Merlin/NF2 Regulates Angiogenesis in Schwannomas through a Rac1/Semaphorin 3F-Dependent Mechanism 1

The Steele Lab of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 02/2012; 14(2):84-94. DOI: 10.1593/neo.111600
Source: PubMed


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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    • "Recent studies have clearly shown that also the tumor-suppressor protein merlin, mutated in NF2, controls Ras activity [35]. Furthermore, merlin probably regulates angiogenesis to support schwannoma growth, although the exact mechanisms are still unexplored [36]. Angiogenesis is an important determinant of tumor growth also in neuroendocrine neoplasms, so merlin could influence their development and growth. "
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    ABSTRACT: Background Gastroenteropancreatic neuroendocrine tumors have occasionally been described in association with neurofibromatosis type 1, whereas an association with neurofibromatosis type 2 has never been reported. Case presentation This report refers to an Italian 69 year old woman with neurofibromatosis type 2 and a pancreatic gastrinoma. In the past she had encephalic meningiomas, a tongue schwannoma and bilateral acoustic neurinomas. She presented with weight loss and a long-term history of diarrhea, responsive to proton pump inhibitors. Upper gastrointestinal endoscopy revealed peptic ulcer of the duodenal bulb. Blood tests were normal, except for the elevation of plasma gastrin (1031 pg/ml; reference value <108) and chromogranin A (337 U/L; reference value <36). After secretin stimulation testing, the plasma gastrin level rose to 3789 pg/ml. The abdomen magnetic resonance imaging and gallium68-DOTATOC positron emission tomography scan demonstrated the presence of a 1.2 x 2 cm lesion in the pancreatic head and a liver metastatis. Pancreatic endoscopic ultrasound with fine needle aspiration revealed cytomorphologic features suggestive of pancreatic gastrinoma. Brain magnetic resonance showed a pituitary microadenoma. There was no evidence of hyperparathyroidism. The genetic test for multiple endocrine neoplasia type 1 syndrome mutation was negative. Conclusion This report focuses on the first case of coexistence of gastrinoma with neurofibromatosis type 2. Although the clinical relevance of this association remains to be determined, our case report will surely give cause for due consideration.
    BMC Gastroenterology 06/2014; 14(1):110. DOI:10.1186/1471-230X-14-110 · 2.37 Impact Factor
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    ABSTRACT: To review the discoveries in molecular pathophysiology contributing to the development of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas and the recent experiences with drug therapies for these tumors. The review includes discussion of diagnostic criteria for NF2, populations to clinically consider for drug therapy and drug targets currently under consideration for NF2. Increased insight into the complex pathways that underlie both the genetic syndrome of NF2 and the specific pathogenesis of vestibular schwannomas has highlighted multiple potential therapeutic targets. These discoveries have been translated into clinical trials with some early promising results. Inhibition of angiogenesis as well as regulation of mammalian target of rapamycin and the epidermal growth factor receptor family of receptors are the focus of current clinical investigations. Although a great deal of work is ongoing to understand the multiple effects of the lack of the regulating protein Merlin on tumorgenesis in patients with NF2, advances are ongoing with clinical therapeutics. There is cause for enthusiasm based on recent results with antiangiogenesis therapy in select patients with NF2 and progressive vestibular schwannomas; however, awareness of the notable risks and limitations of therapies currently in development is required.
    Current opinion in otolaryngology & head and neck surgery 08/2012; 20(5):372-9. DOI:10.1097/MOO.0b013e328357d2ee · 1.84 Impact Factor
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    ABSTRACT: Findings from preclinical and clinical studies show that vascular normalization represents a novel strategy to enhance the efficacy of and overcome the acquired resistance to anti-angiogenic therapies in cancer. Several mechanisms of tumour vessel normalization have been revealed. Among them, secreted class 3 semaphorins (Sema3), which regulate axon guidance and angiogenesis, have been recently identified as novel vascular normalizing agents that inhibit metastatic dissemination by restoring vascular function. Here, we discuss the different biological functions and mechanisms of action of Sema3 in the context of tumour vascular normalization, and their impact on the different cellular components of the tumour microenvironment. © 2012 The Association for the Publication of the Journal of Internal Medicine.
    Journal of Internal Medicine 11/2012; 273(2). DOI:10.1111/joim.12017 · 6.06 Impact Factor
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