Dual targeting of tumor and endothelial cells by Gonadotropin-Releasing Hormone agonists to reduce melanoma angiogenesis

We previously showed that GnRH receptors are expressed in melanoma cells; their activation reduces the cell growth and metastatic behavior. Here, we investigated whether GnRH agonists might affect the expression of genes involved in melanoma progression. By genome wide transcriptomic and by Real Time PCR analysis we first observed that GnRH agonists decrease the expression of the pro-angiogenic factor VEGF (all isoforms) in BLM melanoma cells. Then, we demonstrated that GnRH agonists specifically decrease the expression of the VEGF165 isoform as well as its secretion from BLM cells. These data suggested that activation of GnRH receptors might reduce the pro-angiogenic behavior of melanoma cells. To verify this hypothesis we treated BLM cells with a GnRH agonist; the conditioned medium from these cells was tested to assess its capability to stimulate HUVEC cells motility. The migration of HUVEC cells towards the conditioned medium of GnRH agonist-treated BLM cells was significantly lower than the migration of HUVEC cells towards the conditioned medium of untreated cells. Thus, GnRH agonists reduce the pro-angiogenic behavior of melanoma cells through a decreased production of VEGF. We then found that GnRH receptors are also expressed on HUVEC cells and that GnRH agonists reduce their ability to proliferate and to form capillary-like tubes when stimulated by VEGF. These findings suggest that GnRH agonists exert anti-angiogenic activity indirectly, by decreasing VEGF secretion from tumor cells, and directly, by counteracting the pro-angiogenic activity of the growth factor. These data might lead to the development of novel targeted approaches for melanoma.