Cargando…

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

BACKGROUND: 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. Prior data suggested a d...

Descripción completa

Detalles Bibliográficos
Autores principales: Wegert, Jenny, Bausenwein, Sabrina, Kneitz, Susanne, Roth, Sabine, Graf, Norbert, Geissinger, Eva, Gessler, Manfred
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3239322/
https://www.ncbi.nlm.nih.gov/pubmed/22067876
http://dx.doi.org/10.1186/1476-4598-10-136
_version_ 1782219166917328896
author Wegert, Jenny
Bausenwein, Sabrina
Kneitz, Susanne
Roth, Sabine
Graf, Norbert
Geissinger, Eva
Gessler, Manfred
author_facet Wegert, Jenny
Bausenwein, Sabrina
Kneitz, Susanne
Roth, Sabine
Graf, Norbert
Geissinger, Eva
Gessler, Manfred
author_sort Wegert, Jenny
collection PubMed
description BACKGROUND: 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. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. RESULTS: The 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. CONCLUSIONS: Altered 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.
format Online
Article
Text
id pubmed-3239322
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-32393222011-12-16 Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro Wegert, Jenny Bausenwein, Sabrina Kneitz, Susanne Roth, Sabine Graf, Norbert Geissinger, Eva Gessler, Manfred Mol Cancer Research BACKGROUND: 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. Prior data suggested a deregulation of the retinoic acid (RA) signaling pathway in high-risk WT, but its mode of action remained unclear. RESULTS: The 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. CONCLUSIONS: Altered 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. BioMed Central 2011-11-08 /pmc/articles/PMC3239322/ /pubmed/22067876 http://dx.doi.org/10.1186/1476-4598-10-136 Text en Copyright ©2011 Wegert et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 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.
spellingShingle Research
Wegert, Jenny
Bausenwein, Sabrina
Kneitz, Susanne
Roth, Sabine
Graf, Norbert
Geissinger, Eva
Gessler, Manfred
Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
title Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
title_full Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
title_fullStr Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
title_full_unstemmed Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
title_short Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
title_sort retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3239322/
https://www.ncbi.nlm.nih.gov/pubmed/22067876
http://dx.doi.org/10.1186/1476-4598-10-136
work_keys_str_mv AT wegertjenny retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro
AT bausenweinsabrina retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro
AT kneitzsusanne retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro
AT rothsabine retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro
AT grafnorbert retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro
AT geissingereva retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro
AT gesslermanfred retinoicacidpathwayactivityinwilmstumorsandcharacterizationofbiologicalresponsesinvitro