The recent study published in Journal of Cell Biology (JCB), a prestigious international magazine published by Rockefeller University Press. The study identified the microRNAs needed to maintain cancer stem cells, which contribute to the growth of breast cancers and the return of cancer after treatment. The data reveals that it is enough to block these microRNAs to make stem cells more vulnerable to certain drugs. If the results obtained are confirmed in clinical trials, chemotherapies could be even more effective in the future, improving the prognosis of patients with aggressive forms of breast cancer.
The research was supported by AIRC Foundation for Cancer Research and is part of the studies conducted by Francesco Nicassio, coordinator of the Center for Genomic Science (CGS) dell’IIT– Italian Institute of Technology in Milan. In a previous study, in fact, Nicassio and his group had identified another microRNA, miR-34a, revealing its inhibitory role in the proliferation of cancer stem cells. Unlike miR-146a / b, miR-34a is not present in stem cells but on the contrary is expressed by the more differentiated cells of the breast, which therefore no longer have the stem properties. This latest research introduces further elements of understanding of the genetic components of cancer and opens up new possibilities for the therapeutic application of non-coding RNA – objective at the center of IIT’s “RNA-initiative” (iRNA @ IIT), of which Nicassio is member.
The study was born from collaboration between the IIT research group led by Francesco Nicassio and the one led by Prof. Pier Paolo Di Fiore, Group Leader at theEuropean Institute of Oncology (IEO) and Full Professor of the University of Milan, who has been studying the biology of breast stem cells for years.
Many cancers, including the breast cancer, contain a small population of cancer stem cells, consider the heart as the basis for tumor development. Cancer stem cells are often resistant to radio- and chemotherapy, and therefore can survive the first courses of treatment and promote tumor recurrence and metastasis. In breast cancer, for example, cancers containing a relatively large number of cancer stem cells have a much poorer prognosis than cancers with fewer stem cells. Targeting these cells may therefore be crucial for the effective treatment of breast cancer and other types of cancer.
Molecules that could play an important role in stem cell biology include i microRNA, discovered in recent decades. Despite their small size, these molecules control cell fate and identity by regulating the levels of hundreds of longer “messenger” RNAs that code for proteins.
“Our goal is to identify the microRNAs necessary for the maintenance of cancer stem cells and which may represent potential therapeutic targets in breast cancer.“, he claims Francesco Nicassio, coordinator of the IIT CGS in Milan.
“We identified two closely related microRNAs, miR-146a and miR-146b, present in breast stem cells and also in breast cancer stem cells. Levels of these two microRNAs tend to be very high in more aggressive breast cancers, which have a high number of cancer stem cells”, He comments Chiara Tordonato, researcher at IEO and University of Milan, and first author of the work. “We hypothesized that miR-146a / b may be needed to maintain the tumor stem cell pool. It was enough to destroy these two microRNAs in patient-derived tumor cells to reduce the ability of these cells to form new tumors “.
Nicassio and colleagues determined that miR-146a / b regulates hundreds of messenger RNAs, thereby controlling numerous cellular processes such as metabolism and DNA replication.
“Some molecular details remain to be determined, but our results clearly show that the reduction of miR-146a / b levels represents an approach potentially capable of overcoming some forms of drug resistance in the clinical setting, unmasking a ‘hidden vulnerability’ of the tumor that can be exploited for the development of new therapies capable of targeting cancer stem cells “, conclude Nicassio.
Elimination of miR-146a / b from cancer stem cells could alter these processes in ways that make cells most vulnerable to chemotherapy. In fact, the researchers found that reducing miR-146a / b levels made breast cancer stem cells more than 20 times more sensitive to methotrexate, significantly improving this metabolic inhibitor’s ability to limit tumor growth.