May 16, 2008 Researchers at Cincinnati Children's Hospital Medical Center have identified proteins that could be biological markers of non-cancerous tumors that affect peripheral nerves called Neurofibromatosis 1 (NF1), which can change to a highly aggressive cancer called Malignant Peripheral Nerve Sheath Tumors (MPNST). This new finding could help resolve a current lack of reliable ways to diagnose NF1 and MPNST in patients, according to study findings presented May 16 at the annual meeting of the American Society of Pediatric Hematology/Oncology.
Currently, no reliable methods exist to detect NF1 tumor growth, whether NF1 is transforming to MPNST, or if novel treatments or drugs are having an effect on the disease. About 90 percent of children with NF1 develop multiple small tumors beneath their skin, while some have brown pigment spots on the skin. The tumors begin in the cells that makeup the myelin sheath, a thin membrane that envelops and protects nerve fibers. The web-like tumors, called plexiform neurofibromas, may infiltrate and encase major nerves, blood vessels and other structures, making the tumors impossible to surgically remove.
"The interlaced plexiform tumors in NF1 can invade critical structures of the body and cause death or significant illness," said Trent Hummel, M.D., a physician in the division of Experimental Hematology at Cincinnati Children's and lead researcher in the study. "In our study, we confirmed a method to identify blood proteins that may serve as reliable markers of NF1 and identified a possible association of these markers with the presence of MPNST. If our future studies confirm these findings, we may be able to develop new diagnostic tests for NF1 and MPNST patients."
While many NF1 patients conduct normal lives, children with NF1 can develop learning disabilities, scoliosis and benign brain tumors. In adulthood they are at risk for cardiovascular problems and malignant tumors. The disease symptoms may be evident at birth, during infancy and almost always by the time a child is 10 years old. NF1 patients have an 8- to 13-percent risk of developing MPNST during their lifetime, with a 30 percent chance of surviving five years after diagnosis. The condition affects one of every 3,000 people worldwide.
NF1 is an autosomal dominant inherited disease, which means the gene mutation only needs to occur in one parent for a child to develop the disease. Although most NF1 patients inherit the disorder, between 30 and 50 percent of new cases arise spontaneously through genetic mutation. The NF1 gene makes a large and complex protein called neurofibromin, which may play a role in tumor suppression. Scientists theorize that defects in the NF1 gene may lessen or inhibit the normal output of neurofibromin and allow the irregular cell growth that can lead to tumor development.
Dr. Hummel and his colleagues examined whether other proteins besides neurofibromin might play a role in the tumor development. The researchers theorized that Schwann cells in the tumors would secrete unique proteins correlating with tumor size, either for plexiform neurofibromas or those transformed into MPNST. They used comparative microarray gene expression analysis on normal human Schwann cell cultures and neurofibroma/MPNST cell cultures as well as plexiform neurofibromas and MPNST tumors.
Their results, validated with an additional gene analysis method (Real-Time Quantitative PCR), identified 92 candidate genes that may produce secreted proteins at significantly higher levels in plexiform neurofibromas/MPNST than in the normal Schwann cells. The researchers identified that one protein, adrenomedullin, occurred at the highest levels in blood samples from NF1 patients when compared to blood from healthy patients. The investigators also observed higher levels of adrenomedullin -- a protein linked to the enhancement of tumor cell blood supply -- in all NF1/MPNST cell cultures samples.
"We documented that adrenomedullin is promising as a potential biomarker for NF1, and in higher concentrations this protein may be an indication of MPNST," said Dr. Hummel. "In future investigations we will conduct closer analysis of the remaining candidate proteins, as we may find more possible NF1/MPNST markers. We also want to test what biological effects adrenomedullin has on MPNST cell lines."
Microarray gene expression profiles of normal and NF1/MPNST Schwann cells in the study were obtained on an Affymetrix testing platform. Also participating in the study were members of the University of Cincinnati College of Medicine and the NF1 Microarray Consortium. Funding support was provided by a grant from the Department of Defense Program on Neurofibromatosis.
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