Mutation – masking
Cancer cells mutate against treatment
Kirill Stasevich, Science and Life (nkj.ru ), based on the materials of The Scientist.
Malignant tumors, unfortunately, often become resistant to treatment. Resistance occurs both in non-specific therapy, when agents acting on cancer cells in general and simultaneously affecting healthy ones are used, and when using specific drugs that act only on cells of a certain tumor.
Usually, the return of the disease is explained by the fact that malignant tumors consist of cells with different mutations. Only certain groups of cells die from drugs, and some may remain. And even if there were very few of these remaining in the original tumor, even if they were not allowed to grow other tumor cells – now, after the death of the bulk of the cells, they gain an advantage and begin to multiply actively. That is, there is a natural selection that weeds out cells that are not able to survive in new medicinal conditions (however, such selection is better called involuntary artificial – because our human medicines work here). How this happens, we wrote in the article that mutations in cancer cells obey evolutionary laws.
But the tumor does not necessarily rely on the mutations that it already has. Researchers from the University of Turin and the Cancer Institute in Candiolo have shown that cancer cells, after feeling therapy, begin to actively mutate. There is a certain risk in this, because by allowing a high level of mutations, you can get such genetic damage that is simply incompatible with life. On the other hand, by opening the way to new mutations, you can quickly find a way to survive treatment. This is what bacteria do under the influence of antibiotics – they stop correcting errors in DNA in the hope that with the help of some mutation they will learn how to effectively pump the antibiotic out of the cell or simply be able to split it.
The authors of the article in Science (Russo et al., Adaptive mutability of colorectal cancers in response to targeted therapies) suggested that cancer cells do the same. Researchers experimented with colon cancer cells: with the help of drug antibodies, they closed a receptor on the surface that is needed for division – if no signals go inside from this receptor, the cell stops dividing and dies. Most of the cancer cells died after four days, but there were also those who remained alive for two weeks, despite the drug antibodies. If the dose of the drug was then increased, these surviving cells became sensitive to treatment again, but subsequently acquired resistance to treatment again.
Errors in cellular DNA occur not only because of some external mutagens, but also during normal division: enzymes that copy DNA for daughter cells sometimes confuse the genetic "letters"-nucleotides with which the genetic code is written. Moreover, among the enzymes that copy DNA, there are some that make few mistakes, and others that make many mistakes.
On the other hand, cells have special systems for correcting DNA errors (we described some of these systems in detail on the occasion of the 2015 Nobel Prize.) It turned out that when cancer cells began to be treated, they had more enzymes that copy DNA not very accurately. At the same time, genes encoding those copying enzymes that work with greater accuracy became less active. And at the same time, genes encoding proteins responsible for correcting errors in DNA became less active. The number of errors in DNA was increasing, and, obviously, among them were those that helped cancer cells bypass therapy.
The next question is what molecular mechanism connects the drug and genetic regulation. Perhaps some molecules feel that it becomes difficult for the cell to divide and regulate the activity of genes accordingly, but what these molecules are and why this mechanism works in some cells and does not work in others will become clear only after additional experiments. If we understand what's going on here, we can improve the available methods of chemotherapy so as to prevent cancer cells from increasing the number of mutations and prevent them from surviving due to damage to their own DNA.
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