lecture 2 - causes detections and epidemiology Flashcards
what has improved in treating cancer
- improved screening and early detection
- advances in treatment
- increased access to care
- better understanding of the biology of cancer
- decreased exposure
principles of cancer diagnosis
- clinical presentation - symptoms and signs
- biopsy - removal of tissue for examination
- imaging studies
- lab tests
- staging
- prognosis
why is early diagnosis key
- so surgery and the removal of a tumour mass is still the number one way in which we can cure cancer.
- It’s the clearest thing that we can do To remove any risk of that tumor spreading if we can catch it early enough.
we want to have as many people able to undergo surgery as possible. So the tumor mass is removed as early as possible.
normal cell metabolism
in normal cells, this is how metabolism happens
○ you have glucose entering the cell it undergoes glycolysis to create pyruvate
○ pyruvate then gets shunted by pdh into acetyl Co a
and this enters the Krebs cycle and produces a majority of the ATP in your cells.
- this doesnt happen in cancer cells - Warburg effect
Warburg effect
- in cancer cells we activate a signaling pathway- the map kinase Ras pathway pi3 kinase.
- So from ras GTPase activating the pi3 kinase you have activation of 2 important factors,
- akt - which drives the expression of glut 1 -
○ so this Branch increases the amount of glucose going in - and also activates HIF1 which can also get activated by hypoxia.
○ So when a cells getting more dense and there’s less oxygen there the this also shunts glycolysis.
○ It also switches off pdh.
So instead of pyruvate being shunted into acetyl Co a it stays as pyruvate gets turned into lactate which then gets turned into lactic acid and instead of undergoing the citric acid cycle, We’re only using glycolysis as our main way of getting ATP
how can we utilise cancer hallmarks in diagnosis
- fluorescent glucose analogue
we can use this by having a fluorescently labeled glucose analog,
What this enables is as the cancer cells are increasing their uptake of glucose, They will uptake this glucose analog which fluoresces quicker and accumulates more than the surrounding tissues.
- allows visualisation of tumours in the body that have large concentrated amounts of glucose because of the hyperactivity of the glut 1 transporter
difference between male and female
you are 1.8 x more likely to die if male
what causes the difference between males and females
- riskier behaviours - males are more likely to engage in behaviours such as smoking, alcohol conusption
- different biological susceptibilities - men have a higher risk for certain types of cancer, such as lung, prostate, and colorectal cancer
- delayed diagnosis and treatment - men are less likely to seek medical attention for symptoms
what causes the difference between males and females - occupational exposure
- construction workers: exposure to asbestos and other building materials
- miners: exposure to coal dust and other minerals
- manufacturing workers: exposure to pesticides and other chemicals
- firefighters: exposure to smoke and toxic chemicals
- truck drivers: exposure to diesel exhaust fumes
what causes the difference between males and females - genetic susceptibility
There are a bunch of genes found on the X chromosome that are linked to tumour formation
If you have a mutation as a man on the X chromosome, because you only have one copy of the X chromosome, you don’t have another expression of that chromosome to give you coverage
if you have two Xs and you have a mutation in one, one of the Xs is normally silent, but you still have another copy of that Gene, So the chances of this having oncogenic activation is less.
differences in how the sexes respond to current treatments
women are far more likely to get benefit from surgery and there is little to no research in telling us why exactly this is but they’re far more likely to have a better outcome when it comes to surgery.
- The same is generally true for radiotherapy.
- It’s also true for common chemotherapies.
- It’s also true for some targeted therapies such as the EGF receptor inhibitors
- Immunotherapies tend to affect the sexes in a similar rate.
○ However, some of the immune checkpoint inhibitors specifically for colorectal cancer have a better prognosis if you’re a man.
- multivariant cause
nature vs nurture
people living in Osaka Japan have very low rates of prostate cancer.
○ They have really increased Chance of getting stomach cancer and they have a lower chance of getting breast cancer.
- But when we look at the Japanese population that moved to Hawaii in subsequent years, we can see that their rates changed.
