Cancer Letters

Cancer Letters

Volume 228, Issues 1–2, 18 October 2005, Pages 117-123
Cancer Letters

Wnt-5a gene expression in malignant human neuroblasts

https://doi.org/10.1016/j.canlet.2004.11.061Get rights and content

Abstract

Neuroblastoma (NB), an embryonal malignancy, poses a major challenge in pediatric oncology for the treatment of disseminated forms. Here, we report the decrease of Wnt-5a gene expression in high-risk NB (HR-NB) as well as in cultured metastatic neuroblasts. Wnt-5a is a member of the Wnt signaling pathway which is mainly associated with patterning decisions in the embryonic nervous system. Moreover, Wnt-5a has been involved in metastatic melanoma progression and invasive ductal breast cancer via adhesion and migration alterations. As retinoic acid (RA) plays a major role in the neural crest induction and differentiation, we showed that RA reverses the aberrant negative regulation of Wnt-5a in metastatic neuroblasts. While β-catenin expression remained unchanged, PKC-θ, a protein kinase C isoform, was evidenced to increase and parallel Wnt-5a level. For the first time, the involvement of Wnt-5a through the Wnt/calcium signaling is highlighted in the pathogenesis of a pediatric embryonal malignancy, NB.

Section snippets

The Wnt gene family

Subject of considerable investigation for more than 20 years, the Wnt gene family constitutes one of the major families of developmentally significant molecules, controlling a variety of processes such as cell fate specification, cell migration and cell polarity [1]. Wnt genes encode signaling proteins which are 38–45 kDa secreted cysteine-rich proteins with features typical of secreted growth factors. Nineteen different Wnt genes have been identified in the mouse and human genome (//www.stanford.edu/~rnusse/wntwindow.html

Low Wnt-5a expression in high-risk neuroblastoma

In order to identify metastatic-related genes in NB, we have performed a cDNA macroarray analysis of malignant neuroblasts derived from a human NB experimental model (IGR-N-91 model), established from an HR-NB and previously characterized in our laboratory [28]. Briefly, an in vitro neuroblastoma cell line, IGR-N-91, when injected subcutaneously in nude mice, yielded a primary tumor xenograft (PTX), and metastatic neuroblasts in two sites, myocardium (Myoc) and bone marrow (BM). Then PTX, Myoc

Induction of Wnt-5a expression in RA-differentiated malignant neuroblasts

The development of the neural crest and sympathetic nervous system depends on various factors such as FGFs and retinoic acid (RA) signals [33]. During embryogenesis, RA induces neuroectodermal differentiation with the formation of several cell types, including neurons, glia, and fibroblast-like cells. Interestingly, in undifferentiated human embryonal carcinoma, which do not express Wnt genes, Wnt expression has been shown to occur upon RA-induced differentiation [34], and more specifically to

Conclusions

The Wnt signaling cascade plays a decisive role in development and aberrant regulation is linked to cancer. Here, we described that Wnt-5a, an important regulator of morphogenetic movements during embryonal development [39] and recently involved in the proliferation of progenitor cells [40], is decreased in high-risk NB. These patients present a dramatic prognosis despite intensive high-dose and myeloablative chemotherapy, then followed by a maintenance regimen of 13-cis-retinoic acid [41], [42]

Acknowledgements

This work was supported by the Ligue Contre le Cancer, Comité de Montbéliard. Edited by Englishbooster S.A.

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