Cancer Metabolism

Question 1

Why do cancer cells alter their metabolism?

Answer 1

For rapid growth and proliferation. Cancer cells often need to survive in environments that are less than optimal for their needs, so they adapt their metabolism to get enough materials and energy

Question 2

What are the requirements for cancer cells?

Answer 2

Cancer cells grow and divide rapidly, so the demand for “building blocks” is high

Question 3

What are “building blocks” and what do they each lead to?

Answer 3

Amino acids -> proteins
Lipids -> Membranes and fuel
Nucleotides -> DNA and RNA
Carbohydrates -> Fuel, Energy, Structural

Question 4

Why is altered metabolism recognised as an emerging hallmark?

Answer 4

The fact that cancer cells adapt their metabolism to cope with their growth demands is regarded as generic across multiple different cancer type, thereby making it an emerging hallmark of cancer

Question 5

Why do cancer cells become genetically reprogrammed, leading to improved cellular fitness?

Answer 5

To provide a select advantage during tumorigenesis
To support cell survival in stressful conditions
To allow pathologically elevated proliferation and growth levels

Question 6

What are the 3 main types of alterations that occur in cancer cell metabolism?

Answer 6

Increased bioenergetics
Increased biosynthesis
Altered redox balance

Question 7

Outline aerobic respiration in normal cells

Answer 7

Glucose broken down in glycolysis in cytoplasm to 2X Pyruvate (+2ATP +2NADH), which is used in TCA cycle to create 3NADH and 1FADH2 (+1ATP +2CO2).

Question 8

What are the functions of HIF-1a in mammalian cells?

Answer 8

All mammalian cells have mechanisms to detect and monitor ambient O2 levels (eg HIF-1a TF). This TF upregulates over 60 genes including VEGF for angiogenesis and erythropoetin for rbc production to encourage O2 delivery to hypoxic regions. Also, it induces cell survival gene transcription, as well as glucose and iron metabolism. HIF-1a activation also leads to increased glycolysis (and glucose consumption)

Question 9

How do tumour cells adapt to hypoxia?

Answer 9

Tumour cells activate HIF-1a, increasing their glucose consumption via glycolysis. Glycolysis doesn’t require O2, so cells can produce energy rapidly with no need for O2. This turns glucose into lactate, producing ATP and NADH. Lactate is released from the cells via HIF-1a regulated genes

Question 10

How does the lower extracellular pH surrounding tumour cells benefit them?

Answer 10

Tumour cells have lower extracellular pH because of the lactate they export. It’s advantageous for tumour cell survival because it inhibits cytotoxic T lymphocytes, allowing the cancer to evade the immune system. It also activates enzymes that degrade the surrounding local tissue to allow for invasion. Low pH also makes the local environment less favourable to normal cells

Question 11

How else can glycolysis in cancer cells be upregulated?

Answer 11

Oncogene activation can drive forward glycolysis in cancer cells, eg. Myc activation upregulates glucose uptake genes. PI3K/AKT pathway can stimulate glycolysis.

Question 12

What is the Warburg effect?

Answer 12

The phenomenon where tumour cells are observed to have increased glucose uptake compared to surrounding tissues and the glucose was fermented to lactate, even in the presence of O2. This is termed aerobic glycolysis (Warburg effect)

Question 13

What are the benefits of cancer cells performing aerobic glycolysis?

Answer 13

It allows cancer cells to survive in environments where the O2 conditions vary greatly. Glycolysis also results in rapid production of ATP and NAPDH, which suits the cancer cell’s rapid growth and proliferation

Question 14

What is the important of biomolecules in cancer?

Answer 14

Biomolecules are extremely important for cancer cells as they need them for rapid prolif etc. Carbon is the primary element in lipids, sugars, proteins, etc. The high proportion of glucose broken down by cancer cells results in a carbon rich pool of cellular intermediates. These are building blocks for biomolecules

Question 15

What is the importance of biosynthesis in cancer cells?

Answer 15

Anabolic reactions require energy and NADH as a reducing agent. Biosynthetic needs are greatly increased in cancer cells due to their rapid growth and proliferation

Question 16

What is the importance of glucose for the cancer cell?