○ the rate for prostate cancer in the Japanese population that moved increases to match or the native Population that’s true for lots of different Cancers
this is very good evidence that the nurture side of things when it comes to cancer is probably
the biggest determinant because the genetic drift between these two Japanese populations
is going to be relatively low.
age and cancer
cancer incidence increases with age
- correlation or cause??
alcohol and cancer
cancers caused by drinking alcohol
- You have an increased risk of mouth cancer, throat cancer, esophageal cancer, liver cancer.
- Out of 1,000 people in the UK, and we have a look at how much alcohol they drink on average per week, And we look at the chances of that 1,000 person population whether they’re going to actually get one of these cancers.
○ so if they have no alcohol, Five people out of 1000
○ and if they have 10.5 units it’s six people.
- If you go all the way to 44 units per week, We have 16 people
we have not just the correlation but we have a concentration dependent effect.
- So the more exposure to alcohol the more your risk
and this is one of the important Factors when it comes to knowing whether something is a direct cause or something that is just correlated.
how can alcohol cause cancer
e. So when alcohol (ethanol) enters your body, it gets processed by alcohol dehydrogenase to make acetaldehyde
- In small amounts your liver is able to cope with this, it produces acetaldehyde it can then get processed further Downstream
- the more you drink the more acetaldehyde builds up and then it can get processed into acetate.
- acetate is not a good chemical. It causes fixing of different carbon molecules - So it can directly cause DNA damage and It can be used as an indirect energy source, which causes reactive oxygen species to build up which could cause mistakes in DNA, chromosome rearrangements and different forms of cross-linking events to happen within the DNA, which they need to be processed.
alcohol also increases hormone levels - it can increase oestrogen production - can obviously stimulate particular sorts of cancer, especially in women.
smoking and cancer
in cigarettes, there are 5,000 different chemicals
- quite a lot of these are harmful to your lungs.
- They cause direct damage to the DNA and the more you do it the harder it is for your cells to repair.
Being smoke-free can prevent a majority of the main cancers really that plagues our society.
how can obesity cause cancer
- fat cells increase inflammation and make extra hormones and growth factors
- hormones, growth factors and inflammation cause cells in our body to divide more often
- this increases the chance of cancer cells being made
- which can then continue to divide and cause a tumour
indirect obesity causes of cancer
chronic inflammation - fat cell removal can lead to chronic inflammation
insulin resistance - increased insulin resistance, leads to higher levels of insulin and insulin like growth factors in the blood
hormonal alterations: level of hormones such as oestrogen, testosterone and insulin
- organ pressure: pressure on internal organs, structural changes and build up of waste products
direct cause
means something that causes a mutation
- so mutations can happen in two different types of cells in your body.
- somatic mutations - occur in developed tissues and the carrier has the change
- germline mutations - occur in ovaries and testes and produce offspring carrying the change
monocultured clonal tumour
this is where a mutation that is directly caused within one branch.
○ So this is one set of mutations within this cell.
○ It has all the direct advantages - has the cancer Hallmarks the metabolic rate, the ability to survive the ability to grow forever, . It may well form what is called a monoclonal tumor
- This monoclonal tumor has a more defined genetic background.
polyclonal tumour
in this case, not only is the genetic background of just a pocket of these cells the same
but the differences between these polyclonal tumours could be quite different.
- So for example can have different branches, one Branch could be completely different to the other branch and then both might be able to grow
§ one will normally have a specific growth advantage or survival Advantage.
§ However because the tumor is not just one type Mass, Some of these genetic changes could give it advantages say in the most hypoxic part of the tumor versus a part of the tumor That’s got lots of oxygen. - and this polyclonal tumor where there is not just one type of genetic background Is more hard to treat
because instead of just targeting this one population. We have to be able to Target all of them all at once.
a carcinogen and mutagen
A carcinogen is something that causes cancer and mutagen is something that can cause a mutation.
e.g. smoke, grilled meats, candles, tobacco, paints, dyes
how do we test for mutagenesis
the AMES test is a quick, simple and inexpensive way to screen a large number of chemicals for potential mutagenecity
how do we do the AMES test
Get some processed liver, mix it with a compound that you are interested in and then look for the metabolites that have been activated from a liver
- And you knock it out on the bacteria that requires a mutation to grow
- So in this media these bacteria can’t normally grow unless they acquire a mutation
- The chances of that mutation increase
