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The tyrp1-Tag/tyrp1-FGFR1-DN Bigenic Mouse

A Model for Selective Inhibition of Tumor Development, Angiogenesis, and Invasion into the Neural Tissue by Blockade of Fibroblast Growth Factor Receptor Activity

Benot Rousseau¹, Frédéric Larrieu-Lahargue¹, Sophie Javerzat¹, Frédéric Guilhem-Ducléon¹, Friedrich Beermann² and Andreas Bikfalvi¹

¹ Molecular Angiogenesis Laboratory, Institut National de la Santé et de la Recherche Médicale, Université de Bordeaux, Talence, France; and ² Swiss Institute for Experimental Cancer Research, National Center of Competence in Research Molecular Oncology, Epalinges, Switzerland

We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. Tyrp1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with tyrp1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in tyrp1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when tyrp1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the tyrp1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.