Answer 16

The carbon backbone in the glucose molecule is useful to generate carbon intermediates for use in multiple biosynthetic pathways

Question 17

How is the pentose phosphate pathway modified in cancer cells?

Answer 17

Instead of the isomerisation step in glycolysis (glucose-6-phosphate to fructose-6-phosphate), cancer cells turn glucose-6-phosphate into ribose sugars, which the cell then uses to make nucleotides

Question 18

How is hexosamine biosynthesis altered in cancer cells?

Answer 18

Glucose-6-phosphate is converted into hexosamine via the addition of amine group. This glycosamine is then added to proteins etc. for stabilisation, increased solubility, cell-cell adhesions

Question 19

How is the glycerol-3-phosphate pathway altered in cancer?

Answer 19

Glyceraldehyde-3-phosphate is turned into glycerol-3-phosphate which is joined with fatty acids to make lipids,and then used for membrane synthesis

Question 20

How is serine/glycine biosynthesis altered in cancer cells?

Answer 20

Glucose turned into 3 phosphoglycerate, which it turned into serine (catalysed by glutamine), which can then be turned into glycine and other amino acids, which can build up more complex amino acids

Question 21

What is the role of glutamine in cells?

Answer 21

It provides the main source of nitrogen that cells use for protein synthesis, and DNA replication. It also replenishes TCA cycle intermediates, allowing citrate to be diverted to fatty acid synthesis

Question 22

How is redox balance altered in cancer cells?

Answer 22

The extra metabolism in cancer cells leads to a build up in ROS

Question 23

How does glutathione act as an antioxidant?

Answer 23

Glutathione and other antioxidants are free radical and ROS scavengers. Gluthathione peroxidase uses glutathione as a substrate in order to reduce peroxide to H2O

Question 24

How can oncogenes regulate metabolic pathways?

Answer 24

When stimulated by GFs, normal cells activate downstream signalling pathways eg PI3K/AKT, Myc, Ras, Src, which promote anabolic programmes such as increased glycolytic flux and fatty acid synthesis. c-Myc increases glucose transporter and glycolytic enzyme expression. Also upregulates splice variants of these enzymes, increasing glycolytic activity. c-Myc inhibits HIF-1a breakdown.

Question 25

How can tumour suppressor genes regulate metabolic pathways?

Answer 25

When stimulatory/oncogenic pathways are strongly upregulated, cellular stress response genes (p53) are activated. Myc activation can upregulate p53 and stabilise it. Also, p53 target genes can reverse/inhibit glycolytic pathway, as well as specifically inhibiting glucose transporter expression. TIGAR (TP53 inducible apoptosis regulator) genes produce protein that removes phosphate from fructose 2,6 bisphosphate, regulating glucose breakdown. TSG activity is often lost in cancer, so the ability to downregulate these pathways is also lost

Question 26

Why is the glycolytic pathway specifically important for cancer cells?

Answer 26

Because it avoids using mitochondria to produce energy, and the mitochondria are also involved in apoptotic pathways, so avoiding this is good for the cancer cell.

Question 27

How can we take advantage of the increased glucose uptake by cancer cells for imaging?

Answer 27

Due to the phosphorylation step in glycolysis, the glucose becomes negatively charge and trapped in the cell, where it is further isomerised and phosphorylated. If we introduce deoxyglucose to the cell, it cannot be isomerised, so levels build up in the cell. We can use labelled isotopes to track the glucose in the body and detect the location of the cancer

Question 28

How does PET scanning work?

Answer 28

Scintillation counters are sensors that absorb radiation and emit photons which create an electrical signal and are able to be visualised. If these scintillation counters are arranged in a ring, which the patient (with the radioactive source inside them) passes through, the location of the source can be visualised in 3D.

Question 29

Why do cancer cells result in the production of novel metabolites?

Answer 29

Cancer cells can alter any metabolic pathway for their own needs, which leads to the presence of metabolites that aren’t usually present in normal tissues. Also, as cancer cells undergo necrosis, they release their contents, which can result in novel substances.