Studies of mouse skin were performed to determine the action of carcinogens. These studies demonstrated several important findings.
Types of carcinogens
Carcinogens could be classified as:
- Initiators, without which tumours would be unable to develop, but by themselves would be unable to cause a tumour to form
- Promoters, which could only cause tumours in cells previously exposed to an initiating carcinogen, and only if the cells were exposed to sufficient quantities of the promoter.
There are several possible combinations of carcinogens based on the time of administration. The only scenarios that lead to cancer development are when there is an initiator given first followed by an intense application of a promoter at a later time. There can be a significant time delay between the application of the initiator and the promoter. The possible scenarios are shown in the diagram below:
Some carcinogens may be both initiators and promoters.
Initiators are typically agents which induce DNA mutations. DNA mutations are required for activation of oncogenes, deactivation of tumour suppressing genes or genes associated with the other hallmarks of cancer.
- Chemical initiators include chemicals found in tobacco smoke and cooked animal fats. Chemotherapy agents often cause DNA damage and can act as initiators.
- Radiation may cause mutations in DNA and is therefore an initiator. It is also a promoter (see below).
- Viruses may insert genes or damage genes involved in cell cycle control. These can act as initiators or promoters.
- Inflammation is an initiator due to generation of toxic chemicals through immune cell activation
Promoters are usually agents that promote cell growth. This cell growth allows previously quiescent cells to become active, and if they contain initiating mutations may allow further mutations to occur.
- Chemical promoters promote cellular division, usually by causing a toxic effect on cells and reducing their number. This requires the remaining cells to divide to replace their lost compatriots.
- Radiation acts as a promoter by killing cells, requiring surviving cells to divide and replace the dead cells
- Viruses may either drive cells through the cell cycle, causing proliferation, or induce inflammation which kills infected cells
- Inflammation is an effective promoter, and in a similar way causes death of cells and increased division in survivors.