Carcinogenesis

The carcinogenesis ( cancer development ) is the most complex (and still partly misunderstood) process of carcinogenesis. Part of this process is the change from normal cells of an organ into malignant tumor cells; furthermore, abnormal angiogenesis , in many cases dysregulation of endocrine functions and other processes are involved in the development of cancer .

Possible levels

Nowadays, carcinogenesis is seen as a multi-stage process that consists at least of the phases of initiation, promotion and progression.

initiation

The initiation (activation) represents the first step of the carcinogenesis: A cell undergoes from a carcinogen induced mutation . If this mutation is not eliminated by DNA repair or the cell is not switched off by apoptosis (cell death), then the mutation persists - and it is irreversible. What is important here is that the mutation must be in a gene that is responsible for controlling the cell cycle and cell division , as is the case with tumor suppressor genes : These are genes that control cell division and the cell cycle by causing uncontrolled growth inhibit.

Carcinogens or genotoxic substances that trigger initiation have no threshold values ​​below which there is no risk of mutation. This means that even the smallest amounts of a carcinogen can cause a genetic change.

promotion

In the doctorate (promotion), the second step in cancer development, a growth stimulus takes place in the initiated cell: the cell that has undergone a mutation is multiplied by a growth stimulus. On the one hand, this growth stimulus can originate from non-genotoxic carcinogens that occur e.g. B. promote inflammation , but not specifically trigger a mutation in the genome . On the other hand, the growth stimulus can arise from influences such as B. Hormones that promote the growth stimulus through so-called growth factors. This type of growth stimulus causes breast cancer to grow. The hormone estrogen sends growth signals so that the tumor cell is stimulated to divide (proliferation).

When inflammation, which acts as a promotion in cancer development, takes place, then hormones for wound healing through cell proliferation are released, which couple to the surface receptors and thus exert a growth stimulus on the cell. This is the case with Crohn's disease , which can lead to small bowel cancer , or mastopathy , which can lead to breast cancer. Because this inflammation stimulates cells to divide:

The initiated cell passes on its DNA damage to the daughter cell through cell proliferation . The proliferating cell has unstable DNA, which increases the risk of further mutations in tumor suppressor genes. The constant growth stimulus and cell proliferation result in a preneoplastic stage, i.e. the preliminary stage of cancer (neoplasia): A benign (benign) tumor has developed that grows to a limited extent and does not yet metastasize. With every cell proliferation, however, the risk of new mutations increases, so that a malignant (malignant) tumor can form.

The promotion is reversible in the early phases and a threshold could be set below which no growth stimulus is applied to the initiated cell. Without a doctorate, cancer cannot develop because the cells that are initiated cannot multiply. This could also explain why the risk of carcinoma decreases in some cases after exposure to carcinogens has ceased, as can be the case, for example, with cigarette smokers : After quitting cigarette smoking, no promotion is carried out on the possibly initiated cells, so no further mutations more can be collected and regression of the pre-existing preneoplastic stage can occur.

progression

The third stage is characterized by a progression (increase): Since the cells in the preneoplastic stage have undergone further mutations in tumor suppressor genes through carcinogenic effects and numerous proto-oncogenes have been converted into oncogenes, the actual malignant transformation now takes place. The cell is potentially malignant and divides steadily without interruption; it is immortal, that is, it has become immortal. After numerous cell divisions, a tumor mass is built up and the cells increasingly dedifferentiate, i.e. no longer resemble the other cells in the cell cluster or have different characteristics. The tumor cells displace healthy tissue. For reasons that are still unknown, the tumor cells are given the ability to metastasize , i.e. to form daughter tumors in other parts of the body. It is believed, however, that further mutations are required for this as well. In the progression, the last stage of tumorigenesis, the tumor cells develop their dangerous potential through metastasis. In the case of some types of cancer, it can lead to the death of the affected patient a few months after a cancer diagnosis .

Duration

The development of cancer takes place slowly and over years and decades. This duration is known as the latency period and it can be measured at up to 20–40 years. Why such a long development time is required is unknown, but endogenous factors such as individually different repair capacity or metabolic capacity may play a major role, as well as the fact that it takes several independent mutations to completely degenerate a normal cell.

criticism

Based on animal experiments , the three-stage model of carcinogenesis has been developed, in which there are gaps:

• The hypothetical three-stage model only describes the tumor development, but not the cause.
• Animal experiments cannot be transferred to humans, and tumor development in animal models is not necessarily the same as that in humans.
• The three-step model is based on skin carcinogenesis. It is not certain whether the tumor development in other organs, such as the lungs or the pancreas , proceeds in the same way.
• There are differences in the way carcinogens work: for example, asbestos works in a different way than tar. The carcinogenesis can thus proceed differently. While tar - for example from tobacco smoke - usually requires long-term exposure to trigger bronchial carcinoma , exposure of a few months is sufficient for asbestos to trigger pleural mesothelioma ( pleural cancer ) after 20 to 40 years .

See also

• Dormancy tumor
• Peto's paradox

Individual evidence

1. ↑ Hanahan, D. and Weinberg, RA: The hallmarks of cancer . In: Cell . 100, No. 1, 2000, pp. 57-70. PMID 10647931 .
2. ↑ ^{a b} Toxicology: H. Marquardt, S. Schäfer, H Barth, 3rd edition (2013)
3. ↑ Sascha Beneke: Page no longer available , search in web archives: Biomedicine II: Chemical Carcinogenesis and its Mechanisms, Molecular Toxicology (PDF; 1.8 MB)
4. ↑ ^{a b} Toxicology of Working Materials , Hermann Bolt , IfADo, Dortmund, as of 2005 (PDF; 2.2 MB)

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