the Italian study in Nature

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Researchers from the Bambino Gesù Children’s Hospital in Rome and the Tor Vergata University of Rome, in collaboration with other European and American research centers, have discovered how the process of tumor proliferation is triggered.


After decades of research and many hypotheses – explain from the Capitoline IRCCS – the circle is closed on the mechanisms of the cell cycle, the process through which cells, including cancer cells, mature and proliferate. Researchers have discovered the missing piece: what regulates the life of Cycline D, an essential molecule in cell division. The switch that turns Cycline D activity on and off is a protein called Amber1: when it doesn’t work, it triggers a process that leads to the rapid formation of many types of tumors.

The discovery opens the way to specific therapies that inhibit the defense system of diseased cells until their self-destruction. The results of the study, supported by Airc, have just been published in ‘Nature’.

The cell cycle – experts recall – consists of a series of linked and finely regulated events that leads to the division of cells; a vital process by which the cells of the whole organism are formed from a fertilized egg, as well as the process by which the cells of the skin, blood and organs are renewed. This cycle is regulated by Cycles, a group of proteins classified with the letters A, B, C, D and so on. Each does a piece of the work of cell division and are produced and destroyed in a precise alternation, until the birth of daughter cells. The regulation mechanism of these molecules was already almost entirely known, except – until now – of Cycline D. With the study coordinated by the Infant Jesus the entire path was finally defined.

In the course of the division process, the genes responsible for controlling the cell cycle can undergo mutations from which many types of cancer originate. These anomalies generally develop during the replication of the genetic patrimony (DNA) to be transferred to the daughter cells: if the mechanism jams, any errors accumulated in this crucial phase become the cause of mutations, tumors and cell death.

The study that led to the discovery of the correlation between the Ambra1 and Cycline D proteins was carried out by the researchers of the Bambino Gesù, led by Francesco Cecconi of the Oncohematology Research Area directed by Franco Locatelli, together with the research team of the University of Roma Tor Vergata, and made use of the collaboration of the Danish Cancer Society Research Center and other European and American centers. The research was conducted on hundreds of samples (animal models, cells produced in the laboratory, cells derived from both animal and human tumors), with 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 Cecconi’s team – in some defects of the cell cycle.

In the course of the investigations, the researchers in fact noted that, in the event of the absence or low quantity of Amber1, Cycline D is not destroyed as it should and, therefore, accumulates. Due to this accumulation, the cells begin to divide at an uncontrolled rate, the DNA is damaged and the formation of tumor masses is triggered. The imbalance in the levels of the two proteins has been found in many types of cancer including lung adenocarcinoma, sarcoma and glioblastoma.

The study of the Infant Jesus also describes the experimentation of a therapy for tumors based on the imbalance of Amber1 and Cycline D. As there are currently no drugs able to act directly on the two proteins to restore the right amount, the researchers have identified an alternative solution that exploits one of the weak points of cancer cells: the repair system. The great speed with 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 allows them to survive and proliferate. However, if the repair process is inhibited, the diseased cells accumulate so many defects that they undergo self-destruction.

The therapy – a mix of specific drugs called shelter inhibitors – has been successfully tested on cellular and animal models: the tumor has regressed and survival has increased. The research, therefore, suggests that this treatment strategy, already used for the treatment of some types of human cancer, can also be applied to patients with the altered Amber1-Cycline D combination.

“The idea is that patients diagnosed with cancer are also examined for the levels of Amber1 and Cycline D – says Cecconi, professor of developmental biology at the University of Tor Vergata and researcher of the Bambino Gesù absence or low levels of Amber1, in association with an accumulation of Cycline D, is detected in cancer cells, we could try to suppress with specific drugs, already known in therapy, the ability of cancer cells to repair the genetic material. to limit their repair, we could aim to kill cancer cells, exploiting their Achilles heel, that is the same genomic instability that caused them to proliferate “.

“Our data also extends to the processes of cell proliferation in the developing nervous system – adds Giacomo Milletti, research biologist of the Bambino Gesù, PhD student at the University of Rome Tor Vergata and first co-author of the study – and this new level of regulation could represent a new frontier in the molecular oncology of brain tumors in children “.

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