Low expression of Wnt-5a gene is associated with high-risk neuroblastoma

Blanc, Étienne; Roux, G. Le; Bénard, Jean; Raguénez, Gilda

doi:10.1038/sj.onc.1208255

Cited by 86 publications

(73 citation statements)

References 38 publications

(34 reference statements)

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“…WNT5A has been reported to be reduced in NBs with high-risk features (Blanc et al, 2005), but our datasets demonstrate low expression in both high (Table 3) and lower-risk tumors with no differential expression (data not shown). Still, most tumor-specific pathway deregulation occurs through activating mutations downstream of Wnt/receptor events.…”

Section: Discussionmentioning

confidence: 64%

Deregulated Wnt/β-catenin program in high-risk neuroblastomas without MYCN amplification

et al. 2007

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Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/b-catenin (CTNNB1) signaling might account for this as MYC is a b-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and b-catenin (with aberrant nuclear localization) than MYCNamplified cell lines. Evidence for aberrant b-catenin-TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical b-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated b-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered b-catenin signaling providing a potential candidate pathway for therapeutic inhibition.

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Section: Discussionmentioning

confidence: 64%

Deregulated Wnt/β-catenin program in high-risk neuroblastomas without MYCN amplification

et al. 2007

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“…Although Wnt 5a has been considered predominantly a tumor suppressor (25,26,42), there is evidence that it may also enhance malignant cell motility and foster tumor progression. Wnt 5a expression was associated with invasive behavior in cutaneous melanomas, being detectable predominantly in actually invasive cells (29).…”

Section: Discussionmentioning

confidence: 99%

“…It promotes GSK-3␤-independent ␤-catenin degradation (23) and enhances cell-cell adhesion on collagen matrices (24). Metastatic neuroblasts in a xenograft model displayed lower Wnt 5a expression than the primary neuroblastoma cells (25). In a retrospective analysis of breast cancers, immunohistochemical Wnt 5a detection was inversely correlated with metastasis formation and survival (26).…”

mentioning

confidence: 99%

Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Pukrop

Klemm

Hagemann

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

323

290

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Interactions between neoplastic and stromal cells contribute to tumor progression. Wnt genes, involved in cell migration and often deregulated in cancers, are attractive candidates to regulate these effects. We have recently shown that coculture of breast cancer cells with macrophages enhances invasiveness via matrix metalloproteases and TNF-␣. Here we demonstrate that coculture of MCF-7 cells and macrophages leads to up-regulation of Wnt 5a in the latter. This was accompanied by activation of AP-1͞c-Jun in MCF-7. Recombinant Wnt 5a mimicked the coculture effect. Wnt 5a was also detectable in tumor-associated macrophages in primary breast cancers. Experiments with agonists and antagonists of Wnt signaling revealed that a functional canonical pathway in the tumor cells was a necessary prerequisite; however, noncanonical signaling via Wnt 5a and the Jun-N-terminal kinase pathway was critical for invasiveness. It was also responsible for induction of matrix metalloprotease-7, known to release TNF-␣. All these effects could be antagonized by dickkopf-1. Our results indicate that Wnt 5a is essential for macrophage-induced invasiveness, because it regulates tumor cell migration as well as proteolytic activity of the macrophages. The function of Wnt 5a as either a suppressor or promoter of malignant progression seems to be modulated by intercellular interactions. Wnt 5a detection in tumor-associated macrophages in breast cancer biopsies supports the assumption that similar events play a role in vivo.tumor microenvironment ͉ TNF-␣ ͉ matrix metalloproteases

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“…A role for Wnt5a has indeed been postulated for metastasis of neuroblastoma. 52 Exposure of neuroblastomas to retinoic acid results in tumor differentiation and increase in Wnt5a expression, 52 suggesting involvement of the wnt pathway in neuroblastoma differentiation. In view of these data it would be interesting to study DKK3 involvement in retinoic acid induced neuroblastoma differentiation.…”

Section: Discussionmentioning

confidence: 99%

Dickkopf‐3 expression is a marker for neuroblastic tumor maturation and is down‐regulated by MYCN

Koppen

Ait-Aissa

Koster

et al. 2008

Intl Journal of Cancer

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Neuroblastoma and ganglioneuroma are neuroblastic tumors originating from the developing sympathetic peripheral nervous system. Ganglioneuromas are usually benign, while neuroblastomas have a variable prognosis and include very aggressive tumors. Examples exist of neuroblastomas regressing to ganglioneuromas and ganglioneuromas progressing to neuroblastomas. Little is known of the molecular differences between the tumor types. Here we report that Dickkopf-3 (DKK3), a putative extra cellular inhibitor of the Wnt/b-catenin pathway, showed a strongly differential expression between neuroblastoma and ganglioneuroma. Microarray analyses of 109 neuroblastic tumors revealed that DKK3 is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. Low DKK3 expression in neuroblastoma correlated with a poor prognosis. The expression of DKK3 in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of the MYCN oncogene. Analysis of 2 neuroblastoma cell lines with inducible activity of MYCN showed that DKK3 is down-regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. High DKK3 expression in the benign ganglioneuromas and down-regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types. ' 2007 Wiley-Liss, Inc.

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Low expression of Wnt-5a gene is associated with high-risk neuroblastoma

Cited by 86 publications

References 38 publications

Deregulated Wnt/β-catenin program in high-risk neuroblastomas without MYCN amplification

Deregulated Wnt/β-catenin program in high-risk neuroblastomas without MYCN amplification

Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Dickkopf‐3 expression is a marker for neuroblastic tumor maturation and is down‐regulated by MYCN

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