Cancer Flashcards
What is cancer?
‘A term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer tissues can spread to other parts of the body through the blood and lymph systems’
What are the properties of cancer cells?
TGF-alpha
- Sustaining proliferative signalling –> up-regulation of TGF-alpha signals other cells to keep growing
- Increase in TGF-alpha receptors
p53
- Resisting cell death
- p53 is a tumour suppressant that causes apoptosis of cancer cells –> also
TGF-beta
- Evading growth suppressors –> down-regulation of TGF-beta and it’s associated receptor to block the prevention of cell growth. Causing the cells to keep growing.
E-Cadherin
- Activating invasion and metastasis –> down-regulated which means cells don’t stick together as much making it easier for them to move about and invade other areas
VEGF
- Inducing angiogenesis –> increase of blood vessels near cells to provide energy and nutrients to grow and replicate, e.g. glucose, lactate, glutamine.
- Occurs in hypoxic environment
Telomerase
- Enabling replicative immobility
- Prevents cancer cell death by extending telomere length and preventing it reaching it’s critical point/ hayflick limit
- Enables cancer cell immortality
What is telomerase?
Normal cells have telomeres at the end of chromosomes. After every generation when replicating the telomere shortens. It keeps doing this until it reaches it critical point where it can no longer divide.
Telomerase adds additional segments to the telemores which increases it’s life span. In cancerous cells this enables its immortality –> doesnt go through hayflick limit.
What is p53?
Tumour suppressant
Around 50% of cancers are due to a mutation to 53
- Controls the DNA repair enzymes
- Promotes apoptosis of abnormal cells
What biochemical changes occur in cancer?
- Increased synthesis of DNA and RNA –> can be seen in a lab, especially in haematological cancers. Cells can be infused with iodine and bind to DNA and RNA in a 1:1 fashion, the be put in a flow cytometer and see the difference between cancer cells and normal cells.
- Alteration of activity of certain enzymes
- Inappropriate synthesis of some hormones and growth factors –> e.g. Breast, prostate
- Increased rate of glycolysis - both aerobic and anaerobic –> Cancer cells preferentially produce lactate, even will functional mitochondria and oxygen present.
What is metabolism?
Self-correcting homeostatic system
Housekeeping enzymes respond to bio-energetic demands
What are some different types of homeostasis mechanisms occurring in the body?
- Blood glucose levels
- Carbohydrates conversion to glucose
- Breakdown of dietary proteins to produce carbon atoms that can be utilised for glucose synthesis
- Skeletal muscle and erythrocytes can also provide lactate
- Lactate converted to glucose
What happens in cells when oxygen is limited?
Anaerobic respiration
Usually glycolysis occurs
Pyruvate is converted into lactate by lactate dehydrogenase
This process produces 2 ATP molecules
Lactate dehydrogenase correlates with tumour mass in some solid tumour cells.
Lactate production allows glycolysis to continue by cycling NADH back to NAH+
Minimal ATP production when compared with oxidative phosphorylation
What is the Warburg effect?
Altered metabolism hallmark of cancer cells
Best known metabolic abnormality in cancer cells.
Warburb observed in 1924 that cancer cells preferentially convert most glucose directly to lactate –> regardless of whether oxygen is present or not, or if mitochondria is fully functional –> produce less glucose than aerobic respiration
Cancer cells compensate by consuming more glucose.
Warburg effect gives tumour cells growth advantage - reduced oxygen consumption –> unclear how increasing a less efficient process provides tumours a growth advantage
One hypothesis:
- Glycolysis confers an acidic environment - harmful to normal cells but not to tumour cells - potential defence mechanism for cancer cell growth?
Proliferative tissue or tumour + Oxygen –> Glucose –> Pyruvate –> Lactate or Aerobic respiration
Function of the Warburg Effect
Tumour Microenvironment
- Enhances disruption of tissue architecture and immune cell evasion
Cell signalling
- Allows for signal transduction through ROS and/or chromatin modulation
Biosynthesis
- Promotes flux into biosynthetic pathways
Rapid ATP synthesis
- Increases access to a limited energy source
What is a mutagen?
Substances that change genetic information of an organism usually by changing DNA
What is a carcinogen?
Any substance, radionuclide, or radiation that is an agent directly involved in causing cancer
Most carcinogens are mutagens
Some compounds interact directly with target molecules (target carcinogens), other require metabolic activation before it becomes a carcinogen.
Pro-carcinogen –> Proximate carcinogen –> Ultimate carcinogen
Pro-carcinogen not chemically reactive
Ultimate carcinogen often highly reactive
The metabolism depends on liver enzymes called Cytochrome p450. Each person has different circulating levels in liver, cancer more likely occurs in those with higher levels.
The ability to metabolise e.g. arsenic into an ultimate carcinogen and then develop cancer depends upon the ability to activate it. More p450 has higher ability.
What agents can causes energy?
Radiant energy –> Ultraviolet rays, x-rays and gamma-rays are mutagenic and carcinogenic
- Results in DNA damage, breaking of hydrogen bonds
- UV cross linking of strands - strand breaks
- X-rays and gamma rays - direct damage to DNA and generate ROS –> apoptosis
Viruses
- HPV –> Cervical cancer
- Hepatitis B
Chemical compounds –> 80% human cancers - environmental factors
- Asbestos
- Benzene –> used to be used in a lab as a solvent
- Smoking –> tobacco
- Medications –> chemotherapy can cause secondary cancers
- Diet –> Aflatoxin B1, causes liver cancer –> a mould that grows on nuts, can be absorbed through skin
What is Cytochrome P450?
Relation to cancer
Liver enzyme, normal function to detoxify noxious chemicals
The metabolism of carcinogens depends on liver enzymes called Cytochrome p450. Each person has different circulating levels in liver, cancer more likely occurs in those with higher levels.
The ability to metabolise e.g. arsenic into an ultimate carcinogen and then develop cancer depends upon the ability to activate it. More p450 has higher ability.
What is cancer cachexia?
Hypermetabolic state
Characterised by anorexia, diminished body weight, loss of skeletal muscle, atrophy of adipose tissue.
Factors secreted by tumours, e.g. proteolysis inducible factor, lipid mobilising factor which are produced by the tumours to cause breakdown protein and release lipids.
Cachexia-induced muscle atrophy occurs as a result of reduced protein synthesis and increased protein degradation
Tumour-secreted factors could be the cause of fat atrophy.
Zinc-alpha2-glycoprotein (ZAG) –> adipokine, induces lipid mobilisation which is up-regulated in cancer cachexia
TNFa –> inhibits lipoprotein lipase activity –> prevention of uptake of lipids in to cell
IL-1B –> hypothalamus promotes anorexia, increased thermogenesis and skeletal sarcopenia which leads to additional weight and muscle loss
How does obesity provide a good tumour environment?
High levels of TNFa
- used in cancer cachexia and prevention of lipid uptake into cells by inhibiting lipoprotein lipase activity
