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The incidence of neoplastic diseases increases from year to year. Despite extensive research into the biology of cancer cells, there is still no response which ultimately initiates tumor formation. Most question marks concern the so-called pre-initiation and initiation period. Pre-initiation is the period of exposure to carcinogenic factors that precedes the development of a neoplastic disease. Initiation, in turn, is a phase in which, in response to various external factors, the cells develop and accumulate damage that interferes with the physiological functions of the cell. However, there are currently no tools available to diagnose changes in cells at such an early stage.
The list of carcinogens is long. It includes physical factors (e.g. ultraviolet and ionizing radiation), chemical (e.g. asbestos, chemical compounds such as cyclic aromatic hydrocarbons, chromium, iron, arsenic, dioxin compounds) and biological factors (e.g. infection with hepatitis B virus (HBV ), Epstein-Baara virus (EBV), HIV or herpes virus (HPV). There is no need to convince anyone about the harmful effects of excess UV radiation generated by the sun or common sunbeds. Melanoma, a tumor in 90% located in the skin, is present in In most cases, the result of long-term exposure to UV rays UV rays affect the DNA of cells, initiating a reaction between the two thymine molecules in the DNA The dimer formed in the reaction is very stable, although its removal and DNA repair are possible thanks to the cell’s repair systems. remember that long-term UV exposure generates a large number of defective thymine dimers, the repair of which is limited by efficiency appropriate cellular enzymes. Ultimately, the repair mechanisms break down and the genetic material is permanently damaged. If, in spite of the damage to DNA, cells survive, their functions are disturbed and they themselves often transform and acquire a neoplastic phenotype.
Chemical carcinogens, such as asbestos, are mainly associated with the occupational specificity of specific workplaces. However, you should be aware that we are exposed to thousands of chemicals every day, such as preservatives and dyes present in food, drugs, plant protection products and others. It turns out that the long-term effect of preservatives, especially nitrites, and nitrosamines resulting from their transformation with the participation of microorganisms present in the gastrointestinal tract, may be the cause of the development of neoplastic disease. The addition of preservatives to sausage products prevents the growth of botulinum bacteria and is responsible for their smell and appetizing pink color. However, studies have shown that long-term and excessive consumption of them positively correlates with an increase in the incidence of gastric cancer by about 30%. Apart from the presence of some preservatives in food, the method of food preparation, especially its thermal processing, is also important. It is generally recommended to eat lean cooked meat as opposed to frying and roasting with a lot of fat. Indeed, a diet high in saturated fatty acids is widely considered a risk factor for the development of breast, colon, prostate and pancreatic cancers. The Maillard reaction, a cycle of reactions between amino acids and reducing sugars (e.g. glucose) at elevated temperature, is at the heart of the molecular carcinogenic effects of processed foods. As a result of the reaction, flavor compounds (melanoids) are formed, which are largely responsible for the taste of bread, cookies, beer, meat, chocolate and coffee. To this day, however, little is known about the physiological properties of these compounds. It is known, however, that when food is processed at temperatures above 180 ° C (e.g. frying potato fries, production of crisps) the end product of the Maillard reaction is acrylamide, a compound considered to be potentially toxic and carcinogenic. Researchers postulate that acrylamide damages cell DNA, leading to the formation of mutations. The second common source of acrylamide is cigarette smoke. In addition to acrylamide, cigarette smoke contains over 40 other carcinogenic substances, incl. nitric oxide and its derivatives – benzopyrene, nitrosamines, hydrogen cyanide, acetone, arsenic, vinyl chloride, phenols, formaldehyde, polonium and heavy metals. Components of tobacco smoke damage genetic material, initiate oxidative stress and generate free radicals, inhibit the activity of cell respiratory enzymes and accelerate epithelial cell division. A strong causal relationship between cigarette smoking and cancer has been documented for cancers of the lung, larynx, esophagus, pharynx, mouth, kidney, pancreas and bladder.
When talking about the initiation period in neoplastic disease, one should not forget about the possible influence of stress on the risk of developing the disease. There are many reports documenting the occurrence of such a correlation. One of the postulated mechanisms is based on the role of adrenaline (epinephrine), a hormone released from the adrenal medulla in response to stress. Elevated hormone levels are short-lived, but may recur when stress is chronic. According to Canadian scientists, in prostate and breast cancer cells, adrenaline deactivates the BAD protein, which causes programmed death in healthy cells. The protective effect against neoplastic cells is also attributed to norepinephrine, released by the sympathetic system (flight or attack system), and the secretion of which increases in stressful situations. In addition, it has been proven that chronic stress significantly weakens the immune system, one of the main functions of which is to recognize and destroy abnormal cells. This so-called immunosuppression is the result of elevated plasma levels of adrenocortical glucocorticosteroinds.
