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Oncogenesis

Objective: Understand the biological basis of cancer Summary Cell division occurs through the cell cycle Tightly regulated with several checkpoints Cancer occurs because cell growth becomes unregulated The process is called oncogenesis Associated with two families of genes Suppressor genes Proto-oncogenes/ Activator genes Several factors are known to damage cells to cause them to have their growth unregulated Inherited Chemical Physical Infectious

The cell cycle

G0- "Growth 0" phase. The cell is at rest, no division is occurring (lots of cells are like this in the body, as they are terminally differentiated) G1- "Growth 1" phase. The cell prepares to divide, BECAUSE it's received an instruction to divide. As a result, it will now synthesise proteins and enzymes required for division The instruction can be from a hormone, growth factor, a change in local conditions etc. S- "Synthesis" phase. The cell will now replicate DNA. This is the longest stage clocking in at 6-8 hours. G2- "Growth 2" phase. The cell has two copies of DNA, and it will now produce proteins required for mitosis to occur. Takes 2-3 hours. M- "Mitosis" phase. The cell will now split, taking one copy of the DNA, to
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M- "Mitosis" phase. The cell will now split, taking one copy of the DNA, to produce two identical cells. This is the shortest phase, clocking in at 1 hour. The cell will now return to G0 phase, and can re-enter the cycle if stimulated. Normally, we would expect the number of dying cells to equal the number of cells created to keep the number of cells in the body constant A homeostatic mechanism exists in the body to keep things under control Cells will be killed off due to apoptosis over time While other cells will be triggered to grow to replace these dying cells If the homeostatic mechanism fails, then we get cancer. So the cell cycle is tightly regulated to stop this from happening

Cell division checkpoints


DNA damage is harmful to cells, as it can cause a loss in function, which includes not making a correct protein, or it could even become cancerous. Therefore, cells have defence mechanisms against mutations from being passed down during mitosis Once that mutation passes down through the cell cycle, it becomes fixed into the DNA permanently, because the cell doesn't have an original copy of the DNA to check against. So the cell cycle has several 'checkpoints' where the integrity of the DNA is checked to stop mutations from occurring. If the cell fails to pass the checkpoint test, the cell cycle is immediately halted to allow for repairs to occur before continuing: G1 arrest- the cell cannot enter the cell cycle G2/M arrest- the cell cannot enter mitosis If the DNA cannot be repaired, the cell will undergo apoptosis p53 and the Rb (retinoblastoma) genes are important in cell cycle control, as they will regulate the cell cycle. p53 is especially important, as it is a part of the G1 checkpoint, can induce DNA repair and induce apoptosis if needed Therefore, many tumours will have p53 deactivated Another important mechanism is the use of telomeres Telomeres are straight pieces of DNA at the end of a chromosome The straight ends cannot be perfectly copied, so they shorten with each cell division Once the telomeres are short enough, the cells are triggered to undergo apoptosis The reason for this is to make sure cells have an automatic 'expiry date' to prevent them from accumulating too many mutations, and becoming cancerous. To counter this, a cancerous cell can activate telomerase, which increases the length of the telomeres to prevent apoptosis from being triggered Therefore, it's also another common mutation seen in cancers

Oncogenesis
An important fact is one mutation is not enough to cause cancer Remember: the cell cycle is tightly regulated, so the cell has quite a few barriers which it needs to overcome to become cancerous Normally, these mutations will be prevented by the checkpoints put in place But if the checkpoints are non-functional (either inherited or mutated), then it's much easier for these mutations to occur, so it's easier for the cell to become cancerous REMEMBER: normally a person will carry two copies of the gene, both must be broken to get cancer ('dominant' gene, so hetrozygous people are still at
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be broken to get cancer ('dominant' gene, so hetrozygous people are still at higher risk of getting cancer as a result) Because the cell needs multiple mutations to become cancerous, cancer is a disease which is concentrated in the elderly If you live long enough, by chance you will accumulate enough mutations Also, there are two main groups where mutations will cause cancer, as they are important for regulation of cell growth: Suppressor genes Activator genes (proto-oncogenes) Suppressor genes will work to prevent cancer, so these should be kept ON p53 is again an important suppressor gene, as it contains apoptosis genes BRCA is an important suppressor gene as it is involved in double stranded DNA repair If BRCA is mutated, the incidence of breast cancer shoots through the roof Anything inhibiting growth, such as growth regulator genes are important Contact inhibition genes- normally these will stop cells from dividing if they are in contact with each other, as it indicates there's no space to grow. Activator genes are also called proto-oncogenes, as normally they are not cancerous, but if mutated, will cause cancer. Therefore, to prevent cancer, these should be kept 'INACTIVATED' (not completely off, normal body function might need them, like healing) Angiogenic genes are very important in tumours, as the tumour must be able to get a blood supply set up to grow properly. Otherwise the tumours will be small and most likely unsuccessful. Some genes will allow cells to escape immune survellance, or be immunosuppressive Others will help them survive outside the tumour, which allows distant metastasis to occur (surviving outside the original tumour is quite difficult)

How do we get cancer?


Inherited As stated before, you need functional suppressor and non-activated activator genes to NOT have cancer. Sometimes, people will inherit a non-functional copy (or copies) or suppressor genes Or receive one (or two) copies of an activated activator gene Therefore, these people are at a higher risk of getting cancer Think about it as they've already accumulated mutations required for cancer. Chemical Carcinogens are chemicals which will cause damage to DNA (either directly or indirectly through metabolites/breakdown products) Again, these mutations need to hit a suppressor or activator/protooncogene. Physical Ionising radiation Direct damage to DNA Non-ionising radiation Damage via production of radicals Either will cause DNA damage, which might give you cancer if the wrong genes are turned on/off (see above) Infectious agents Can inhibit p53 Quite a range of viruses can do this Why? Because p53 can trigger apoptosis and ruin their plans
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Why? Because p53 can trigger apoptosis and ruin their plans Human Papillomavirus (HPV) and Epsein-Barr virus Cause increased division, which leads to more chances of being mutated and causing cancer This is probably why hepatitis B and C cause liver cancer Insertion into oncogenic gene Yeah this can only end badly Seen by retroviruses (can enter the host's DNA) like HTLV-1 or HIV

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