The IGF/IGFBP system in CNS malignancy

Zumkeller, Walter; Westphal, Manfred

doi:10.1136/mp.54.4.227

Cited by 71 publications

(63 citation statements)

References 37 publications

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“…Both SDF1 and its receptor, CXCR4, are expressed in the brain and are important for neuronal cell migration (Ma et al, 1998). IGFs are growth regulators of neurons and astrocytes, and IGFBPs are a family of at least six extracellular proteins that bind to IGFs with high affinities (Murphy, 1998;Zumkeller and Westphal, 2001). IGFBP6 binds IGF-II with high affinity and may inhibit IGF-II actions and both IGFBP6 and IGF-II are expressed in the central nervous system (Murphy, 1998;Zumkeller and Westphal, 2001).…”

Section: Resultsmentioning

confidence: 99%

“…IGFs are growth regulators of neurons and astrocytes, and IGFBPs are a family of at least six extracellular proteins that bind to IGFs with high affinities (Murphy, 1998;Zumkeller and Westphal, 2001). IGFBP6 binds IGF-II with high affinity and may inhibit IGF-II actions and both IGFBP6 and IGF-II are expressed in the central nervous system (Murphy, 1998;Zumkeller and Westphal, 2001). The sigma 1 receptor is associated with both plasma and intracellular membranes and is expressed in the CPu, NAc, and amygdala in the brain (Matsumoto et al, 2002;Romieu et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…These results suggest that IGFBP6 and SDF1 can be induced by repeated cocaine administration in the CPu in mice, and that the induction is at least partially dependent on a functional D1 receptor. IGFs promote the proliferation of neurons and astrocytes (Murphy, 1998;Zumkeller and Westphal, 2001). IGFBP6 binds to IGF-II with high affinity and may inhibit IGF-II actions (Murphy, 1998;Zumkeller and Westphal, 2001).…”

Section: Extracellular Moleculesmentioning

confidence: 99%

“…IGFs promote the proliferation of neurons and astrocytes (Murphy, 1998;Zumkeller and Westphal, 2001). IGFBP6 binds to IGF-II with high affinity and may inhibit IGF-II actions (Murphy, 1998;Zumkeller and Westphal, 2001). SDF1 affects neuronal cell migration through its receptor CXCR4 (Ma et al, 1998).…”

Section: Extracellular Moleculesmentioning

confidence: 99%

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Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Zhang

Tang

et al. 2005

Neuropsychopharmacol

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Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects of cocaine correlate with underlying changes in gene expression, we have used D1 receptor mutant and wild-type mice to identify chronic cocaine-induced gene expression changes mediated via the D1 receptors. We focused on the caudoputamen and nucleus accumbens, two key brain regions that mediate the long-term effects of cocaine. Our analyses demonstrate that repeated cocaine administration induces changes in the expression of 109 genes, including those encoding the stromal cell-derived factor 1, insulin-like growth factor binding protein 6, sigma 1 receptor, regulators of G-protein signaling protein 4, Wnt1 responsive Cdc42 homolog, Ca 2 þ /calmodulin-dependent protein kinase II a subunit, and cyclin D2, via the D1 receptors. Moreover, the seven genes contain AP-1 binding sites in their promoter regions. These results suggest that genes encoding certain extracellular factors, membrane receptors and modulators, and intracellular signaling molecules, among others, are regulated by cocaine via the D1 receptor, and these AP-1 transcription complex-regulated genes might contribute to persistent cocaine-induced behavioral changes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Extracellular Moleculesmentioning

confidence: 99%

Section: Extracellular Moleculesmentioning

confidence: 99%

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Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Zhang

Tang

et al. 2005

Neuropsychopharmacol

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“…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). Therefore, we wondered what role IGFBP-1 has in schwannoma development.…”

Section: Introductionmentioning

confidence: 97%

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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Insulin-like growth factor binding protein-4 (IGFBP-4) is a novel anti-angiogenic and anti-tumorigenic mediator secreted by dibutyryl cyclic AMP (dB-cAMP)-differentiated glioblastoma cells

Moreno

Ball

Andrade

et al. 2006

Glia

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cAMP has been shown to reverse the transformed phenotype of various cancer cells. Human glioblastoma U87MG cells exposed to 500 microM dB-cAMP for 6 days showed reduced proliferation, attenuated invasiveness, and inability to induce angiogenic responses in human brain endothelial cells (HBECs) grown in Matrigeltrade mark. VEGF was the principal mediator of angiogenic actions of U87MG conditioned media (CM), since VEGF neutralizing antibody completely inhibited U87MG-induced angiogenic responses and no detectable levels of IGF, bFGF, and PlGF were found in U87MG CM. VEGF release was induced ( approximately 20%) in dB-cAMP-treated U87MG cells, suggesting a simultaneous induction of anti-angiogenic mediators. Down-stream effectors of dB-cAMP actions in U87MG were investigated by microarray gene expression analysis. Detected increases in differentiation genes, staniocalcin-1 and Wnt-5a, and angiogenesis-related genes, PAI-1, SPARC, IGFBP-4, IGFBP-7, PAPP-A, and PRSS-11 in dB-cAMP-treated U87MG cells were validated by real-time PCR, Western blot, and/or ELISA. A subsequent series of experiments identified IGFBP-4 as the principal anti-angiogenic mediator secreted by glioblastoma cells in response to dB-cAMP. Human recombinant IGFBP-4 inhibited the angiogenic response of HBEC induced by U87MG CM, whereas anti-human IGFBP-4 antibody restored the pro-angiogenic activity of dB-cAMP-treated U87MG CM. Since neither U87MG nor HBEC cells secreted detectable levels of IGF-I, and there are no known cellular IGFBP-4 receptors, the anti-angiogenic effect of IGFBP-4 was likely IGF-I-independent and indirect. IGFBP-4 also antagonized angiogenic effects of VEGF(165), PlGF, and bFGF, and reduced U87MG colony formation in soft-agar. IGFBP-4 is a novel dB-cAMP-induced anti-angiogenic and anti-tumorigenic mediator that may be a promising candidate for glioblastoma therapy.

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The IGF/IGFBP system in CNS malignancy

Cited by 71 publications

References 37 publications

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

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

Insulin-like growth factor binding protein-4 (IGFBP-4) is a novel anti-angiogenic and anti-tumorigenic mediator secreted by dibutyryl cyclic AMP (dB-cAMP)-differentiated glioblastoma cells

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