Scientists have made a breakthrough in understanding the cause of a rare childhood muscle cancer, called Rhabdomyosarcoma (RMS).
The discovery could lead to the development of improved therapies to treat the disease and other types of cancer in the future.
Around 60 and 350 new cases of RMS are diagnosed in the UK and Europe/US respectively, each year. Most RMS tumours occur in children younger than 10 years old.
A collaborative study led by scientists from Harvard University and involving experts from the University of Aberdeen, The Institute of Cancer Research, London, and the Swiss Institute of Bioinformatics has revealed for the first time the key role a protein called Yap plays in triggering RMS.
The findings were published on Thursday July 31 in Cancer Cell.
Dr Annie Tremblay from 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 - called myoblasts - that divide, before finally fusing together to form long muscle fibres.
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 them to stop dividing and fuse together to form functional muscles.
Findings from the study show that in instances of RMS cancer, the Yap protein remains active - like the accelerator of a car being stuck.
By combining the results from animal models with histological and bioinformatics approaches using human RMS samples, researchers at the University of Aberdeen, the Swiss Institute of Bioinformatics and The Institute of Cancer Research (ICR) additionally showed that Yap is actually hyper-active in a large proportion of human RMS cases.
Dr Henning Wackerhage, from the University of Aberdeen's Institute of Medical Sciences, 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 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.
"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."
Dr Janet Shipley, leader of the Sarcoma Molecular Pathology team at The Institute of Cancer Research, London, said: "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."
The three-year study was supported by funding from Aberdeen charity, Friends of Anchor, Sarcoma UK, the Medical Research Council, Cancer Research UK, the Chris Lucas Trust, and Stand Up to Cancer-AACR innovative research programs and the Canadian Institutes of Health Research.
Ross Anderton (6). Diagnosed with Orbital Rhabdomyosarcoma. As described by his mother Lesley Lauder. The family are from Ormiston, East Lothian.
We had noticed that Ross's eye looked puffy. We took him to our GP who said it was probably a blocked duct and would refer Ross to the eye pavilion for clarification.
Five weeks later Ross's eye started to get bigger, eye pavilion appointment had not arrived so I returned to our GP surgery. The doctor said that there was not much more he could do, so I decided to use my private medical insurance.
The doctor referred us to the private hospital so I called to make an appointment. When I phoned I was told that there was only one eye specialist that would see children and he was on holiday.
The following week Ross's eye grew rapidly so I took him back to the same GP I'd seen the week before and managed to persuade him to refer Ross as an emergency to the eye pavillion. We got an appointment for that afternoon.
Once the eye specialist looked at Ross I started to feel really worried. He consulted with the senior doctor who sent us straight away for an ultrasound and booked us in for a biopsy on the Monday (this was a Friday). Once the biopsy was performed we were told that Ross had cancer - that was the worst moment of our lives.
The days that followed were just a blur of hospital appointments and procedures for Ross. The staff in ward 2 at Edinburgh Sick kids' hospital were just fantastic and helped us through everything that happened in the first few weeks. It was so much information to take in, so many things to learn. Chemotherapy was tough, Ross was kept in hospital as he was hooked up to fluids constantly, after the first chemo cycle, when neutropenic, Ross contracted Staphylococcus aurous septicaemia, he was so very ill and there was that realisation that we could lose him, but thankfully after seeking advice from experts around the country, the right combination of medications were found to help Ross fight the blood infection.
The cancer did not respond as well as expected after three intensive cycles of chemo so a course of radiotherapy was on the cards. This didn't sound too bad to us and the ward staff did not make a big deal out of it.
Then, we met with the radiotherapy oncologist and learned of the side effects that traditional radiotherapy has including increasing the chance of developing a secondary cancer throughout his life. As any radiation would be targeted under the eye, it is close to the pituitary gland (responsible for his growth) and the front of his brain (where his learning and development could be affected) and the likelihood of cranio-facial surgery, as his facial bones and their growth would be affected by it. As Ross was only one years old the more severe the side effects would be for him.
We went home and I researched and hunted the internet and came up with Proton Beam therapy (no one from the hospital had told us about this which I was very disappointed about). The down side - this was not available in the UK. I then started to contact the leading NHS specialists and approached our radiation doctor. She was happy to submit Ross for approval. After four weeks of fighting and stress, Ross had NHS funding and approval (the first patient in Scotland) to travel to Jacksonville USA for 5 weeks of proton treatment.
We left the UK on 18th December 09. We had to organise everything ourselves so, as well as looking after a very sick child, we had travel arrangements, insurance etc to sort out. First thing when we arrived in US was that Ross had to get titanium screws fitted into his skull. This was to ensure the utmost accuracy during the treatment. Proton is accurate to 2 mm as opposed to over 1cm with traditional radiation - a huge difference in a one year old child. It also does not have an exit point which meant very little radiation to his brain.
Our time in the US was long but it was enlightening and interesting, meeting other families and experiencing the US culture and hospitality. The positive outcome of our journey is that other families have been able to follow us over to US for treatment.
We had a scan in March 09 which was inconclusive but after a further scan in June 09, we heard the fantastic word REMISSION!
Ross will have lifelong eye issues, he has had cataract surgery and eyelid surgery and will require both again in the future. He will probably have some growth issues but hopefully nothing requiring surgery, kidney failure and unlikely to father kids.
He also has some trouble with memory, which makes us even more grateful that he had proton radiation as this would be so much more if he had received radiotherapy in the UK. All this is a lot when your only five - but he's still here, he survived and every day I am so, so thankful for that and every day I hope that it doesn't come back.