The cancer-causing trigger has been found after three years of searching for a better understanding of the rare childhood muscle cancer rhabdomyosarcoma (RMS). Thanks to the collaborative effort from an international group of scientists, the breakthrough study, which has revealed the cause of a rare but deadly cancer affecting children, was published in the journal Cancer Cell on Thursday.

“RMS is a muscle cancer that can arise from any skeletal muscles in the body, although approximately 40 percent of the cases arise in the head and neck regions,” Dr. Annie Tremblay from Harvard University said in a press release.

Scientists from Harvard University, the Institute of Cancer Research in London, the Swiss Institute of Bioinformatics, and the University of Aberdeen joined together to study the cause of RMS and come up with a treatment approach for the up to 350 newly diagnosed cases every year around the world.

“The current therapies for RMS, although relatively efficient, are very aggressive and drastically alter the quality-of-life of the children who survive. Indeed, most of the survivors will suffer life-altering consequences such as loss of mobility or vision, growth impairment and developmental problems, or the need for life-long hormone replacement therapies,” Tremblay said.

In RMS, when a child grows, his normal muscle development transforms stem cells into muscle cells called myoblasts. The myoblasts divide until the Yap protein turns them off and fuses them together to form the long muscle fibers in the body, which are the functional muscles throughout an adult’s body.

“We discovered that in cases of the disease, excessive activity of a protein called Yap causes muscle stem cells to permanently divide instead of stopping and becoming normal muscle tissue. Yap does that by inhibiting the activity of muscle determination proteins, which are key to the formation of muscle tissue,” Tremblay said. “In contrast to normal muscle stem cells, the high Yap muscle stem cells fail to develop into normal muscle tissue and RMS develops as a consequence.”

Scientists took results from animal models along with human RMS samples and found Yap is hyperactive in a large percentage of human RMS cases. Moving forward, if researchers can figure out how to control the Yap protein and develop a treatment approach to make it turn the fiber fusion step off, a cure won’t be far away.

“Our identification of the Yap protein’s crucial role in the development of Rhabdomyosarcoma is the first step on the road toward understanding how we can target this rare disease,” Dr. Henning Wackerhage, from the University of Aberdeen’s Institute of Medical Sciences, said. “Our work will now focus on how the Yap protein works in cancer and how its activity can be controled.”

This specific type of cancer can affect children younger than 10 years of age and ruin the normal development of their skeletal muscles that control the body, smooth muscles that wrap internal organs, and cardiac muscles within the heart. Common places of the body RMS affects are the head and neck, usually near the eye, inside the nasal sinuses, and throat, along with the bladder and reproductive organs, arms and legs, and the chest and abdomen muscles, according to the American Cancer Society.  

“If we can achieve the inhibition of Yap locally in the tumours, we could cause the cancer to stop and regress by turning the RMS into normal muscle instead. This would most likely produce significantly less side effects than the current therapies,” Wackerhage said.

It isn’t just RMS that Yap causes, but the protein culprit also plays an active role in other cancers, according to Wackerhage, including liver and skin cancers. He believes the results could become significantly important in helping researchers around the world understand the role Yap plays in all different types of cancer developments.

"This study has promising therapeutic implications for targeting YAP1-driven pathways for the treatment of children with RMS. Through our analyses of human tumour samples, we were able to demonstrate that the findings in the mouse model are highly relevant to these cancers in humans," Dr. Janet Shipley, leader of the Sarcoma Molecular Pathology team at the Institute of Cancer Research, London, said.

Source: Tremblay A, Wackerhage A,  and Shipley J. Cancer Cell. 2014.