Carcinogenesis (oncogenesis; tumorigenesis) can be simplified as follows:
- Mutations in DNA cause a cell to have an advantage over neighboring cells and displace surrounding tissue.
- In this process, mutations occur in replicating cells and at the same time DNA repair is turned off.
- Environmental factors can lead to a disruption of the balance between mutation and repair.
The exact causes of carcinogenesis are the subject of intensive basic research. The exact mechanisms are currently still unclear. However, there is ultimately a disruption of the genetically regulated balance between cell cycle (growth and division) and apoptosis (cell death). Regulatory signals are not recognized or not carried out, because in most cases the genetic code required for this is defective. About one in five genes, or 5,000 of the total of about 25,000 genes in humans, is responsible for the orderly maintenance of the genetic code from one cell generation to the next. These so-called protooncogenes and tumor suppressor genes monitor the correct sequence of base pairs in the DNA after each reduplication. They decide on the need for repair, halt the cell cycle until repairs are made, and, if necessary, induce apoptosis if repair is unsuccessful. Tumor cells are often aneuploid, which means they then have an altered chromosome number. The three phases of carcinogenesis:
- Initiation – the DNA is modified by genotoxic carcinogens, these are chemical (e.g. nitrosamines, tobacco smoke), physical or viral influences, ie, A mutation occurs (correction is possible in this phase by DNA repair mechanisms/ apoptosis).The important thing here is that the mutation must be present in a gene that is responsible for controlling the cell cycle and cell division, such as tumor suppressor genes.Tumor suppressor genes that are altered and can no longer carry out their function are known as oncogenes. These promote cell growth and proliferation.
- Promotion – Promoters (non-genotoxic carcinogens or hormones, e.g. estrogens) are able to stimulate initiated cells to grow and thus to form tumors: The constant growth stimulus and cell proliferation gives rise to a preneoplastic cell, which is a precursor to carcinoma. Promotion is reversible in the early stages and it has been possible to establish a threshold below which no growth stimulus is exerted on the initiated cell.
- Progression – this is the final step toward tumorigenesis; the preneoplastic cell becomes an invasively growing tumor (loss of the ability to differentiate; the more dedifferentiated the tumor cell, the faster it grows) due to mutations in tumor suppressor genes by carcinogenic action and conversion of tumor suppressor genes to oncogenes.
In this context, epigenetics (epi = Greek for “over”) is of particular importance for carcinogenesis. Epigenetics deals with the hereditary changes in gene function that occur without a change in the DNA sequence (= sequence of nucleotides in a DNA molecule / building blocks of DNA / genetic material). Thus, “hypermethylation” (excessive methylation) in the promoter region (= “on/off switch”) of a suppressor gene can contribute significantly to carcinogenesis. The gene itself is not altered. However, it can no longer perform its function adequately because the DNA (genetic information) is no longer accessible. Lifestyle factors, such as an unhealthy diet, consumption of stimulants, insufficient physical activity and psychomental stress, as well as environmental pollution, etc., can cause epigenetic changes, i.e. chromosome modifications (changes in the chromosomes, which are carriers of genetic information in the cell nucleus) that are not based on changes in the DNA sequence. The molecular genetic fingerprint (DNA fingerprint) of a tumor also provides information, for example, as to whether a laryngeal carcinoma has developed due to many years of tobacco consumption. In the future, tumor therapy will only take place after a genome analysis, which will then enable personalized medicine, i.e. patient-specific therapy.
