Research by the Children’s Hospital of the Holy See, Bambino Gesù, in collaboration with the University of Rome “Tor Vergata” and other European and American research centers, sheds light on the cycle of cell division. The relationship between the proteins Ambra1 and Cyclin D has been identified: an imbalance can cause the process that leads to a tumor. Below is a working translation of a joint press release from the Bambino Gesù Hospital and the University of Rome “Tor Vergata”.
By the writer of the Vatican News staff
This new discovery opens the way to therapies that block the immune system of diseased cells. After decades of research and many hypotheses, it closes the loop around the mechanisms of the cell cycle, the process by which cells, including cancer cells, mature and multiply. Researchers from the Bambino Gesù Children’s Hospital and the University of Rome “Tor Vergata”, in collaboration with other European and American research centers, have discovered the missing piece: what regulates the life of Cyclin D, an essential molecule in cell division. The switch that turns the activity of Cyclin D on and off is a protein called Amber1: when it doesn’t work, it initiates a process that leads to the rapid formation of many types of cancer. The discovery opens the way to specific therapies that inhibit the immune system of the diseased cells up to their self-destruction. The results of the AIRC-supported study have just been published in the scientific journal Nature.
The cell cycle
The cell cycle consists of a series of linked and precisely regulated events that lead to cell division, a vital process by which the cells of the entire organism are formed from a fertilized egg, as well as the process of renewing the cells of the skin, blood and organs. This cycle is regulated by the cyclins, a group of proteins classified with the letters A, B, C, D, and so on. Each does part of the work of cell division and is produced and destroyed in a precise alternation, up to the birth of daughter cells.
The regulatory mechanism of these molecules was already almost completely known, except – until now – for Cyclin D. With the study coordinated by Bambino Gesù, the whole path has finally been defined.
Tumors: the “mistakes” of the cell cycle
During the division process, the genes responsible for controlling the cell cycle can be subject to mutations from which many types of tumors originate. These abnormalities usually arise during the replication of the genetic heritage (DNA) that is transferred to the daughter cells: if the mechanism fails, any errors that accumulate at this crucial stage become the cause of mutations, tumors and cell death.
The study that led to the discovery of the correlation between the proteins Ambra1 and Cyclin D was conducted by the researchers at the Bambino Gesù Hospital – led by Professor Francesco Cecconi from the Research Area of Oncohaematology, led by Professor Franco Locatelli – together with the University of Rome research team “Tor Vergata” and has benefited from the collaboration of the Danish Cancer Society Research Center and other European and American centers.
The research has been conducted on hundreds of samples (animal models, cells produced in the laboratory, cells derived from both animal and human tumors) using a combination of advanced techniques (imaging, microscopy, fluorescence, genetic engineering, biochemistry, histology) starting from the intuition of a possible role of Ambra1 – a molecule discovered in 2007 by Professor Cecconi’s team – in some defects of the cell cycle.
During the studies, the researchers noticed that in the absence or a low amount of Amber1, Cyclin D is not destroyed as it should be and thus accumulates. This accumulation causes cells to divide at an uncontrolled rate, damage the DNA and initiate the formation of tumor masses. The imbalance of the levels of the two proteins has been found in many cancers, including lung adenocarcinoma, sarcoma, and glioblastoma.
The Bambino Gesù study describes the testing of a therapy for tumors based on the imbalance of Amber1 and Cyclin D. As no drugs are available to date that can act directly on the two proteins to restore the correct amount, researchers have found an alternative solution. which exploits one of the weaknesses of cancer cells: the repair system.
The rapid rate at which cancer cells divide generates a series of errors in their DNA that are gradually corrected by a system of enzymes (present in all cells of the human body) that allow them to survive and multiply. However, if the repair process is inhibited, the diseased cells accumulate so many defects that they self-destruct.
The therapy (a mix of specific drugs called “repair system inhibitors”) has been successfully tested on cellular and animal models: the tumor deteriorated and survival increased. The research therefore suggests that this treatment strategy, which is already used to treat some types of human tumors, can also be used in patients with the Amber1 – Cyclin D combination modified.
“The idea is that patients diagnosed with cancer will also be tested for Ambra1 and Cyclin D levels,” said Francesco Cecconi, Professor of Developmental Biology at the University of Rome “Tor Vergata” and a researcher at Bambino Gesù. “If the absence or low levels of Ambra1 in combination with an accumulation of Cyclin D is detected in tumor cells, we can try to suppress the ability of tumor cells to repair the genetic material with specific drugs already used in therapy. Thus their might limit recovery, we could try to kill cancer cells using their Achilles heel, which is that same genomic instability that prompted them to multiply. ”
“Our data also extends to the processes of cell proliferation in the developing nervous system and this new level of regulation could set a new frontier in the molecular oncology of childhood brain tumors,” adds Dr. Giacomo Milletti, research biologist at Bambino Gesù, to. PhD student at the University of Rome “Tor Vergata” and first co-author of the study.
3 studies in nature
The results of the research of the Bambino Gesù and the University of Rome “Tor Vergata” are further confirmed by two other international studies conducted in the United States of America – in New York and San Francisco – which reach the same conclusion from different starting points: Ambra1 controls Cyclin D. Due to the high scientific value of the discovery, the three studies have been published consecutively in the same issue of Nature.