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
What host and tumour reactions occur in cancer cachexia syndrome?
Tumour
- Specific catabolic factors
- Proteolysis Inducible Factor –> Protein degradation
- Lipid Mobilising Factor –> Lipid Mobilisation
Host
- Inflammatory cytokines
- IL-1B –> Central appetite suppression
- IL-6 –> Decreased protein synthesis
- TNFa –> Inhibit lipoprotein lipase activity reducing lipid uptake into cells
- INFy –> Acute phase response
- UCP1 –> increase WAT browning which increases mitochondria and thermogenesis
What is the link between obesity and cancer?
BMI over 40 increases risk of dying cancer by 50-60%
Clear links to colon, pancreatic, liver and stomach cancer
Increased visceral adiposity
- Increased TNFa –> cell survival
- Increased insulin
- Decreased Adiponectin
- Macrophage recruitment
- T-cell infiltration
- IL-6 –> STAT3 pathway –> Cell survival
- Increased leptin –> MAPK pathway –> increase cell proliferation
Contributes to a pro-tumourigenic environment
- Increase inflammation
- Increase resistance
- Increased angiogenesis
What are some dietary mutagens?
Aflotoxin B1
Nitrites –> smoked fish, process meats
- cooked at high temps, high levels of HCAs and PAH which have links to cancer (converted by cytochrome p450
Alcohol
- Animal studies show ethanol acts as a co-carcinogen
- Ethanol by product acetaldehyde is toxic and can cause DNA damage
- May enhance role of other carcinogens, increase absorption of carcinogens
- Ethanol breakdown - acetaldehyde - DNA adducts DNA damage - tumour proliferation
How can dietary fibre influence cancer risk?
High fibre diets have shows reduction in risk for colorectal cancer, in both animal and human studies
- High fibre intake increase stool bulk, reduces transit time through colon, may minimise absorption of carcinogens
- Fibre may bind with carcinogen
- Fermentation of fibre produces SCFA which may be ant-carcinogenic
What is the link between dietary antioxidants and cancer?
Consumption of certain vitamins and minerals may reduce risk for many cancers
High incidence of certain cancer types in developed countries, e.g. stomach and oesophagus, associated with micronutrient deficiencies
Trials of antioxidant nutrients have almost always been negative
Conflicting research
What are plant ant-carcinogens?
Plant products investigated for anti-carcinogenic properties
- Flavonoids –> Onions
- Lycopene –> Tomatoes
- Sulphur containing Allium species –> Onions
- Iso-thicyanates –> Cruciferous vegetables
Is there any link with a vegetarian diet and lower cancer risk?
It has been observed that vegetarian diet are associated with lower cancer rates.
Reasons not well known
- reduced red meat consumption
- higher antioxidant and plant-carcinogen intake
How can food preparation influence cancer?
Heating meat to high temperatures creates HCAs which are part of the charred ares on the meat
This is linked to the haemoglobin
Safe at low levels
Those at risk of colorectal cancer are more likely to be impacted
Lower risk with fish due to having less RBC and Hb
HCAs are formed during drilling from fat dripping into flames and adhere to food surface.
Also present in tobacco smoke
Carcinogenic in animal lab studies
What are some dietary risk factors of common cancers?
Stomach
- Salt/ salt preserved food
Colon/ rectum
- Obesity
- Red and preserved meat
Liver
- Alcohol
Breast
- Obesity
- Alcohol
- Saturated fat
Upper digestive tract
- Alcohol
- Obesity
- Very hot drinks
