Differential gene expression between human schwannoma and control Schwann cells

Hanemann, C. Oliver; Bartelt-Kirbach, Britta; Diebold, Ruth; Kämpchen, K.; Utermark, Tamara

doi:10.1111/j.1365-2990.2006.00769.x

Cited by 37 publications

(27 citation statements)

References 66 publications

(73 reference statements)

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“…In (b) (first panel), the data are normalized to the basal (non-stimulated) levels, in (b) (second panel) normalization is to mock shRNA-infected cells and in (b) (third panel) to basal mock shRNA-infected cells. In (a) and (b), RhoGDI is used as a loading control as previously described in (Hanemann et al, 2006). N represents number of samples from different patients (*Po0.05, **Po0.01).…”

Section: Discussionmentioning

confidence: 99%

“…ECL-plus (Amersham, Buckinghamshire, UK) was utilized for detection. Rho-GDI was used as a loading control, (anti-RhoGDI antibody; Santa Cruz Biotechnology), as it has previously been shown not to be regulated in our system (Hanemann et al, 2006;Ammoun et al, 2008). In one occasion, anti-GAPDH antibody (Millipore, Billerica, MA, USA) was used as a loading control.…”

Section: Methodsmentioning

confidence: 99%

“…b1-integrin shRNA completely abolished IGFBP-1-mediated FAK phosphorylation at Tyr397 (Figure 2b, fourth panel). We used RhoGDI as a loading control since we have previously shown that this protein, in contrast to cytoskeleton proteins, for example, actin or tubulin, is not regulated in schwannoma cells (Hanemann et al, 2006;Ammoun et al, 2008).…”

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

“…4). In all western blots but (c) (left panel), where GAPDH was used as a loading control, RhoGDI was used as a loading control (Hanemann et al, 2006;Ammoun et al, 2008Ammoun et al, , 2010b. In (c) (left panel), the data are normalized to Schwann cells (NF2 þ / þ ) and in the rest of experiments to the basal (non-stimulated) levels.…”

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

“…Previously, we showed that insulin-like growth factor-binding protein-1 (IGFBP-1) is overexpressed in schwannoma, detected by DNA array and reverse transcriptase-PCR (Hanemann et al, 2006). As shown in other cancer models IGFBP-1, through its COOHterminal RGD motif (Jones et al, 1993b;Yee, 2002), can act via b1-integrin toward FAK (Zumkeller and Westphal, 2001;Zhang and Yee, 2006;Perks et al, 2007) both strongly overexpressed and basally activated in schwannoma Ammoun et al, 2008) and may potentiate cell proliferation, migration and survival (Giancotti and Ruoslahti, 1999).…”

Section: Introductionmentioning

confidence: 95%

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Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

et al. 2011

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Merlin is a tumour suppressor involved in the development of a variety of tumours including mesotheliomas. Neurofibromatosis type 2 (NF2), a dominantly inherited tumour disease, is also caused by loss of merlin. NF2 patients suffer from multiple genetically well-defined tumours, schwannomas are most frequent among those. Using our in vitro model for human schwannoma, we found that schwannoma cells display enhanced proliferation because of the overexpression/activation of platelet-derived growth factor receptor and ErbB2/3, increased cell-matrix adhesion because of the overexpression of integrins, and decreased apoptosis. Mechanisms underlying schwannomas basal proliferation and cell-matrix adhesion are not understood. Here, we investigated insulin-like growth factor-binding protein-1 (IGFBP-1), which is expressed and released from central nervous system tumours and strongly overexpressed in schwannoma at the mRNA level. IGFBP-1 acts via b1-integrin and focal-adhesion-kinase (FAK), which are strongly overexpressed and basally activated in schwannoma. Using short hairpin RNA knockdown, small inhibitors and recombinant IGFBP-1, we demonstrate that schwannoma cells, in contrast to Schwann cells, release IGFBP-1 that activates the Src/FAK pathway, via integrin b1, potentiating schwannoma's proliferation and cell-matrix adhesion. We show that FAK localizes to the nucleus and Src triggers IGFBP-1 production. Further, we observed downregulation of the tumour-suppressor phosphatase and tensin homolog in schwannoma cells leading to increased activity of antiapoptotic AKT. Thus, IGFBP-1/integrin b1/Src/FAK pathway has a crucial role in merlin-related tumourigenesis and therefore represents an important therapeutic target in the treatment of merlin-deficient tumours.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

