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Nuclear accumulation of beta-Catenin protein indicates frequent activation of Wnt-signaling in chemically-induced rat nephroblastomas


Ehrlich, D; Bruder, E; Thome, M; Gutt, C; von Knebel Doeberitz, M; Niggli, F; Perantoni, A; Bode, M; Koesters, R (2010). Nuclear accumulation of beta-Catenin protein indicates frequent activation of Wnt-signaling in chemically-induced rat nephroblastomas. Pediatric and Developmental Pathology, 13(1):1-8.

Abstract

Aberrant wnt-signaling caused by mutations in CTNNB1 occurs in about 15% of Wilms tumors. Nuclear beta-catenin protein, a substitute marker of active wnt-signaling, has been detected in an even higher proportion (>50%) of Wilms tumors suggesting alternative genetic pathways leading to beta-catenin activation. Thus, targeting wnt-signaling may become an important future therapeutic strategy in Wilms tumor patients. Currently, chemically-induced rat nephroblastomas provide the only available rodent model for this tumor. To determine the contribution of active wnt-signaling in this model, we investigated 25 chemically-induced rat nephroblastomas for beta-catenin protein expression and for Ctnnb1 exon 3 mutations. Using immunohistochemistry 16 of 25 tumors showed strong nuclear accumulation of beta-catenin protein although in a heterogenous pattern. Blastemal and mesenchymal compartments displayed nuclear positive cells more frequently than areas of epithelial differentiation. Interestingly, we found no mutation of exon 3 of Ctnnb1 in any of the 25 tumors analysed. In conclusion, our findings suggest activation of wnt-signaling in the vast majority of chemically-induced rat nephroblastomas. Nuclear expression of beta-catenin in the absence of Ctnnb1 mutations implies, however, alternate mutational targets in rat nephroblastomas. Chemically-induced rat nephroblastomas may constitute a suitable model system to test future anti-cancer drugs targeting the wnt-signaling pathway. betabeta.

Abstract

Aberrant wnt-signaling caused by mutations in CTNNB1 occurs in about 15% of Wilms tumors. Nuclear beta-catenin protein, a substitute marker of active wnt-signaling, has been detected in an even higher proportion (>50%) of Wilms tumors suggesting alternative genetic pathways leading to beta-catenin activation. Thus, targeting wnt-signaling may become an important future therapeutic strategy in Wilms tumor patients. Currently, chemically-induced rat nephroblastomas provide the only available rodent model for this tumor. To determine the contribution of active wnt-signaling in this model, we investigated 25 chemically-induced rat nephroblastomas for beta-catenin protein expression and for Ctnnb1 exon 3 mutations. Using immunohistochemistry 16 of 25 tumors showed strong nuclear accumulation of beta-catenin protein although in a heterogenous pattern. Blastemal and mesenchymal compartments displayed nuclear positive cells more frequently than areas of epithelial differentiation. Interestingly, we found no mutation of exon 3 of Ctnnb1 in any of the 25 tumors analysed. In conclusion, our findings suggest activation of wnt-signaling in the vast majority of chemically-induced rat nephroblastomas. Nuclear expression of beta-catenin in the absence of Ctnnb1 mutations implies, however, alternate mutational targets in rat nephroblastomas. Chemically-induced rat nephroblastomas may constitute a suitable model system to test future anti-cancer drugs targeting the wnt-signaling pathway. betabeta.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2010
Deposited On:09 Mar 2010 10:59
Last Modified:07 Dec 2017 01:29
Publisher:Alliance Communications Group
ISSN:1093-5266
Publisher DOI:https://doi.org/10.2350/08-03-0443.1
PubMed ID:19348510

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