Abstract

Neurofibromatosis type 2 (NF2) is an autosomal-dominant multiple neoplasia syndrome that results from mutations in the NF2 tumor suppressor gene. Patients with NF2 develop hallmark schwannomas that require surgery or radiation, both of which have significant adverse effects. Recent studies have indicated that the tumor microenvironment-in particular, tumor blood vessels-of schwannomas may be an important therapeutic target. Furthermore, although much has been done to understand how merlin, the NF2 gene product, functions as a tumor suppressor gene in schwannoma cells, the functional role of merlin in the tumor microenvironment and the mechanism(s) by which merlin regulates angiogenesis to support schwannoma growth is largely unexplored. Here we report that the expression of semaphorin 3F (SEMA3F) was specifically downregulated in schwannoma cells lacking merlin/NF2. When we reintroduced SEMA3F in schwannoma cells, we observed normalized tumor blood vessels, reduced tumor burden, and extended survival in nude mice bearing merlin-deficient brain tumors. Next, using chemical inhibitors and gene knockdown with RNA interference, we found that merlin regulated expression of SEMA3F through Rho GTPase family member Rac1. This study shows that, in addition to the tumor-suppressing activity of merlin, it also functions to maintain physiological angiogenesis in the nervous system by regulating antiangiogenic factors such as SEMA3F. Restoring the relative balance of proangiogenic and antiangiogenic factors, such as increases in SEMA3F, in schwannoma microenvironment may represent a novel strategy to alleviate the clinical symptoms of NF2-related schwannomas.

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Authors

Wong HK, Shimizu A, Kirkpatrick ND, Garkavtsev I, Chan AW, di Tomaso E, Klagsbrun M, Jain RK

Institution

The Steele Lab of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA.

Source

Neoplasia (New York, N.Y.) 14:2 2012 Feb pg 84-94

MeSH

Animals
Blood Vessels
Brain Neoplasms
Cell Line, Tumor
Down-Regulation
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Human Umbilical Vein Endothelial Cells
Humans
Kaplan-Meier Estimate
Membrane Proteins
Mice
Mice, Nude
Neoplasm Transplantation
Neovascularization, Pathologic
Nerve Tissue Proteins
Neurilemmoma
Neurofibromatosis 2
Neurofibromin 2
Permeability
Signal Transduction
Thrombospondins
rac1 GTP-Binding Protein

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22431917