INTERFERON LAMBDA 2 PROMOTES MAMMARY TUMOR METASTASIS VIA ANGIOGENESIS EXTENSION AND STIMULATION OF CANCER CELL MIGRATION

Myeloid-derived suppressor cells (MDSCs) support tumor development by stimulation of angiogenesis and immune response inhibition. In our previous study, we showed that interferon lambda 2 (IFN-lambda 2), secreted by MDSCs, enhances production of pro-angiogenic factors by cancer cells via phosphorylation of STAT3 and therefore promotes blood vessels formation. In the present study IFN-lambda 2 level was evaluated by ELISA in serum of tumor-bearing mice, whereas its expression in MDSCs isolated from the lungs with metastatic tumors and normal lungs was assessed by qPCR. The effect of IFN-lambda 2 on mouse mammary cancer cells motility was tested in Boyden chamber migration assay. In order to evaluate its pro-angiogenic function we performed in vitro tubule formation assay and in ovo angiogenesis assay on chicken embryo chorioallantoic membrane (CAM). Moreover, in order to design small molecule inhibitors of IFN-l 2 and its receptor we performed molecular modeling followed by the identification of potential natural inhibitors. Then, we examined their ability to inhibit angiogenesis in vitro. Our results showed that IFN-lambda 2 predisposed mouse mammary cancer cells to migration in vitro. It also enhanced angiogenesis induced by mouse mammary cancer cells in vitro and in ovo. For the first time we selected potential IFN-lambda 2 inhibitors and we validated that they were capable to abolish proangiogenic effect of IFN-lambda 2, similarly to blocking antibodies. Therefore, IFN-lambda 2 and its receptor may become targets of anti-cancer therapy, but their mechanism of action requires further investigation.