Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro

Molecular Cancer

Research

Jenny Wegert¹  Manfred Gessler¹  Sabrina Bausenwein¹  Norbert Graf²  Eva Geissinger³  Sabine Roth³  Susanne Kneitz⁴ 

[1] Developmental Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany;Division of Pediatric Oncology and Hematology, Saarland University Hospital, Homburg/Saar, Germany;Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany;Laboratory for Microarray Applications, University of Wuerzburg, Wuerzburg, Germany;

关键词: Wilms tumor;    nephroblastoma;    primary tumor cell culture;    tumor model;    retinoic acid;   

DOI  :  10.1186/1476-4598-10-136

 received in 2011-04-27, accepted in 2011-11-08,  发布年份 2011

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Wegert et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.