The key mechanism of the appearance of cancer metastases is identified

mechanism of the appearance of cancer metastases

Scientists managed to determine the principle of the appearance of metastases.

Cancerous metastases, the migration of cells from the primary tumor with the formation of distant foci in the body, can be caused by DNA leakage in tumor cells, scientists said Weill Cornell Medicine.

The origin of metastases was one of the main mysteries of cancer biology. The team of experts led by Samuel Bahum approached the solution by tracing a complex chain of events that arises from chromosomal instability, a common feature of cancer cells in which DNA is copied incorrectly every time these cells divide. Using models of breast and lung cancer, the researchers found that chromosomal instability leads to changes in the cells that lead to metastasis.

Bahum reiterates: "We have shown that chromosomal instability can cause DNA leakage from the nuclei of cancer cells and this leads to a chronic inflammatory response within the cells, and the cell response allows them to spread to distant organs." The co-author of the discovery, Lewis Cantley, added: "Metastases lead to a 90 percent death from cancer, and this work opens up new opportunities for therapeutic effects on the disease."

Previous studies have linked chromosomal instability with metastases, although the cause of the connection was not clear. "Our initial hypothesis was that chromosomal instability generates many genetically distinct tumor cells and that the Darwinian selection process helps to survive cells that can spread and form distant tumors," Bahum said.

When scientists injected chromosomally unstable tumor cells to animals, they found that many newer tumors spread and form many times in rodents, which indicates that the chromosomal instability itself was the cause of metastasis. The researchers studied the activity of genes in two sets of tumor cells and found that patients with high chromosomal instability had abnormally increased activity. "These were cancer cells cultivated in a dish, and not in the presence of any immune cells. We were very surprised by this and wondered what could have caused this inflammatory reaction, "the authors noted.

Recent studies have shown that chromosomes in unstable tumor cells can sometimes flow from the cell nucleus where they normally live. These misplaced chromosomes encapsulate themselves, forming "micronuclei" in the fluid or cytosol in the main part of the cell outside the main nucleus. Nevertheless, micronuclei tend to break eventually, releasing the exposed DNA into the cytosol. Cells interpret DNA in the cytosol as a sign of an infectious virus, which usually releases its DNA in the cytoplasm when it first attacks the cell. Human cells evolved to combat this type of viral infection by detecting naked cytosolic DNA using the cGAS-STING molecular machine. After activation, this pathway starts an anti-inflammatory antiviral program.

Bachum and colleagues examined chromosomal-unstable tumor cells and found that they did have a lot of cytosolic DNA, and showed signs of chronic activation of cGAS-STING antiviral proteins. Decreased cGAS-STING levels reduced inflammation and prevented the metastasis of other aggressive tumor cells when injected into mice. In an ordinary cell, an antiviral reaction stimulated by DNA leakage from the nucleus will result in cell death. The experts found that the tumor cells succeeded in suppressing the lethal elements of the cGAS-STING response. At the same time, they use other parts of the answer to allow themselves to disconnect from the tumor and become mobile inside the body.

"They start acting as if they were certain types of immune cells that are usually activated by the infection. In response, they very quickly move to a place of infection or trauma in the body and the cancer cells participate in some form of lethal immune mimicry, "the researchers added.

It is estimated that about half of the metastases in humans occur this way. Currently, they are studying strategies to block the process. "One of our next steps is to better understand how these cells change the normal response and how we can restore it," Bahum said.

Source: telegraf

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