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Scientists at Joslin Diabetes Center in Boston have uncovered important molecular and genetic keys to the development of soft-tissue sarcomas in skeletal muscle, giving researchers and clinicians additional targets to stop the growth of these often deadly tumors.
Published in the Proceedings of the National Academy of Sciences, the study identified two major molecular signaling pathways (the Ras and mTOR pathways) that are common in tumor growth and development. These molecular pathways regulate cell growth and division, two cellular properties whose over-activation are hallmarks of cancer biology.
"In humans, some sarcomas respond to chemotherapy, but many don't. With these findings, we have vetted a list of new candidate targets whose inhibition may lead to regression of these tumors" says lead author Amy J. Wagers, PhD, an associate professor of stem cell and regenerative biology at Harvard Medical School and Joslin Diabetes Center.
Many soft-tissue sarcomas, which tend to develop in bone and muscle, carry unique gene signatures, which can allow scientists to develop more precise, targeted therapies. Wagers and her colleagues engineered a tumor system in mice by introducing into mouse skeletal muscle a cancer-carrying gene known to cause tumors in humans. They used this engineered system to identify a small set of genes that are active in sarcoma tumors.
There are many different types of soft-tissue sarcomas, which develop in tissues that connect, support or surround other structures and organs, including muscle, tendons, nerves, fat and blood vessels. If diagnosed early, surgical removal of the tumor, radiation therapy or chemotherapy, can be effective. If the tumor has spread, however, the tumor can be controlled for a period of time, but treatment does not often cure the disease.
By inducing sarcoma tumors in mice, the scientists knew when the tumors would form and where in the body they would develop, helping them identify the molecular and genetic disease pathways. With this knowledge, they developed new interventions to interfere and stop the tumor growth.
"With the engineered system we developed, we can find new fragile points in the tumor to target," says first author Simone Hettmer, MD, a pediatric oncologist at the Dana-Farber/Children's Hospital Cancer Center, who treats children with these tumors. This system allows scientists to look at genetic changes in sarcomas and apply that knowledge to sarcomas in tissues other than skeletal muscle.
Surprisingly, the research found tumors could be induced using several different "beginning" cells. They generated tumor cells using stem cell-like cells which make either muscle or connective tissues. Tumors that develop from muscle cells were rhabdomyosarcomas, the most common form of soft-tissue sarcoma seen in children.
Wagers and her colleagues are now working on establishing a similar model system using human cells to test the effectiveness of anti-sarcoma medications. They hope to identify the most promising human candidates for treatment of soft-tissue sarcoma - then ultimately pursue human clinical trials. Early studies have identified several chemical compounds that in cell cultures appear to slow the growth of sarcoma cells.
In addition to Wagers and Hettmer, other Joslin co-authors of the study were Jianing Liu, Christine Miller, and Melissa Lindsay, as well as Cynthia Sparks and David Guertin of the University of Massachusetts Medical School, Roderick Bronson of the Tufts University School of Veterinary Medicine, and David Langenau of Massachusetts General Hospital.
Joslin Diabetes Center is the world's preeminent diabetes research and clinical care organization. Joslin is dedicated to ensuring that people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure. Joslin is an independent, nonprofit institution affiliated with Harvard Medical School. For more information about Joslin, visit www.joslin.org. Keep up with Joslin research and clinical news at Inside Joslin at www.joslin.org/news/inside_joslin.html, Become a fan of Joslin on Facebook at www.facebook.com/joslindiabetes and follow Joslin on Twitter at www.twitter.com/joslindiabetes
Original article: http://www.joslin.org/news/unlocking-the-genetic-and-molecular-mystery-of-soft-tissue-sarcoma.html