Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells

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

Research output: Contribution to journalArticle

40 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)1858-1869
Number of pages12
JournalHuman molecular genetics
Volume15
Issue number11
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Munchhof, A. M., Li, F., White, H. A., Mead, L. E., Krier, T. R., Fenoglio, A., Li, X., Yuan, J., Yang, F. C., & Ingram, D. A. (2006). Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. Human molecular genetics, 15(11), 1858-1869. https://doi.org/10.1093/hmg/ddl108