Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

Abstract

<jats:p>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 <jats:italic>NF1</jats:italic> 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 <jats:italic>NF1</jats:italic> 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 <jats:italic>NF1</jats:italic><jats:sup>+/–</jats:sup> heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including <jats:italic>INK4A/ARF</jats:italic> and <jats:italic>P53,</jats:italic> with resulting abnormalities of their respective signal cascades. Further, abnormalities of the <jats:italic>NF1</jats:italic> 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.</jats:p>

A Case of Neurofibromatosis Type 1 Coinciding with Bilateral Pheochromocytomas, Multiple Gastrointestinal Stromal Tumors, and Malignant Peripheral Nerve Sheath Tumor

“…Activated Ras also activates the phosphoinositol 3 kinase (PI3K), Akt, and mTOR pathways, protecting cells from apoptosis. Neurofibromin downregulates Ras through its GAP-related domain; thus, at decreased levels in NF1, signaling is increased through all of these pathways, resulting in cell proliferation and inhibition of apoptosis (2). NF1-associated GISTs were reported to lack c-kit or PDGFRA mutations, which are typically observed in sporadic GIST (14,15,23).…”

“…The pathogenesis of NF1 is based on mutations of the NF1 tumor suppressor gene, which generally cause a decreased production of the intracellular neurofibromin protein. This leads to increased Ras signaling to downstream effectors, including Ras/mitogen-activated protein kinase (MAPK) and the Akt/ mammalian target of rapamycin (mTOR) (2). Clinical expression in NF1 is extremely variable, including neoplastic or non-neoplastic disorders, primarily involving tissues of neuroectodermal or mesenchymal origin in different regions, such as the skin, bone, eye, and central nervous system.…”

Vascular Anomalies: From Genetics toward Models for Therapeutic Trials

“…These include dominant-negative Ras, anti-Ras antibodies, inhibitors targeting the Ras-signaling pathway, and inhibitors directed against PI3K or MEK (Gottfried et al 2010).…”

Neurofibromatosis tipo 1 y sangrado de intestino delgado. Reporte de caso

“…Esta enfermedad la describe por primera vez en 1882 el patólogo alemán Frederich von Recklinghausen (1) y en la actualidad su prevalencia es cercana a 1 por cada 3 000 habitantes, con mayor presencia en niños (2). En la etiopatogenia de esta enfermedad está involucrada la mutación del gen NF-1, un gen supresor tumoral que se localiza en el cromosoma 17q11.2 y codifica la neurofibromina (3).…”