Introduction: The importance of the interaction between tumor cells and stromal tissue for tumor invasion and metastasis is becoming well-recognized lately. In this respect, tumor-associated macrophages are of special interest as they appear to promote angiogenesis and invasiveness. One of the factors expressed at increased levels by macrophages in intestinal tumors is noncanonical Wnt5a. Interestingly, despite the 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 that Wnt5a is involved in tumor cell growth and migration, angiogenesis and epithelial to mesenchymal transition, all key steps in cancer progression. At present, it is however unclear 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. Currently, the contribution of transgenic Wnt5a expression during the development of intestinal tumors in Apc mutant mice is being analyzed. Successful induction of Wnt5a expression in the developing tumors has been confirmed. Preliminary results suggest that induced Wnt5a expression underlies a shift in distribution pattern of the tumors along the gastrointestinal tract.

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, of which we are currently investigating the possible contribution to tumor progression.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4156.