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Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism.

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

    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