Pathological Adhesion of Primary Human Schwannoma Cells is Dependent on Altered Expression of Integrins

Utermark, Tamara; Kaempchen, Katherine; Hanemann, C. Oliver

doi:10.1111/j.1750-3639.2003.tb00034.x

Cited by 31 publications

(39 citation statements)

References 49 publications

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Section: Integrins and Related The Rac/pak/jnk Fak/src And Mtorc1 Pamentioning

confidence: 99%

“…Loss of merlin in schwannomas leads to pathological adhesion [11,12]. Utermark et al [12] showed that the enhanced adhesion is linked to increased expression of integrins a6, b1 and b4 at protein level and mRNA level. The upregulation of integrins a6, b1 and b4 was confirmed in an array analysis when mRNA from schwannomas was compared to Schwann cells [13].…”

Section: Integrins and Related The Rac/pak/jnk Fak/src And Mtorc1 Pamentioning

confidence: 99%

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Merlin, a multi‐suppressor from cell membrane to the nucleus

Zhou

Hanemann

2012

FEBS Letters

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Edited by Wilhelm JustKeywords: NF2 Merlin DCAF1 Integrin RTK a b s t r a c t Recent evidence suggests that the neurofibromatosis type 2 (NF2) gene encoded protein merlin suppresses mitogenic signalling not only at the cell membrane but also in the nucleus. At the membrane, merlin inhibits signalling by integrins and tyrosine receptor kinases (RTKs) and the activation of downstream pathways, including the Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/ JNK, mTORC1, and Wnt/b-catenin pathways. In the nucleus, merlin suppresses the E3 ubiquitin ligase CRL4 DCAF1 to inhibit proliferation. Gene expression analysis suggested that CRL4 DCAF1 could also regulate the expression of integrins and RTKs. In this review, we explore the links between merlin function at the membrane and in the nucleus, and discuss the potential of targeting the master regulator CRL4 DCAF1 to treat NF2 and other merlin-deficient tumours.

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Section: Integrins and Related The Rac/pak/jnk Fak/src And Mtorc1 Pamentioning

confidence: 99%

Section: Integrins and Related The Rac/pak/jnk Fak/src And Mtorc1 Pamentioning

confidence: 99%

Merlin, a multi‐suppressor from cell membrane to the nucleus

Zhou

Hanemann

2012

FEBS Letters

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“…Integrins are transmembrane receptors that mediate cell-matrix or cell-cell adhesion, and transduce signals that regulate gene expression and cell growth, including Schwann cells. Altered expression of the ITGB4 has been shown in schwannomas (37) and MPNSTs (5). Therefore, it is likely that the amplification of ITGB4 gene provides growth advantage to the Schwann cells in malignant tumors.…”

Section: Deleted Genesmentioning

confidence: 99%

High-Resolution DNA Copy Number Profiling of Malignant Peripheral Nerve Sheath Tumors Using Targeted Microarray-Based Comparative Genomic Hybridization

Mantripragada

Spurlock

Kluwe

et al. 2008

Clinical Cancer Research

116

111

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Purpose: Neurofibromatosis type1 (NF1) is an autosomal dominant condition that predisposes to benign and malignant tumors. The lifetime risk of a malignant peripheral nerve sheath tumor (MPNST) in NF1is f10%.These tumors have a poor survival rate and their molecular basis remains unclear.We report the first comprehensive investigation of DNA copy number across multitude of genes in NF1tumors using high-resolution array comparative genomic hybridization (CGH), with the aim to identify molecular signatures that delineate malignant from benign NF1tumors. Experimental Design: We constructed an exon-level resolution microarray encompassing 57 selected genes and profiled DNA from 35 MPNSTs, 16 plexiform, and 8 dermal neurofibromas. Bioinformatic analysis was done on array CGH data to identify concurrent aberrations in malignant tumors. Results: The array CGH profiles of MPNSTs and neurofibromas were markedly different. A number of MPNST-specific alterations were identified, including amplifications of ITGB4, PDGFRA, MET, TP73, and HGF plus deletions in NF1, HMMR/RHAMM, MMP13, L1CAM2, p16INK4A/ CDKN2A, andTP53. Copy number changes of HMMR/RHAMM, MMP13, p16INK4A/CDKN2A, and ITGB4 were observed in 46%, 43%, 39%, and 32%, respectively of the malignant tumors, implicating these genes in MPNST pathogenesis. Concomitant amplifications of HGF, MET, and PDGFRA genes were also revealed in MPNSTs, suggesting the putative role of p70S6K pathway in NF1tumor progression. Conclusions: This study highlights the potential of array CGH in identifying novel diagnostic markers for MPNSTs.Neurofibromatosis type 1 (NF1; OMIM # 162200) is a common autosomal dominant disorder with a prevalence of 1 in 3,000 individuals worldwide. The majority of individuals with NF1 develop benign dermal neurofibromas, and approximately one third have benign plexiform neurofibromas (1, 2). In 5% to 10% of NF1 patients, neurofibromas (predominantly plexiform) develop into malignant peripheral nerve sheath tumors (MPNST; ref. 3). Whereas approximately half of all MPNSTs in the general population occur in the context of NF1, the other 50% are sporadic in origin. To date, understanding of histogenesis and the molecular mechanisms leading to the malignancy in NF1 remains fragmentary.

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“…Using our in vitro model for human schwannoma, we have previously shown that merlin loss leads to enhanced proliferation and decreased apoptosis (5), increased cell-matrix adhesion (due to the overexpression of integrins; ref. 6), and decreased cell-cell adhesion (7). The RhoGTPases Rac1 and Cdc42 and their downstream effector p21-activated kinase (PAK) are activated in human primary schwannoma cells and have been linked to the aforementioned characteristics of schwannoma cells (8,9).…”

Section: Introductionmentioning

confidence: 99%

Dissecting and Targeting the Growth Factor–Dependent and Growth Factor–Independent Extracellular Signal-Regulated Kinase Pathway in Human Schwannoma

et al. 2008

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Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin. Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat. We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells. Due to a strong and prolonged activation of platelet-derived growth factor receptor B (PDGFRB), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation. Using specific inhibitors, we discovered that ERK1/2 activation involves the integrin/focal adhesion kinase/Src/Ras signaling cascades and PDGFRB-mediated ERK1/2 activation is triggered through the phosphatidylinositol 3-kinase/protein kinase C/Src/c-Raf pathway. Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways. The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRBmediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas. We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials. [Cancer Res 2008;68(13):5236-45]

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Pathological Adhesion of Primary Human Schwannoma Cells is Dependent on Altered Expression of Integrins

Cited by 31 publications

References 49 publications

Merlin, a multi‐suppressor from cell membrane to the nucleus

Merlin, a multi‐suppressor from cell membrane to the nucleus

High-Resolution DNA Copy Number Profiling of Malignant Peripheral Nerve Sheath Tumors Using Targeted Microarray-Based Comparative Genomic Hybridization

Dissecting and Targeting the Growth Factor–Dependent and Growth Factor–Independent Extracellular Signal-Regulated Kinase Pathway in Human Schwannoma

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