As mentioned above, as a result of environmental factors, DNA damage accumulates in cells. As a result, growth signals may be intensified while at the same time weakening the activity of mechanisms inhibiting the proliferation (increasing the number) of cells. The molecular mechanism responsible for cell proliferation is based on the greater activity of genes from the group of the so-called protooncogenes. The transformation of protoncogenes into oncogenes (mutations) results in higher activity of tyrosine kinases (src, fgr and others) and serine-threonine (Raf, Mos), non-receptor kinases (kRas, nRas) and transcription factors (e.g. NK-kB). As a result, cell division intensifies. The most common cause of increased activity of proto-oncogenes is a mutation resulting from the influence of physical and chemical factors or oncogenic viruses on DNA. Simultaneously with the activation of cell division, the functions of suppressor (inhibitory) genes are weakened. The consequence of the aforementioned molecular changes is the acquisition by cells of an unlimited proliferation potential and the formation of a tumor, which at this stage does not yet have malignancy. As the tumor size grows, some cells lose the ability to take up nutrients and oxygen from blood vessels located outside. However, neoplastic cells are protected against such an eventuality and under the conditions of hypoxia, the so-called the transcription factor HIF-1a, which in turn activates the production of angiogenesis-stimulating substances, the process of blood vessel formation. The induction of angiogenesis characterizes the next phase of carcinogenesis, the so-called the promotion stage in which cells acquire a neoplastic phenotype. In addition to the formation of new, irregularly shaped blood vessels and disturbed blood flow, cancer cells secrete lytic enzymes that create free space for the growing tumor. In the later stage of tumor development, the so-called during the progression phase, neoplastic cells are selected – cells with the ability to migrate gain the advantage. Cell migration takes place by penetrating into leaky walls of new blood vessels and displacing with the blood flow around the body. Some of the migrating cells that survive the dangerous journey (most die), by hitting a niche that suits them, create a secondary tumor focus.
The above-mentioned examples clearly show the great influence of the environment on the development of neoplastic disease. In most cases, neoplastic disease is not hereditary. However, it should be remembered that the incidence of some types of cancer may be due to mutations in reproductive cells. The mutations most often concern proto-oncogenes and tumor suppressor genes. Congenital “gain of function” mutations for protoncogenes or “loss of function” mutations for tumor suppression genes may explain the occurrence of tumors at an earlier age, or the multifocal nature of tumors. Examples of neoplasms with a significant contribution to the genetic background are, inter alia, neurofibromatosis type 1, internal multiple neoplasms, Li Fraumeni syndrome (multiple tumors of the adrenal glands, breast, leukemias, sarcomas), familial adenomatous polyposis of the intestine, non-polyposis colon cancer, Peutz-Jeghers syndrome (cancers of the pancreas, uterus, colon, esophagus , nipple, lungs). In turn, in the case of breast and ovarian neoplasms, about 5% of cases are associated with the inheritance of mutations in one of the susceptibility genes (BRCA1, BRCA2, TP53, PTEN), of which the BRCA1 gene is most often mutated. It should be emphasized that the presence of the defective variant of the gene, despite a strong correlation with the incidence of ovarian and breast cancer, is not a determinant of cancer incidence. Likewise, the presence of normal gene copies does not protect against disease induction by other agents. Cancer is a multifactorial disease and its development often takes many years. However, a large share of environmental factors gives us hope that our lifestyle, thanks to the awareness of the current threats, can be changed in terms of minimizing exposure to potential carcinogens. Rational diet low in unwanted fats (pork and beef) and enriched with fats from cold sea animals (salmon, halibut, mackerel), increasing the proportion of fresh, unpreserved food and, moreover, rich in vegetables and fruits, containing antioxidants, protecting cells against the harmful effects of damaging free radicals, physical activity to mobilize antioxidant defenses, and the ability to deal with stress or simply avoid it can reduce the risk of cancer.
Text: Beata Pająk, Ph.D.
Department of Cell Ultrastructure
Institute of Experimental and Clinical Medicine M. Mossakowski PAN