Abstract 2408: Generation of an inducible Wnt5a transgenic mouse model to study the contribution of increased Wnt5a expression to intestinal tumor growth
Authors: Bakker Elvira R.M , van Veelen Wendy , Helvensteijn Werner , Kuipers Ernst J. , Smits Ron 
Published: June 2012

Abstract
Introduction: The importance of the interaction between tumor cells and stromal tissue for tumor invasion and metastasis is becoming well-recognized lately. Noncanonical Wnt5a ligand is expressed at increased levels by stromal cells in intestinal tumors. Despite well known importance of Wnt signaling in colorectal cancer, Wnt5a is one out of only two Wnt ligands described to be upregulated in gastrointestinal tumors. In vitro data suggest involvement of Wnt5a in tumor cell migration, angiogenesis and epithelial to mesenchymal transition. At present, it is unclear however to which extent and through which mechanisms Wnt5a contributes to the malignant behavior of colorectal tumors in vivo. Therefore, we have generated a mouse model in which expression of Wnt5a can be controlled in a tissue-specific and temporal fashion.
Methods: We generated a transgenic mouse line carrying the Wnt5a gene driven by a doxycycline (dox)-responsive promoter, which was crossed with hnRNP-rtTA animals expressing the rtTA2 transcription factor in all their tissues. In this way a model was generated in which Wnt5a expression can be induced by dox administration in double transgenic animals. Subsequently, double transgenics were crossed with Apc1638N mice that develop gastrointestinal tumors spontaneously. These mice were provided with dox in their drinking water from the age of 3-8 months, where after they were analyzed for the development of intestinal tumors.
Results: We identified transgenic lines showing a tightly controllable dox-induced expression of Wnt5a in vitro and in vivo. Whereas induced Wnt5a expression appears well-tolerated in adult mice, the induction during embryonic development results in a severe embryonic phenotype. Induction of transgenic Wnt5a expression in the developing gastrointestinal tumors is successful. Despite this, the enhanced Wnt5a expression appears not to affect tumor number, tumor size or degree of malignancy. We observe a minor shift in the distribution pattern of the tumors towards a more distal intestinal location. Analysis of tumor cell proliferation and stromal content of the tumors shows no alteration upon Wnt5a induction.
Conclusions: We have successfully generated a transgenic model in which robust and tightly controllable Wnt5a expression can be induced upon dox administration. Although induced Wnt5a expression appears to be well-tolerated in adult animals, embryonic development is severely affected. Additionally we have successfully induced Wnt5a expression within the intestinal tumors developing in an Apc mutant model. Our results suggest that increased Wnt5a expression has no major effect on intestinal tumor growth in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2408. doi:10.1158/1538-7445.AM2011-2408