A new way to protect against the damage caused by high doses of radiation has been discovered – ScienceDaily

Damage to healthy intestinal cells is the main disadvantage of radiotherapy, which leads to the cessation of effective anticancer treatment and its failure, which can lead to rapid tumor recurrence. Now, a discovery published in Science Scientists in the Growth Factors, Nutrients and Cancer group at the National Cancer Research Center (CNIO) in Spain could help protect healthy intestinal cells from radiation damage. The consequences of their findings in mice could dramatically change the way humans manage exposure to high radiation levels; both for cancer research and treatment and for other areas such as space exploration, nuclear war or nuclear accidents.

The work of the group is focused on URI, a protein whose functions are not yet well understood. However, previous studies of the group had shown that abnormal levels of expression of this protein in certain organs could cause cancer. The study now published in Science shows that high levels of URI proteins protect mice against radiation-induced intestinal damage, while low or no detectable protein levels can lead to gastrointestinal syndrome and death.

"The precise functions of the URI have not yet been identified," says Nabil Djouder, head of CNIO's Growth, Nutrients and Cancer Growth Group and head of the study. "Just like the pH or temperature, which the body must maintain within a certain range, URI levels must also be kept in a very narrow window in order to regulate the correct functioning of other proteins. When URI levels are higher or lower to promote or protect against the development of the tumor as well as other diseases, depending on the context. "

Djouder, who has been studying URI for a long time, developed the first genetic mouse models to study the functions of this protein in mammals. His team had observed that high levels of URIs protected intestinal cells from damage from DNA during a culture in culture. Djouder and the doctoral student Almudena Chaves-Pérez therefore suggested studying whether the protective function of the URI was also effective in vivo and whether it was able to attenuate the effects of high-dose irradiation and therefore of the gastrointestinal syndrome. To solve these problems, three genetic mouse models have been developed. These are the first experimental genetic mouse models designed to specifically study the role of URI and the effects of radiation on the intestine. One of them served as a control model to identify where exactly the URI was expressed in the intestine; another mouse model had high levels of protein expressed in the intestine and, in the third, the gene had been suppressed to decrease the levels of URI in the intestinal epithelium.

Control mice showed that URI is expressed in a specific population of dormant stem cells located in intestinal crypts (called Lieberkühn crypts). URI protects these cells from the toxicity caused by high-dose radiation. "We found that when radiotherapy is complete, it is the cells that regenerate the damaged tissue," says Chaves-Pérez, the first author of the paper. "There has been a lot of debate lately about the stem cell population that is responsible for doing this work," she added.

After being subjected to a high dose of radiation, 100% of mice designed to express high levels of URI in the intestine survived the gastrointestinal syndrome, whereas under normal conditions 70% of them died. In contrast, all mice in which the gene had been deleted died of gastrointestinal syndrome.

Chaves-Pérez explains these findings: "What distinguishes this population from stem cells is that under normal conditions (when they express URI), these cells are at rest, which means that they do not have any cells. that is, they do not proliferate, therefore, they are not exposed to radiation damage, but when the URI is not present in these stem cells, the well-known oncogene c- MYC is overexpressed, which leads to cell proliferation and increases the susceptibility of these cells to damage by radiation., The intestine does not repair itself and, subsequently, the mouse dies. "

Although their results have yet to be confirmed by other studies, Djouder believes that c-MYC inhibitors may be useful in alleviating radiation-induced gastrointestinal syndrome in patients. "Our work opens new avenues for treating and preventing gastrointestinal syndrome by inhibiting or eliminating c-MYC.These inhibitors will reduce the fatal side effects of high-dose radiation therapy, thus increasing the doses of radiation to effectively treat cancer and protect patients from gastrointestinal syndrome. ", explains Djouder. "In addition to protecting against the deadly side effects of radiation, c-MYC inhibitors are used in the treatment of cancer, which means that they can have double efficacy," he adds.

Now, it would be interesting to know if other organs with regenerative capabilities, such as skin, possess a certain population of stem cells with high levels of URI. Djouder and his team are currently researching this topic.

Djouder believes that, in addition to its importance in the field of cancer, "this discovery could have important consequences for radiation protection in large doses, as in the case of nuclear accidents, nuclear war or radiation exposure. cosmic during long space exploration ".

The study was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by the European Regional Development Fund, the "La Caixa" Foundation and the National Institute of health Carlos III.