Abstract
BackgroundWilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear.ResultsThe association of retinoid signaling and clinical parameters could be validated in a large independent tumor set, but its relevance in primary nephrectomy tumors from very young children may be different. Reduced RA pathway activity and MYCN overexpression were found in high risk tumors as opposed to tumors with low/intermediate risk, suggesting a beneficial impact of RA especially on advanced WT. To search for possible modes of action of retinoids as novel therapeutic options, primary tumor cell cultures were treated in vitro with all-trans-RA (ATRA), 9cis-RA, fenretinide and combinations of retinoids and a histone deacetylase (HDAC) inhibitor. Genes deregulated in high risk tumors showed opposite changes upon treatment suggesting a positive effect of retinoids. 6/7 primary cultures tested reduced proliferation, irrespective of prior RA signaling levels. The only variant culture was derived from mesoblastic nephroma, a distinct childhood kidney neoplasm. Retinoid/HDAC inhibitor combinations provided no synergistic effect. ATRA and 9cis-RA induced morphological changes suggestive of differentiation, while fenretinide induced apoptosis in several cultures tested. Microarray analysis of ATRA treated WT cells revealed differential expression of many genes involved in extracellular matrix formation and osteogenic, neuronal or muscle differentiation. The effects documented appear to be reversible upon drug withdrawal, however.ConclusionsAltered retinoic acid signaling has been validated especially in high risk Wilms tumors. In vitro testing of primary tumor cultures provided clear evidence of a potential utility of retinoids in Wilms tumor treatment based on the analysis of gene expression, proliferation, differentiation and apoptosis.
Highlights
Wilms tumor (WT) is one of the most common malignancies in childhood
First hints on beneficial effects of retinoic acid (RA) were obtained when two primary WT cell cultures were treated with all-trans RA (ATRA) [5]
The most prominent differences in gene expression were found when comparing low/intermediate vs. high risk tumors (Figure 1): RARG, RARRES1, RARRES3, CTGF, ENPP2 and IGFBP3 were downregulated, while CRABP2, EZH2 and MYCN were overexpressed in high risk WT
Summary
Wilms tumor (WT) is one of the most common malignancies in childhood. With current therapy protocols up to 90% of patients can be cured, but there is still a need to improve therapy for patients with aggressive WT and to reduce treatment intensity where possible. Wilms tumor (WT) - or nephroblastoma - is one of the most frequent solid tumors in childhood This malignant kidney tumor affects about 1 of 10000 children. In a previous study using a microarray strategy to detect new stratification markers for WT, the expression levels of several genes involved in the retinoic acid (RA) signaling pathway were found to be associated with disease progression [4]. These data suggested a contribution of RA signaling to tumor progression and RA treatment as an additional approach for therapy of WT. First hints on beneficial effects of RA were obtained when two primary WT cell cultures were treated with all-trans RA (ATRA) [5]
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