Inhibition of tumor angiogenesis by cell-permeable dominant negative SOX18 mutants

Angiogenesis play a key roles in tumor growth, invasion and metastasis, and has become an attractive target for anticancer drug development. Though a number of anti-angiogenic agents had entered clinical trials, few of them could reproduce the spectacular results in cancer patients as that had been seen in pre-clinical tumor models. Therefore, exploring novel anti-angiogenic agents is highly deserved. SOX18, a member of the Sry-related HMG box-containing family of transcription factors, is expressed transiently in endothelial cells during the development of blood vessels. And mutations resulting in expression of dominant negative SOX18 have been shown to severely impair the vascular development. Recent research demonstrated that SOX18 is expressed during the initial steps of tumor vascularization and involved in regulation of the expression of the VEGF receptor Flk-1 and the vascular cell adhesion molecule-1 (VCAM-1). Moreover, allograft tumor growth in mice heterozygous for Ra(Op) (RaOp mice) which express a dominant negative mutant form of SOX18 (SOX18RaOp) that does not interact effectively with the endothelial partner protein MEF2C, was dramatically slower than that of wild-type mice. In this article, we postulate that recombinant cell-permeable dominant negative SOX18 mutants, prepared by fusion with protein transduction domains, would inhibit tumor angiogenesis with high efficiency by impairing endothelial tube formation. If the hypothesis was proved to be practical, the fusion proteins would show promise as single anti-angiogenic agents in cancer therapy.