat is released, decreased white adipose tissue, browning of white adipose tissue

Because cancers use lipids to produce metabolites for proliferation, _________. Tumourkines and inflammation promote _______ and ______.