Tumour Development (AQA A Level Biology): Revision Note

Tumour development

• Cancers demonstrate how important it is that cell division is precisely controlled, as cancers arise due to uncontrolled mitosis

• Cancerous cells divide repeatedly and uncontrollably, forming a tumour

• Cancers start when the expression of genes that control cell division changes. If the mutated gene causes cancer, it is referred to as an oncogene

  • Mutations are common events and don’t lead to cancer most of the time

  • Most mutations either result in early cell death or in the cell being destroyed by the body’s immune system

  • As most cells can be easily replaced, these events usually have no harmful effect on the body

• The mutations that result in the generation of cancerous cells do not result in apoptosis or the cell being destroyed by the body’s immune system

• This means that the harmful mutation occurring in the original cell can be passed on to all of that cell’s descendants

• A typical tumour contains around a thousand million cancerous cells by the time it is detected

• Carcinogens are any agents that may cause cancer (e.g. UV light, tar in tobacco smoke and X-rays)

Tumour suppressor genes

• Tumour suppressor genes are normal genes that code for proteins that regulate the cell cycle

• The proteins encoded by tumour suppressor genes carry out the following functions:

  • DNA repair

  • Slowing the cell cycle by ensuring checks are made

  • Signalling apoptosis when the cell is faulty

• These proteins ensure that cells do not replicate if they contain mutated DNA or are faulty, as these characteristics can lead to tumour formation

• Tumours develop if tumour suppressor genes are mutated or silenced

  • There are many different kinds of mutations, some of which are more likely to have harmful effects

  • Silencing can occur through epigenetic changes and RNAi

• BRCA-1 is an example of a human tumour suppressor gene expressed mainly in breast tissue

  • The role of the BRCA-1 protein is to repair broken or mutated DNA

  • If the BRCA-1 protein cannot repair the DNA it signals for apoptosis to begin

  • In breast cancers, inhibition of BRCA-1 expression leads to a lack of DNA repair and apoptosis, leading to the formation of cancerous tumours

Oncogenes

• Proto-oncogenes are normal genes that code for proteins that regulate cell growth (growth factors) and cell differentiation

• Proto-oncogenes can mutate to become oncogenes

  • Mutation occurs because of carcinogens

• Oncogenes are mutated genes that have the ability to cause cancer through the deregulation of cell growth

  • Mutations that produce oncogenes usually causes the proteins that stimulate cell growth and division to be constantly activated

  • When these proteins are activated, the cell cycle is sped up

  • If the proteins involved in apoptosis are also mutated, this can lead to tumour formation

• Mutations of proto-oncogenes to produce oncogenes can occur through inversion or translocation mutations where an activating segment of a gene is attached to a proto-oncogene leading to either:

  • gene expression being upregulated

  • the protein produced being constantly activated (unable to be switched off)

• Within cells there are common ways in which proteins are activated/deactivated, these include:

  • Phosphorylation - the addition of a phosphate group from ATP

  • Complex formation - binding to another protein or coenzyme which changes the protein's conformation, potentially opening up another binding site or revealing an active site

Abnormal methylation

• Cancer often involves disrupted control of cell division, caused not just by mutations but also by epigenetic changes, especially abnormal methylation of key genes like tumour suppressor genes and oncogenes

• Hypermethylation of DNA can prevent transcription by allowing inhibitory proteins to bind. If this occurs in tumour suppressor genes, their expression is silenced, stopping production of regulatory proteins and potentially leading to tumour formation

  • RNA interference by siRNAs targeting tumour suppressor genes for breakdown can also lead to tumour development for the same reason

• Hypomethylation of proto-oncogenes can lead to:

  • Increased gene accessibility

  • Overexpression of proto-oncogenes

• The gene behaves like an oncogene, even without a mutation

Oestrogen-dependent breast tumours

• Oestrogen is a steroid hormone that upregulates transcription of certain genes through the stimulation of the ERα oestrogen receptor

  • High concentrations of oestrogen can lead to the development of breast cancer

  • High concentrations can be a result of over-expression of the oestrogen gene or from supplementary oestrogen taken in medication

• About 70% of breast tumours are categorised as oestrogen receptor-positive; these breast tumours are also called oestrogen-dependent breast tumours

  • Oestrogen is needed by these tumours to stimulate the expression of cell cycle genes that lead to growth and replication

  • The cancer cells within these tumours have oestrogen receptors that promote cell growth when stimulated by oestrogen

  • The genes are switched on through the oestrogen-dependent gene expression pathway, in which oestrogen diffuses into the cell and through a nuclear pore until it reaches the oestrogen receptors

• The main treatment of this type of tumour is a drug called tamoxifen, which has a similar chemical structure to oestrogen and therefore acts as a competitive inhibitor

  • This means that tamoxifen permanently binds to oestrogen receptors, stopping oestrogen from binding and therefore inhibiting the receptor's action

  • So the genes that are usually upregulated by oestrogen are not expressed as the oestrogen receptor cannot bind to the promoter

  • Therefore, tumours cannot grow