Section: Igfbp-1 Is Upregulated and Released Only From Schwannoma Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

et al. 2011

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Overexpression of CXCL16 and its receptor CXCR6/Bonzo promotes growth of human schwannomas

Held‐Feindt

Rehmke

Mentlein

et al. 2008

Glia

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Chemokines and their receptors play a decisive role in tumor progression and metastasis. Here, we describe the expression of the CXCL16-CXCR6-system in human schwannomas of different localization and in malignant peripheral nerve sheath tumors. The transmembrane chemokine CXCL16 and its receptor CXCR6/Bonzo were overexpressed on the mRNA and protein levels in all tumor samples investigated as compared with normal peripheral or 8th cranial nerve tissues. Chromogenic immunostaining and confocal laser microscopy revealed that CXCL16 and CXCR6 were localized mainly on S-100 positive schwannoma cells. Cultured schwannoma cells responded to CXCL16-stimulation by phosphorylation of kinases p42/44 (Erk 2/1) that could be inhibited by the MEK1/2-inhibitor U0126 indicating an involvement of the mitogen-activated protein kinase signal transduction pathway. As a biological response, CXCL16 increased proliferation and induced migration of schwannomas. Hence, CXCL16 appears to be a novel growth factor for schwannomas of different localization.

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The role of insulin‐like growth factors signaling in merlin‐deficient human schwannomas

Ammoun

Schmid

Ristic

et al. 2012

Glia

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Loss of the tumor suppressor merlin causes development of the tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas occurring spontaneously or as part of a hereditary disease Neurofibromatosis Type 2 (NF2). Current therapies, (radio) surgery, are not always effective. Therefore, there is a need for drug treatments for these tumors. Schwannomas are the most frequent of merlin-deficient tumors and are hallmark for NF2. Using our in vitro human schwannoma model, we demonstrated that merlin-deficiency leads to increased proliferation, cell-matrix adhesion, and survival. Increased proliferation due to strong activation of extracellular-signal-regulated kinase 1/2 (ERK1/2) is caused by overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) and ErbB2/3 which we successfully blocked with AZD6244, sorafenib, or lapatinib. Schwannoma basal proliferation is, however, only partly dependent on PDGFR-β and is completely independent of ErbB2/3. Moreover, the mechanisms underlying pathological cell-matrix adhesion and survival of schwannoma cells are still not fully understood. Here, we demonstrate that insulin-like growth factor-I receptor (IGF-IR) is strongly overexpressed and activated in human primary schwannoma cells. IGF-I and -II are overexpressed and released from schwannoma cells. We show that ERK1/2 is relevant for IGF-I-mediated increase in proliferation and cell-matrix adhesion, c-Jun N-terminal kinases for increased proliferation and AKT for survival. We demonstrate new mechanisms involved in increased basal proliferation, cell-matrix adhesion, and survival of schwannoma cells. We identified therapeutic targets IGF-IR and downstream PI3K for treatment of schwannoma and other merlin-deficient tumors and show usefulness of small molecule inhibitors in our model. PI3K is relevant for both IGF-IR and previously described PDGFR-β signaling in schwannoma.

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Differential gene expression between human schwannoma and control Schwann cells

Cited by 37 publications

References 66 publications

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates human schwannoma proliferation, adhesion and survival

Overexpression of CXCL16 and its receptor CXCR6/Bonzo promotes growth of human schwannomas

The role of insulin‐like growth factors signaling in merlin‐deficient human schwannomas

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