Human Molecular Genetics Advance Access originally published online on April 28, 2006
Human Molecular Genetics 2006 15(11):1858-1869; doi:10.1093/hmg/ddl108
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Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells
1Department of Pediatrics, 2Herman B Wells Center for Pediatric Research and 3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1044 W. Walnut St. R4/470, Indianapolis, IN 46202, USA
* To whom correspondence should be addressed. Tel: +1 3172788245; Fax: +1 3172748679; Email: dingram{at}iupui.edu
Received February 28, 2006; Accepted April 14, 2006
Genetic inactivation of tumor suppressor genes initiates human cancers. However, interaction of accessory cells with the tumor-initiating cell within the microenvironment is often required for tumor progression. This paradigm is relevant to understanding neurofibroma development in neurofibromatosis type I patients. Somatic inactivation of the Nf1 tumor suppressor gene, which encodes neurofibromin, is necessary but not sufficient to initiate neurofibroma development. In contrast, neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/–) microenvironment. Neurofibromas are highly vascularized, and recent studies suggest that Nf1+/– mice have increased angiogenesis in vivo. However, the function of neurofibromin in human endothelial cells (ECs) and the biochemical mechanism by which neurofibromin regulates neoangiogenesis are not known. Utilizing Nf1+/– mice, primary human ECs and endothelial progenitor cells harvested from NF1 patients, we identified a discrete Ras effector pathway, which alters the proliferation and migration of neurofibromin-deficient ECs in response to neurofibroma-derived growth factors both in vitro and in vivo. Thus, these studies identify a unique biochemical pathway in Nf1+/– ECs as a potential therapeutic target in the neurofibroma microenvironment.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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