Osteosarcoma is an aggressive bone cancer characterised by high rate of recurrence and metastasis. It is the most common primary bone cancer in children, adolescents and young adults. Symptoms include chronic bone pain, swelling and limping.
Osteosarcoma cells often remain locked in an immature developmental state. This allows them to grow rapidly and invade surrounding tissues. Although chemotherapy and surgery have improved survival for localised disease, once the tumours have spread to the lungs or return, outcomes remain poor.
Exploring solutions
To explore potential solutions to this challenge, a research team has conducted a study on whether the RNA-editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) could reverse aggressive behaviour of osteosarcoma cells.
The research team was led by two experts from Bambino Gesù Children’s Hospital in Rome. These experts are Dr Del Fattore, head of the Bone Physiopathology Research Unit and Professor Angela Gallo from the Unit of Genetic and Epigenetics of paediatric tumours.
Results
Results indicate that restoring ADAR2 slows tumour growth, reduces invasion, promotes bone-like differentiation and improves chemotherapy sensitivity in models. The team published their findings in volume 14 of the journal Bone Research in April.
The team first found that ADAR2 levels naturally rise when healthy mesenchymal stem cells develop into bone-forming osteoblasts.
“In contrast, osteosarcoma tissues and highly aggressive cancer cell lines showed markedly reduced ADAR2 expression. Lower ADAR2 levels were also associated with poorer metastasis-free survival and overall survival in patient datasets, suggesting that loss of this enzyme may be linked to more dangerous disease” said Dr Michela Rossi from the Bone Physiopathology Research Unit, Bambino Gesù Children’s Hospital, first author of the manuscript.
Researchers found when they increased ADAR2 expression in osteosarcoma cells several changes occurred. Tumour-like behaviour sharply declined, cell growth slowed, invasive capacity dropped and migration reduced. In one osteosarcoma model, the treated cells began producing mineralised matrix. Genes linked to osteoblast differentiation increased, while markers associated with stemness and malignancy decreased.
“Our findings suggest that osteosarcoma cells are not irreversibly fixed in an aggressive state. By restoring ADAR2, we were able to reactivate developmental programs that steer these cells toward a more mature and less harmful identity,” said Dr Del Fattore.
Overall, the study provides preclinical evidence that restoring ADAR2 can suppress osteosarcoma progression. Results suggest that targeting the developmental state of cancer cells rather than only destroying them could provide a successful avenue of treatment.
Ultimately, the results could also have implications for other cancer treatments in the future. Replacing toxic treatments with therapies designed to reprogramme cancer cells toward maturation could result in better results for other cancers.
