How are inflammation and cancer related
Kirill Stasevich, "Science and Life"
It is often heard that chronic inflammation increases the likelihood of cancer – it is believed that one in five cases of cancer begins with prolonged inflammatory reactions of the immune system.
After doctors noticed the statistical relationship between the two, an active search for molecular mechanisms began. As is known, the immune system responds with inflammation to the appearance of pathogens or some dangerous substances in the body (or substances that it takes for dangerous). The response involves cells that must absorb the infection, and special aggressive molecules that destroy and neutralize what irritates the immune system.
Among such "combat toxic substances" can be called hydrogen peroxide, nitrogen oxide NO and hypochlorous acid. These are quite strong oxidizing agents, and, in addition to pathogens, pathogenic molecules and diseased tissues, they can also damage healthy cells located near the focus of inflammation.
Researchers from the Massachusetts Institute of Technology managed to notice that in mouse tissues inflamed by the bacterium Helicobacter hepaticus, specific DNA damage occurs due to the fact that the nitrogenous base cytosine is converted into 5-chlorocytosine (Helen Knight, How chronic inflammation can lead to cancer). The modifying agent here was clearly the aforementioned hypochlorous acid. Usually unnecessary modifications of genetic "letters" are corrected in a timely manner by DNA repair systems, however, 5-chlorocytosine accumulated and accumulated, which indicated the inability of repair systems to correct such an error.
Harmful mutations often occur due to the fact that altered bases in DNA undergo a number of transformations, and as a result are replaced by others that should not be in their place. (And the replacement can occur as part of DNA repair.)
Can the conversion of cytosine into chlorocytosine cause malignant cell degeneration? To find out, John Essigmann and his colleagues introduced a "chlorine" mutation into the DNA of a bacterial virus and allowed it to multiply into a bacterium. Nitrogenous bases, our "genetic letters", are arranged according to the principle of complementarity, that is, if cytosine (C) stands in one DNA chain, then guanine (G) will stand in front of it in the other, and thymine (T) will stand opposite adenine (A). But, as the authors write in the journal PNAS (Fedeles et al., Intrinsic mutagenic properties of 5-chlorocytosine: A mechanical connection between chronic inflammation and cancer), 5-chlorocytosine "demanded" not guanine, but adenine as a partner. That is, after modification, structural tension arose in the DNA due to the unpaired nucleotides, which special enzymes serving DNA were in a hurry to eliminate. As a result, adenine appeared in the neighboring chain "at the request" of chlorocytosine – and at the next cycle of doubling of the molecule opposite adenine, not cytosine appeared, which had been there before the appearance of the chlorine label on it, but thymine. In other words, there was a mutation with a nucleotide replacement – the code was originally different. The protein encoded here, after synthesis, will carry some other amino acid, just because A was replaced with T.
It is known that when gastrointestinal tumors appear in cells, two types of mutations actively occur: adenine is replaced by guanine, cytosine by thymine. It was the second mutation that we managed to see by observing the fate of chlorocytosine, and its frequency turned out to be exactly what is observed in oncological processes. Recall that hypochlorous acid, which is capable of modifying cytosine, is used by the immune system as a chemical weapon, which, as we see, is quite capable of provoking carcinogenic mutations. The authors believe that modifications can occur not only in DNA itself, but also in free-floating nucleotides with cytosine, which serve as raw materials for DNA synthesis.
So far, the experiments have been performed in a model system, with a virus and bacteria, and now they need to be repeated with human tissues. However, the fact that human proteins can create the same mutations, the authors of the work have already checked: if a human enzyme was engaged in DNA repair, then it, like its bacterial "colleague", "went on about" the modified cytosine and embedded adenine in the complementary chain, that is, opened the way to a mutant code change.
It is possible that the same mechanism provokes other types of cancer, not just gastrointestinal, but here again, additional research is needed. On the other hand, this may not be the only way that the immune system is able to provoke the development of a tumor: for example, a year ago an article was published in the journal Nature, which stated that inflammatory molecular signals released by neutrophils induce skin cancer to metastasize.
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12.08.2015