Review
Tumorigenesis in neurofibromatosis: new insights and potential therapies

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Abstract

The neurofibromatoses NF1 and NF2 are inherited cancer predisposition syndromes in which affected individuals are prone to development of mostly benign, but occasionally malignant, tumors. The NF1 and NF2 genes function as tumor suppressor genes (negative growth regulators), such that their loss of expression predisposes to tumor formation. Neurofibromin, the protein product of the NF1 gene, acts as a negative regulator of the ras proto-oncogene, to reduce cell growth. Merlin, the NF2 gene product, is involved in regulating cell proliferation and motility, and probably plays a role in integrating multiple cell-signaling pathways. By understanding the function of these tumor suppressors, we have a unique opportunity to develop targeted pharmacotherapeutic interventions for these disorders.

Section snippets

Clinical features

NF1 is also referred to as peripheral neurofibromatosis or Von Recklinghausen's disease and is characterized by the development of pigmentary abnormalities, such as café-au-lait macules, skinfold freckling and iris hamartomas (Lisch nodules). In addition to these features, individuals with NF1 can develop skeletal and vascular abnormalities, and have a greater incidence of certain learning disabilities. Tumors that develop in individuals with NF1 include neurofibromas, optic pathway gliomas,

Clinical features

NF2 is also referred to as central or bilateral acoustic neurofibromatosis 1. Individuals with NF2 develop bilateral vestibular schwannomas affecting the VIIIth cranial nerve and meningiomas, as well as schwannomas involving other cranial or peripheral nerves. The vestibular schwannomas can often grow to affect the temporal bone or eighth cranial nerve function. Unlike in NF1, NF2 patients have few pigmentary abnormalities, such as café-au-lait spots, and the majority of their symptoms relate

Future targeted therapies

Over the past few years, we have learned a tremendous amount about the function of the NF1 and NF2 gene products. Based on these insights, it is now possible to consider applying treatments that specifically target the cellular abnormalities in NF1 and NF2. In the case of NF1, we now appreciate the critical role of ras regulation in cell proliferation (Fig. 3a). Potential therapies include inactivation of ras by preventing it from undergoing secondary post-translational modifications, such as

Outstanding questions

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    Are there tissue-specific functions for the NF1 and NF2 gene products that need to be determined to design tissue-specific targeted therapies?

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    Which molecules downstream of ras transduce its growth-promoting signal in response to the absence of NF1 protein (neurofibromin) in Schwann cells and astrocytes?

  • •

    How does the NF2 protein (merlin) function in Schwann and leptomeningeal cells?

  • •

    What are the other genetic influences that determine whether an affected individual with NF1 will manifest with a

References (50)

  • D.H. Gutmann

    The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2

    J. Am. Med. Assoc.

    (1997)
  • D.A. Marchuk

    cDNA cloning of the type 1 neurofibromatosis gene: Complete sequence of the NF1 gene product

    Genomics

    (1991)
  • R.M. Cawthon

    A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations

    Cell

    (1990)
  • M.L. Nordlund

    Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains

    J. Neuropathol. Exp. Neurol.

    (1995)
  • L.M. Messiaen

    Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals an increased frequency of unusual splicing defects

    Human Mut.

    (2000)
  • T.N. Basu

    Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients

    Nature

    (1992)
  • J.E. DeClue

    Abnormal regulation of mammalian p21(ras) contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis

    Cell

    (1992)
  • N. Lau

    Loss of neurofibromin is associated with activation of ras/MAPK and PIS-K/akt signaling in a neurofibromatosis 1 astrocytoma

    J. Neuropathol. Exp. Neurol.

    (2000)
  • M.M Feldkamp

    Acute presentation of a neurogenic sarcoma in a patient with neurofibromatosis type 1: a pathological and molecular explanation

    J. Neurosurg.

    (1996)
  • T. Jacks

    Tumor predisposition in mice heterozygous for a targeted mutation in NF1

    Nat. Genet.

    (1994)
  • C.I. Brannan

    Targeted disruption of the neurofibromatosis type 1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues

    Genes Dev.

    (1994)
  • K. Cichowski

    Mouse models of tumor development in neurofibromatosis type 1

    Science

    (1999)
  • J.L. Rutkowski

    Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1

    Hum. Mol. Genet.

    (2000)
  • L.S. Sherman

    Single cell Ras-GTP analysis reveals altered ras activity in a single population of neurofibroma Schwann cells but not fibroblasts

    J. Biol. Chem.

    (2000)
  • A.J. Cappione

    A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors

    Am. J. Hum. Genet.

    (1997)

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