Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells.
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.
Munchhof
Amy M
AM
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut Street, Indianapolis, IN 46202, USA.
Li
Fang
F
White
Hilary A
HA
Mead
Laura E
LE
Krier
Theresa R
TR
Fenoglio
Amy
A
Li
Xiaohong
X
Yuan
Jin
J
Yang
Feng-Chun
FC
Ingram
David A
DA
D000483:Alleles; D000818:Animals; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009455:Neurofibroma / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics* / Q000502:physiology; D011509:Proteoglycans / Q000737:chemistry; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction
D004338:Drug Combinations; D006133:Growth Substances; D007797:Laminin; D025542:Neurofibromin 1; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases