CBIO6: Cancer Metabolism Flashcards
Why do cancer cells become genetically reprogrammed to allow for improved cellular fitness?
1) To provide a selective advantage during tumourigenesis
2) To support cell survival under stressful conditions
3) To allow cells to grow and proliferate at pathologically elevated levels
What are the three main alterations that occur in cancer cells?
- Increased bioenergetics
- Increased biosynthesis
- Alteration in redox balance
When are the alterations in cancer cells important?
These 3 pathways are closely interlinked. Some activities become essential very early on in tumourigenesis as the primary tumour begins to experience nutrient limitations. Other changes occur later as cells undergo metastasis
What is the main energy source for most organisms?
Glucose
What is glycolysis?
The enzymatic process of breaking down glucose into pyruvate to extract ATP and NADH for cellular metabolism. Occurring mainly in cytoplasm.
Where does TCA/Krebs cycle occur?
Matrix of mitochondria
What happens in TCA cycle?
Set of chemical reactions used by aerobic organisms that completely oxidize the two carbon atoms of acetate (acetyl-CoA), into two molecules each of carbon dioxide and water with the release of stored energy in the form of ATP, NADH and FADH2 are also produced
What do glycolysis and the TCA cycle require?
Oxygen
Oxygen can range from _____ in the centre of solid tumours
0 – 2%
Why do cancer cells often exist in low nutrient low oxygen environments?
Tumours is that they grow very fast and rapidly outgrow the blood supply that feeds them
What is tumour hypoxia?
Occurs when cells are deprived of oxygen
Why would cancer cells become hypoxic?
They grow so fast that they out grow the developing blood supply
As the oxygen concentration decreases the further cells are away from blood vessels, what may happen to the centre of the tumour?
may become hypoxic and necrotic
What does the hypoxia Inducible Factor (HIF-1a) transcription factor in mammalian cells do?
It detects and monitors the levels of ambient oxygen
How does HIF-1 work?
HIF-1a stability, localisation, and activity are affected by oxygen levels. Under normal oxygen (normoxic) conditions, the HIF-1a protein is targeted for degradation. However, under low oxygen (hypoxia), HIF-1a protein degradation is prevented and levels accumulate. The HIF-1a transcription factor then binds DNA and activates hypoxia response genes
How many genes does HIF-1a activate? Give examples
60
VEGF and Erythropoiesis
What kind of genes does HIF-1a activate?
- increase angiogensis
- increase erythropoiesis
- increase cell survival
- glucose and iron metabolism
- Increased glucose flux
- Waste secretion
What does anaerobic respiration produce
Glucose -> lactate
Large amounts of ATP and NADH
Why do tumour cells ahve a lower extracellular metabolism?
Result of lactic acid export
Why is lower pH an advantage for tumour cells?
1) it can inhibit cytotoxic T lymphocytes which helps
tumour cells evade the immune system
2) helps activate enzymes required to digest local tissue for invasion
3) makes the local environment generally less favourable for normal cells
What is the normal and cancerous pH levels of cells?
Normal: 7.3-7.4
Cancer: 6.2-6.9
What else can drive forward glycolysis in cancer cells? Give two examples
Oncogene activation
- The activation of the oncogene Myc can upregulate genes involved in glucose uptake from the surroundings.
- The PI3kinase/Akt signalling axis can also stimulate glycolysis
What is the Warburg effect?
Where tumours take up large amounts of glucose compared to what was observed in the surrounding tissue. Additionally, the glucose is fermented to produce lactate. More importantly, it was discovered that tumours did this even in the presence of normal levels of oxygen.
What are the two major advantages of aerobic glycolysis in cells?
1) Cancer cells can live in conditions of varying oxygen levels (due to irregular functions of blood vessels) that would be harmful or lethal to normal cells that rely on oxidative phosphorylation to generate ATP .
2) Glycolysis generates rapid amounts of NADH and ATP – this is not as efficient as the TCA cycle - but is faster and better suits their rapid growth.
What is aerobic glyclysis also called?
The Warburg effect
Why would tumour cells break down so much glucose?
They need to obtain energy in the form of ATP & NADH - building blocks for biosynthesis
List the key generic types of biomolecules found in living cells?
DNA / RNA (nucleotides)
Proteins
Lipids
Carbohydrates
What are most biomolecules made from
hydrocarbons, carbohydrates, aldehydes and carboxylic acids.
Where do cancer cells siphon off carbon intermediates?
From glycolysis
What is NADH used for in the cell after aerobic glycolysis?
Used as a reducing agent in the anabolic reactions required for biosynthesis