Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients

Nevo, Ido; Oberthuer, André; Botzer, Edry; Sagi‐Assif, Orit; Maman, Shelly; Pasmanik‐Chor, Metsada; Kariv, Naam; Fischer, Matthias; Yron, Ilana; Witz, Isaac P.

doi:10.1002/ijc.24889

Cited by 16 publications

(21 citation statements)

References 42 publications

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“…The expression of CGNL1 was also lower in the metastatic variants generated in our laboratory than in the local adrenal tumors. 15 Surprisingly, the results of the present study indicated that DisNB variants, although exhibiting a lesser malignant phenotype in vivo than MetNB variants, expressed lower levels of CGNL1 than MetNB variants.…”

Section: Discussioncontrasting

confidence: 78%

“…15 The expression of CGNL1 was lower in the high grade, stage 4 NB tumors than in stage 1 tumors. The expression of CGNL1 was also lower in the metastatic variants generated in our laboratory than in the local adrenal tumors.…”

Section: Discussionmentioning

confidence: 90%

“…Nonetheless, a small set of genes that were differentially expressed in the metastatic and the local variants could segregate stage 4 and stage 1 NB patients. 15 The molecular signatures shared by metastatic NB variants and stage 4 NB patients, and the signature shared by local NB variants and stage 1 NB patients, highlights the translational significance of the orthotopic mouse model for human NB metastasis.…”

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confidence: 99%

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Lung-Residing Metastatic and Dormant Neuroblastoma Cells

Botzer

Maman

Sagi‐Assif

et al. 2011

The American Journal of Pathology

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The mechanism by which dormant tumor cells can begin growing after long periods of inactivity and accelerate disease recurrence is poorly understood. The present study characterizes dormant neuroblastoma (NB) cells, as well as metastatic cells, which reside in the same organ microenvironment. A xenograft model of human NB consisting of variants that generate nonmetastatic local tumors in the orthotopic inoculation site and variants that generate lung metastatic NB (MetNB) cells was developed in our laboratory. The present study shows that lungs of mice inoculated with nonmetastatic NB variants contain disseminated neuroblastoma (DisNB) human cells. Both DisNB and MetNB variants expressed a similar tumorigenicty phenotype in vivo, whereas the MetNB variants produced a heavy metastatic load and the DisNB variants produced no or little metastasis. A comparative in vitro characterization of MetNB and DisNB cells revealed similarities and differences. DisNB, but not MetNB cells, expressed the minimal residual disease markers PHOX2B and TH. MetNB cells demonstrated higher migratory capacity, an elevated matrix metalloproteinase (MMP) secretion, and a higher constitutive phosphorylation of extracellular signalregulated kinase (ERK) than DisNB cells. We suggest that characteristics common to both MetNB and DisNB cells were acquired relatively early in the metastatic process and the characteristics that differ between these variants were acquired later. We hypothesize that the DisNB cells are metastasis precursors, which may progress toward metastasis under certain microenvironmental conditions. Neuroblastoma (NB) is the most common extracranial solid tumor in children comprising 8% to 10% of all childhood cancers. More than half of these patients have a metastatic disease at diagnosis. 1-3 NB cells disseminate either by hematogenous spread, producing metastasis most frequently in bone marrow, bone, liver, and skin, or by lymphatic spread to regional and distant lymph nodes. 4 Lung metastases are considered a terminal event representing a widely disseminated metastatic disease. [5][6] Approximately 50% of children with high-risk NB that complete consolidation therapy develop early or late relapse, often from minimal residual disease in the form of circulating NB cells or micrometastases. 7 Most of the children with NB present metastatic disease at diagnosis with poor outcome, despite intensive treatment protocols. 8 The presence of circulating NB cells and/or NB micrometastasis may indicate a significant high-risk disease. 9 However, the question whether NB micrometastases develop into metastatic disease is yet to be answered.Previous studies from our laboratory were aimed to identify molecular pathways that are involved in NB metastasis. We focus on the cross talk between metastatic NB cells and components of their microenvironment, and on the downstream effects of such interactions.We suggested that NB cells might use chemokinechemokine receptor axes in their progression to metastasis. For example the CXCR4 -CXCL12 10 ...

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Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 90%

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confidence: 99%

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Lung-Residing Metastatic and Dormant Neuroblastoma Cells

Botzer

Maman

Sagi‐Assif

et al. 2011

The American Journal of Pathology

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“…Interestingly, our glioma dataset highlights the down-modulation of EMT related genes that implicate a phenotypic shift toward a mesenchymal-epithelial transition (MET) as a major process undergone by tumor cells at the AOI. Previous genomic profiling of metastatic tumors has shown that the disseminated tumor cells are strikingly similar to primary tumor cells [39], [40]. These studies suggested that phenotypic transitions might be driven not only by cell intrinsic affecters but also by the influence of the microenvironment.…”

Section: Discussionmentioning

confidence: 95%

Identification of Molecular Pathways Facilitating Glioma Cell Invasion In Situ

et al. 2014

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Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion.In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.

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“…Although the molecular signature of HR-NB is being investigated in detail, 5,65,66 as a result of its complexity, this analysis has only provided markers to categorize patients rather than validated targets to treat them. Nevertheless, a few such potential targets are starting to emerge, such as MYCN, [67][68][69][70] 41 Finally, the Mcl-1 gene maps to 1q21, a region that is frequently seen in high copy number in many NB cell lines and primary NB tumors, and is associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells

Bettayeb¹,

Baunbæk²,

Delehouzé³

et al. 2010

Genes & Cancer

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Neuroblastoma (NB), the most frequent extracranial solid tumor of children accounting for nearly 15% of all childhood cancer mortality, displays overexpression of antiapoptotic Bcl-2 and Mcl-1 in aggressive forms of the disease. The clinical phase 2 drug roscovitine (CYC202, seliciclib), a relatively selective inhibitor of cyclin-dependent kinases (CDKs), and CR8, a recently developed and more potent analog, induce concentration-dependent apoptotic cell death of NB cells (average IC 50 values: 24.2 µM and 0.4 µM for roscovitine and CR8, respectively). Both roscovitine and CR8 trigger rapid downregulation of the short-lived survival factor Mcl-1 in the 9 investigated human NB cell lines. This effect was further analyzed in the human SH-SY5Y NB cell line. Down-regulation of Mcl-1 appears to depend on inhibition of CDKs rather than on interaction of roscovitine and CR8 with their secondary targets. CR8 is an adenosine triphosphate-competitive inhibitor of CDK9, and the structure of a CDK9/cyclin T/CR8 complex is described. Mcl-1 downregulation occurs both at the mRNA and protein levels. This effect can be accounted for by a reduction in Mcl-1 protein synthesis, under stable Mcl-1 degradation conditions. Mcl-1 down-regulation is accompanied by a transient increase in free Noxa, a proapoptotic factor. Mcl-1 down-regulation occurs independently of the presence or up-regulation of p53 and of the MYCN status. Taken together, these results suggest that the clinical drug roscovitine and its novel analog CR8 induce apoptotic tumor cell death by down-regulating Mcl-1, a key survival factor expressed in all NB cell lines. CDK inhibition may thus constitute a new approach to treat refractory high-risk NB.

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Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients

Cited by 16 publications

References 42 publications

Lung-Residing Metastatic and Dormant Neuroblastoma Cells

Lung-Residing Metastatic and Dormant Neuroblastoma Cells

Identification of Molecular Pathways Facilitating Glioma Cell Invasion In Situ

CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells

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