Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas

Schulte, Johannes H.; Schramm, Alexander; Klein-Hitpaß, Ludger; Klenk, Michael; Wessels, Hendrika; Hauffa, Berthold P.; Eils, Jürgen; Eils, Roland; Brodeur, Garrett M.; Schweigerer, Lothar; Havers, W.; Eggert, Angelika

doi:10.1038/sj.onc.1208000

Cited by 73 publications

(65 citation statements)

References 41 publications

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“…rGal-1 alone was not sufficient to induce the full invasive capacity of SY5Y-TrkB cells, suggesting that other BDNF-induced factors are involved in invasion as well. We and others have previously suggested MCSP and c-Met as TrkB-regulated, proinvasive factors in NB (Hecht et al, 2005;Schulte et al, 2005). Our current findings identify Gal-1 as a third player contributing to TrkB-mediated invasiveness in NB.…”

Section: Discussionsupporting

confidence: 71%

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

et al. 2009

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Expression of Trk receptors is an important prognostic factor in neuroblastoma (NB) and other cancers. TrkB and its ligand brain-derived neurotrophic factor (BDNF) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. Galectin-1 (Gal-1) has emerged as an interesting cancer target, as it is involved in modulating cell proliferation, cell death and cell migration, all of which are linked to cancer initiation and progression. We previously identified Gal-1 mRNA to be upregulated in patients with aggressive, relapsing NB and found that Gal-1 protein was upregulated in human SY5Y NB cells on activation of ectopically expressed TrkB (SY5Y-TrkB), but not TrkA (SY5Y-TrkA). Here, we report that Gal-1 mRNA levels positively correlated with TrkB expression and anticorrelated with TrkA expression in a cohort of 102 primary NB. Immunohistochemical analyses of 92 primary NB specimens revealed high Gal-1 expression in stromal septae and in neuroblasts. BDNF-mediated activation of TrkB enhanced invasiveness and migration in vitro, which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1. The addition of recombinant Gal-1 (rGal-1) in the absence of BDNF partially restored migration and invasive capacity. Using the Trk inhibitor K252a, we could show that the upregulation of Gal-1 protein strictly depended on activated TrkB. Our data suggest that targeting Gal-1 might be a promising strategy for the treatment of aggressive NB.

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Section: Discussionsupporting

confidence: 71%

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

et al. 2009

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“…In addition, TrkA may signal to p53 in other ways, because it can bind both p53 and c-Abl, a p53 activator (55)(56)(57), and promote the deacetylation of p53 in PC12 cells (58). It is likely that the modulation of p53 and Bcl-2 levels by TrkA occurs at the post-transcriptional level, because several recent cDNA expression profiling studies on NB tumors or SH-SY5Y NB cells stably transfected with TrkA did not report changes in p53 or Bcl-2 genes expression (59,60). We are currently characterizing the TrkA signals that lead to enhanced p53 expression.…”

Section: Discussionmentioning

confidence: 99%

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Lavoie

LeSauteur

Kohn

et al. 2005

Journal of Biological Chemistry

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Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X L also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. Neuroblastoma (NB)1 is the most common solid extracranial solid tumor of childhood and likely arises from sympathoadrenal precursor cells. The median age at diagnosis is ϳ18 months, and spontaneous tumor regression is frequently observed in patients diagnosed at 1 year of age or younger. In contrast, children older than 1 year diagnosed with NB often experience aggressive tumors that are disseminated, resistant to chemotherapy, and metastasized to bone, and often fatal. An important correlative characteristic of NB is the expression of two of the neurotrophin receptors, the TrkA/nerve growth factor (NGF) receptor and the TrkB/brain-derived neurotrophic factor receptor (1-4). The expression of TrkB, a poor prognosis marker, mediates survival, proliferation, and chemotherapeutic drug resistance (5-10), whereas expression of TrkA, a favorable prognosis marker, induces cell growth arrest and differentiation of cultured NB cells (11)(12)(13). This is consistent with TrkA being expressed in tumors that spontaneously regress. Most NB cell lines, which are derived from malignant tumors, lack or have very low levels of TrkA protein expression. Cell lines with low TrkA expression respond to NGF by differentiating into neuronal-like cells (11). Similarly, expression of TrkA by transfection converts NGF non-responsive NB cells into NGF-responsive cells, both in culture and in vivo, with the typical responses being the cessation of cell growth and differentiation into neural and Schwann cells (12). Thus, TrkA converts malignant NB cells into quiescent differentiated cells.An alternative or additional explanation for why TrkA is a good prognosis marker for NB that might contribute to spontaneous tumor regression is that it may induce apoptosis. Paradoxic...

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“…Therefore, although these stress-activated kinases have been shown to contribute to apoptotic cell death, by upregulating proapoptotic BH3-only Bcl-2 family members (e.g., Whitfield et al 80 ), BDNF is unlikely to modulate this death pathway under the experimental conditions used in this work. Recent studies have shown that activation of TrkB receptors elicits a complex program of changes in gene expression, 81 which will cause multiple changes in the proteome. Therefore, in addition to Bcl-2, other proteins are likely to contribute to neuroprotection by BDNF under excitotoxic conditions.…”

mentioning

confidence: 99%

Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways

et al. 2005

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Neurotrophins protect neurons against glutamate excitotoxicity, but the signaling mechanisms have not been fully elucidated. We studied the role of the phosphatidylinositol 3-kinase (PI3-K) and Ras/mitogen-activated protein kinase (MAPK) pathways in the protection of cultured hippocampal neurons from glutamate induced apoptotic cell death, characterized by nuclear condensation and activation of caspase-3-like enzymes. Pre-incubation with the neurotrophin brain-derived neurotrophic factor (BDNF), for 24 h, reduced glutamate-evoked apoptotic morphology and caspase-3-like activity, and transiently increased the activity of the PI3-K and of the Ras/MAPK pathways. Inhibition of the PI3-K and of the Ras/MAPK signaling pathways abrogated the protective effect of BDNF against glutamate-induced neuronal death and similar effects were observed upon inhibition of protein synthesis. Moreover, incubation of hippocampal neurons with BDNF, for 24 h, increased Bcl-2 protein levels. The results indicate that the protective effect of BDNF in hippocampal neurons against glutamate toxicity is mediated by the PI3-K and the Ras/MAPK signaling pathways, and involves a longterm change in protein synthesis.

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Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas

Cited by 73 publications

References 41 publications

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism*[boxs]

Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways

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