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Cause of Rare Childhood Cancer Discovered

Scientists pinpoint rogue protein

Researchers have made a breakthrough in understanding the cause of rhabdomyosarcoma (RMS), a rare childhood muscle cancer.

The discovery could lead to the development of improved therapies to treat the disease and other types of cancer in the future, according to a report published in Cancer Cell.

Approximately 410 new cases of RMS are diagnosed in the U.S. and Europe each year. Most RMS tumors occur in children younger than 10 years of age.

A 3-year collaborative study led by scientists at Harvard University and involving experts at the University of Aberdeen, Scotland; the Institute of Cancer Research, London; and the Swiss Institute of Bioinformatics has shown for the first time the key role that a protein called Yap plays in triggering RMS.

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

“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.

“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.

“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.”

During normal muscle development, stem cells turn into developmental muscle cells (myoblasts), which divide before finally fusing together to form long muscle fibers.

The Yap protein is fundamental to this process, with the myoblasts experiencing a marked increase in its activity during the division stage. Once enough myoblasts are present, Yap gets turned off, which allows the myoblasts to stop dividing and to fuse together to form functional muscles.

Findings from the study show that the Yap protein remains active in RMS — like the accelerator of a car being stuck.

By combining the results from animal models with histologic and bioinformatics approaches using human RMS samples, the researchers also showed that Yap is hyperactive in a large proportion of human RMS cases.

Dr. Henning Wackerhage of the University of Aberdeen said: “Our identification of the Yap protein’s crucial role in the development of rhabdomyosarcoma is the first step on the road towards understanding how we can target this rare disease.

“Our work will now focus on how the Yap protein works in cancer and how its activity can be controlled.

“If we can achieve the inhibition of Yap locally in the tumors, 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.

“Other research has shown that Yap is active in several other types of cancer, including liver and skin cancers. These results could therefore be of wider significance in also enhancing our global understanding of the role of Yap in cancer.”

Source: University of Aberdeen; July 31, 2014.

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