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Human Molecular Genetics Advance Access published online on April 28, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl108
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received February 28, 2006
Revised April 14, 2006
Accepted April 14, 2006

Article

Neurofibroma Associated Growth Factors Activate a Distinct Signaling Network to Alter the Function of Neurofibromin Deficient Endothelial Cells

Amy M. Munchhof 1, Fang Li 2, Hilary A. White 2, Laura E. Mead 2, Theresa R. Krier 2, Amy Fenoglio 2, Xiaohong Li 2, Jin Yuan 2, Feng-Chun Yang 2, and David A. Ingram 3 *

1 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
2 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202
3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, 1044 W. Walnut St. R4/470, Indianapolis, IN 46202

* To whom correspondence should be addressed.
David A. Ingram, E-mail: dingram{at}iupui.edu


  Abstract

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 and the biochemical mechanism by which neurofibromin regulates neoangiogenesis are not known. Utilizing Nf1 +/-  mice, primary human endothelial cells, and endothelial progenitor cells harvested from NF1 patients, we identified a discrete Ras effector pathway, which alters the proliferation and migration of neurofibromin deficient endothelial cells in response to neurofibroma derived growth factors both in vitro and in vivo. Thus, these studies identify a unique biochemical pathway in Nf1 +/-  endothelial cells as a potential therapeutic target in the neurofibroma microenvironment.


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