Radiotherapy is a very effective way to destroy cancerous cells and to shrink tumors. About half of patients with tumors in the gastrointestinal cavity which includes the liver, pancreas, colon, prostate, etc. are given radiotherapy treatments. This has increased the cancer survival rates in recent years. Unfortunately, the intense radiation used in the treatment not only kills cancer cells but can also damage healthy intestinal cells. This results in toxicity for about sixty percent of the patients. The toxicity decreases after the treatments end but about ten percent of patients develop gastrointestinal syndrome. This is a disease that is characterized by intestinal cell death which results in the destruction of the entire intestine and death of the patient.
Damage to healthy intestinal cells is a major disadvantage of radiotherapy which results in the discontinuation and failure of an efficient cancer treatment. With the cessation of radiotherapy, there can be a quick tumor resurgence. Now a team of researchers from the Growth Factors, Nutrients and Cancer group at the Spanish National Cancer Research Centre (CNIO) have published a report of a discovery in the journal Science that might be able to protect healthy intestinal cells from radiation damage. This discovery involving mice may ultimate lead to radical changes in the way that high levels of radiation are managed in human patients. This could be useful for mitigating the negative effects of radiotherapy as well as dealing with radioactive materials and radiation in space missions.
The researchers focused on a protein called URI whose biological functions are not well understood. It is known that abnormal levels of URI in some organs can cause cancer. While high levels of URI can protect mice from intestinal damage caused by radiation, low or no URI can result in gastrointestinal syndrome and death.
Nabil Djouder is the Head of the Growth Factors, Nutrients and Cancer Group at CNIO and leader of the study. He said, “The precise functions of URI have not been identified yet. Just like pH or temperature, which the organism needs to maintain within a certain range, URI levels must also be kept within a very narrow window to regulate the proper functioning of other proteins. When URI levels are higher or lower than optimal, they may promote or protect against tumor development as well as other diseases, depending on the context.”
Djouder has been investigating URI for years and he created the first genetic mouse models to analyze the function of URI in mammals. His team found that DNA damage could be prevented in tissue cultures by high levels of URI. Djouder and Almudena Chaves-Pérez, one of his PhD students, then investigated whether the radiation protective action of URI was also present in vivo.
In order to investigate these questions, Djouder developed three genetic mouse models. These models were the first ever experimental mouse models created to facilitate the study of the role of URI and the effects of radiation exposure in the intestines. The first model was used as a control to identify where URI was expressed in the intestine. The second mouse model expressed high levels of URI in the intestine. The third mouse model deleted the gene that expressed URI in the intestinal epithelium.
The control set of mice revealed that URI is expressed in a population of dormant stem cells located in the intestinal crypts. URI protects these cells from toxicity induced by high levels of radiation. Chaves-Perez said, “We found that when radiation treatment is over, these are the cells that regenerate the damaged tissue. There has been much debate recently about which stem cell population is in charge of doing this job”.
The second set of mice were subjected to high levels of radiation. They were designed to express high levels of URI. They all survived gastrointestinal syndrome. With normal levels of URI expression, seventy percent of them would have died. The third set of mice with the gene expressing URI removed all died when exposed to high-levels of radiation.
Chaves-Perez explained these results: “What distinguishes this specific stem cell population is that under normal conditions (when they express URI), these cells are quiescent, that is, they do not proliferate. Consequently, they are not exposed to radiation damage, which only affects proliferating cells. However, when URI is not present in these stem cells, the well-known oncogene c-MYC is overexpressed, which leads to cell proliferation and increases susceptibility of these cells to radiation damage. As a result, these cells die, the intestine does not repair itself, and subsequently, the mouse dies.”
Djouder said, “Our work opens up new avenues to treat and prevent gastrointestinal syndrome by inhibiting or eliminating c-MYC. Such inhibitors will reduce lethal side effects of high-dose radiotherapy, allowing the increases of radiation doses to efficiently treat cancer and protect patients from gastrointestinal syndrome. In addition to protecting against the lethal side effects of radiation, c-MYC inhibitors are used in cancer treatment, which means that they may have dual efficacy.”
The researchers are now investigating whether organs with regenerative capacities such as the skin also have stem cell populations with high levels of URI.