In the adult, aberrant neo-formation of lymphatic vessels (lymphangiogenesis) is associated with a wide range of pathological conditions such as inflammatory diseases, obesity and secondary lymphedema. Further, most solid tumours critically depend on neo-lymphangiogenesis for metastasis. Despite the integral role of neo-lymphangiogenesis in diseases, little is understood about its molecular basis and therefore how it might be managed pharmaceutically. We have recently discovered that the Sox18 gene acts as the master regulator of lymphatic vessel development in the embryo and demonstrated that it is also important for lymphangiogenesis at the onset of tumour metastasis and for lymphedema in humans.
　 With the view to unlocking innovative ways to pharmaceutically manage lymphangiogenesis, we have successfully developed a screening strategy to identify and characterise small inhibitory molecules able to modulate SOX18 protein activity. Using a pipeline of assays, ranging from in vitro fluorescence polarization technology to in vivo zebrafish screening and pre-clinical mouse model, we have discovered a novel class of small molecules that disrupt SOX18 ability to activate its target genes.
　 Our findings provide a basis for innovative pharmacological SOX18-based strategies to modulate neo-lymphangiogenesis. Further, our discovery raises the prospect of complementing anti-angiogenic treatment with an anti-lymphangiogenic approach, one of the most relevant therapies for cancer.
[Reference]
　 François et al., Nature. 456, 643, 2008;
　 Hosking / François, et al., Development. 136, 2385, 2009
　 François et al., Dev Biol. 364, 89, 2012
　 Duong et al., Cancer Res. 72, 3105, 2012.

【要旨を閉じる】