Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression

Muir, David

doi:10.1007/bf00133486

Cited by 60 publications

(41 citation statements)

References 40 publications

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“…Tissues from rat mammary carcinomas, known to express activated c-H-ras, show increased MMP production compared to normal breast tissue (5). In recent studies, Schwann cells derived from neurofibromas have been shown to secrete high levels of MMP-1 (collagenases) and MMP-9 (gelatinase B) and also to invade a collagen barrier resembling basement membranes (44). It has been suggested that increased Ras activity in neurofibromaderived Schwann cells might be responsible for the invasiveness of the cells through stimulation of MMP production.…”

Section: Discussionmentioning

confidence: 99%

Nf1-Deficient Mouse Schwann Cells Are Angiogenic and Invasive and Can Be Induced To Hyperproliferate: Reversion of Some Phenotypes by an Inhibitor of Farnesyl Protein Transferase

Kim

Ling

Ratner

1997

Molecular and Cellular Biology

136

120

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We have developed a potential model of Schwann cell tumor formation in neurofibromatosis type 1 (NF1). We show that mouse Schwann cells heterozygous or null at Nf1 display angiogenic and invasive properties, mimicking the behavior of Schwann cells from human neurofibromas. Mutations at Nf1 are insufficient to promote Schwann cell hyperplasia. Here we show that Schwann cell hyperplasia can be induced by protein kinase A activation in mutant cells. Removal of serum from the culture medium also stimulates hyperplasia, but only in some mutant cells. After serum removal, clones of hyperproliferating Schwann cells lose contact with axons in vitro, develop growth factor-independent proliferation, and exhibit decreased expression of the cell differentiation marker P0 protein; hyperproliferating cells develop after a 1-week lag in Schwann cells heterozygous at Nf1. The experiments suggest that events subsequent to Nf1 mutations are required for development of Schwann cell hyperplasia. Finally, an anti-Ras farnesyl protein transferase inhibitor greatly diminished both clone formation and hyperproliferation of null mutant cells, but not invasion; farnesyl transferase inhibitors could be useful in treating benign manifestations of NF1.Neurofibromatosis type 1 (NF1) is one of the most common inherited human autosomal dominant diseases, with a worldwide incidence of 1 in 3,500 individuals (56). Benign manifestations frequently associated with NF1 include pigmented lesions of the skin (café au lait spots), hamartomas of the iris (Lisch nodules), learning disabilities, formation of optic pathway gliomas, and neurofibromas (22). Neurofibromas are one of the major defining features of NF1. Cutaneous neurofibromas (benign peripheral nerve sheath tumors) are associated with small nerve branches, plexiform neurofibromas develop along major peripheral nerves, and malignant peripheral nerve sheath tumors (MPNST) develop in about 4% of NF1 patients (56). Genetic studies show that malignant tumors in NF1, including MPNSTs, contain cells with mutations in both the constitutionally inactivated and previously normal somatic allele, consistent with NF1 acting as a tumor suppressor (19,36,64). The mechanism of neurofibroma formation is less clear. While recent studies demonstrated loss of heterozygosity (LOH) at the NF1 locus in some neurofibromas (12, 60), LOH could be associated with either of the major cell types in the benign tumors, fibroblasts or Schwann cells.Schwann cells may be the primary pathogenic cells in neurofibromas. The majority (40 to 85%) of cells in neurofibromas are Schwann cells (18,49), and in contrast to Schwann cells in normal nerve, neurofibroma Schwann cells are found without association with axons (28, 50). Furthermore, in vitro, Schwann cells, but not fibroblasts, from neurofibromas show angiogenic and invasive properties (63). Because the genetic status of neurofibroma Schwann cells is unknown, it remains unclear if a single NF1 mutation is sufficient for manifestation of some neurofibroma Schwann cell phenotype...

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Section: Discussionmentioning

confidence: 99%

Nf1-Deficient Mouse Schwann Cells Are Angiogenic and Invasive and Can Be Induced To Hyperproliferate: Reversion of Some Phenotypes by an Inhibitor of Farnesyl Protein Transferase

Kim

Ling

Ratner

1997

Molecular and Cellular Biology

136

120

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“…57,88 This Schwann cell, which lacks functional neurofibromin, has a substantial growth advantage 77 and a loss of negative autocrine growth control. 76 The stage of differentiation of the Schwann cell as the progenitor cell for NF1 tumors is still the subject of some debate. 53,61 In 2009, Le and coworkers 61 proposed that the neural crest stem cell is the cell of origin for cutaneous neurofibromas after identifying a population of stem/progenitor cells residing in the dermis (called skin-derived precursors) that, through loss of NF1, form neurofibromas.…”

Section: Neurofibromasmentioning

confidence: 99%

Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

Gottfried¹,

Viskochil

Couldwell³

2010

FOC

112

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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.

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“…36 Candidates include expression of epidermal and vascular endothelial growth factors and their receptors and matrix metalloproteinases. 37,38 Normal cellular relationships within the perineurium are contingent upon closely regulated signalling between Schwann cells, axons, fibroblasts and perineurial cells. Impaired signalling between the components of neurofibromas might promote neurofibroma development.…”

Section: Pathogenesis Of Neurofibromasmentioning

confidence: 99%

Neurofibromatosis 1

2006

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Neurofibromatosis 1 predisposes affected individuals to the development of benign and malignant tumours that are frequently disfiguring and difficult to manage. However, advances in molecular biology and the development of mouse models have facilitated our understanding of disease pathogenesis. Positron emission tomography has demonstrated that sophisticated imaging techniques have a role in diagnosing complex problems like malignant peripheral nerve sheath tumours, while the prospect of targeted therapies for Nf1 complications is tantalisingly close.

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Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression

Cited by 60 publications

References 40 publications

Nf1-Deficient Mouse Schwann Cells Are Angiogenic and Invasive and Can Be Induced To Hyperproliferate: Reversion of Some Phenotypes by an Inhibitor of Farnesyl Protein Transferase

Nf1-Deficient Mouse Schwann Cells Are Angiogenic and Invasive and Can Be Induced To Hyperproliferate: Reversion of Some Phenotypes by an Inhibitor of Farnesyl Protein Transferase

Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

Neurofibromatosis 1

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