HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications.

Abstract
Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in tumor formation in NF1. Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1(+/-) heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.
AuthorsOren N Gottfried, David H Viskochil, William T Couldwell
JournalNeurosurgical focus (Neurosurg Focus) Vol. 28 Issue 1 Pg. E8 (Jan 2010) ISSN: 1092-0684 [Electronic] United States
PMID20043723 (Publication Type: Journal Article)
Chemical References
  • Intracellular Signaling Peptides and Proteins
  • Neurofibromin 1
  • MTOR protein, human
  • mTOR protein, mouse
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins
Topics
  • Animals
  • Cell Proliferation
  • Disease Models, Animal
  • Genes, Neurofibromatosis 1 (physiology)
  • Genes, Tumor Suppressor (physiology)
  • Humans
  • Intracellular Signaling Peptides and Proteins (genetics)
  • Loss of Heterozygosity (genetics)
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases (genetics)
  • Models, Genetic
  • Mutation (genetics)
  • Nerve Sheath Neoplasms (genetics)
  • Neurofibroma, Plexiform (genetics)
  • Neurofibromatosis 1 (genetics)
  • Neurofibromin 1 (genetics)
  • Optic Nerve Glioma (genetics)
  • Protein Serine-Threonine Kinases (genetics)
  • Signal Transduction (genetics)
  • TOR Serine-Threonine Kinases
  • ras Proteins (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: