In a study in mice, the scientists influenced the expression of the enzymes of the urinary cycle in colon cancer tumors, and found that these mice - unlike mice in the control group - had low levels of urine in their blood * Afterwards, the scientists examined the medical files of children with cancer who were treated at the Tel Aviv Medical Center Named after Sorasky (Ichilov). "We found that in these children, on the day they were admitted to the hospital, the levels of urine in the blood were much lower compared to healthy children of the same age and sex," says Dr. Erez.
Nitrogen is a building block of all proteins in the body, as well as DNA and RNA molecules. Therefore it is no wonder that cancerous tumors also want to get their hands on this foundation. Researchers at the Weizmann Institute of Science, together with researchers from the National Cancer Institute in the United States, have shown that in many types of cancer, the patient's nitrogen metabolism goes wrong - a disruption that leads to detectable changes in body fluids, and contributes to the development of new mutations in the cancerous tissue. The findings of the study, which Recently published in the scientific journalCell, may help in the future for the early detection of cancer and to predict the chances of success of immunotherapy treatment.
When the body uses nitrogen, it produces nitrogenous waste from the remains. This waste, called urea, is created in the liver in a series of biochemical reactions called the "urine cycle", following which the waste is excreted into the blood and later eliminated from the body in the urine.
In a previous study, Dr Ayelet Erez from the Department of Biological Control that one of the enzymes active in the urinary cycle is inactive in many cancerous tumors, thus increasing the amount of nitrogen available to build the organic pyrimidine compound, which is used to create DNA and RNA and enables cancer cell culture.
In the new study, conducted with Prof. Eitan Rupin from the National Cancer Institute and other researchers, Dr. Erez's group was able to identify changes in additional enzymes of the urinary cycle, which together increase the amount of nitrogen available to create pyrimidine molecules. These changes lead to high pyrimidine levels within the tumor and increase the number of mutations in cancer.
In a study in mice, the scientists influenced the expression of the enzymes of the urine cycle in colon cancer tumors, and found that in these mice - unlike mice in the control group - there were low levels of urine in the blood; Also, pyrimidine was found in the urine of these mice. After that, the scientists examined the medical files of children with cancer who were treated at the Soraski (Ichilov) Tel Aviv Medical Center. "We found that in these children, on the day they were admitted to the hospital, the levels of urine in the blood were much lower compared to healthy children of the same age and sex," says Dr. Erez.
These findings show that disruption of the renal cycle in the liver and tumors produces nitrogen markers, which may facilitate the early detection of cancer. Future tests that will rely on a combination of urine measurements in the blood and pyrimidine measurements in the urine, may warn of cancer developing in the body.
"Normal laboratory tests check whether the levels of urine in the blood are not too high, but now we have shown that even levels that are too low may indicate a problem," says Dr. Erez. "The cancer cells do not waste anything, they use as much nitrogen as possible, instead of taking it out of the body in the form of urine, as healthy cells do."
Later, the scientists examined large-scale genomic databases, and discovered that the disruption in the expression of enzymes of the mitochondrial cycle appears in many types of cancer, and that it is accompanied by certain mutations resulting from increased pyrimidine production. These mutations are a double-edged sword. On the one hand, they make the cancer more violent and thus reduce the patient's chances of survival, but they also produce protein segments that make the tumor more "vulnerable" to the influence of the immune system. Therefore, tumors in which the expression of modified cycle enzymes is disrupted, are more sensitive to immunotherapy - a treatment method in which the patient's own immune system is activated in order to fight the tumor. Accordingly, the scientists found that melanoma patients with a disruption in the expression of the enzymes of the urinary cycle in the tumor, responded better to immunotherapy than patients without these disruptions. When the scientists disrupted the enzymes of the urine cycle within the tumors in mice, these mice responded much better to immunotherapy than mice with tumors in which the enzymes of the urine cycle were functioning normally.
If these findings are confirmed in larger scale experiments in animals and humans, they may lead to a test that will make it possible to assess in advance the chances of success of immunotherapy based on a biopsy of the tumor, instead of a genomic analysis which is much more complex to perform. Disruption of a certain type in the expression levels of an altered enzyme in the tumor tissue in the biopsy will indicate that the patient has a better chance of responding to immunotherapy.
"Another possibility that should be examined is whether proactive genetic disruptions in urinary cycle enzymes before treatment can increase the chances of success," says Dr. Erez. This type of genetic disruption will involve the introduction of disruptions in the expression of circulating enzymes in the tumor in the hope that these will lead to the overproduction of pyrimidine molecules and thus contribute to the formation of mutations in proteins, and help the immune system identify and destroy the tumor.
The research participants included Dr. Little Adler, Dr. Narin Carmel, Shiran Rabinowitz, Dr. Rom Keshet, Dr. Noa Stettner, Dr. Alon Zilberman, Hila Weiss and Sion Pinto from the Department of Biological Control, Dr. Lilach Agami and Prof. Avigdor Shertz from the Department of Plant and Environmental Sciences, Dr. Raya Elam from the Department of Veterinary Resources, Dr. Alexander Brandis, Dr. Sergey Malitsky and Dr. Maxim Itkin from the Department of Life Science Research Infrastructures, Shelly Klaura, Dr. Ronan Levy and Prof. Jordana Samuels from the Department of Molecular Biology of the Cell, and Dr. Noam Ginoser from the Department of Molecular Genetics - all from the Weizmann Institute of Science; Dr. Joe Sang Lee, Hiran Karthia, Noam Auslander and Prof. Sridhar Hannahalli from the University of Maryland; Daniel Helbling and Dr. David Dimock from Wisconsin Medical College; Dr. Kin Son and Dr. Sandesh Nagmani from Baylor College of Medicine; Elon Barnea and Prof. Aryeh Admon from the Technion; Miguel Onda and Prof. Arcaice Crachado from the University Hospital of Bilbao, Spain; Dr. David Wilson III from the National Institute on Aging; and Dr. Ronit Alchasid from the Sourasky Tel Aviv Medical Center.
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