Anti-Angiogenic Activity of Factors Secreted by Normal Fibroblasts of Hypoxia Tolerant and Cancer Resistant Blind Mole Rat Spalax: in Vitro Investigation

Blind subterranean mole rat Spalax evolved adaptive strategies to cope with hypoxia (1). Recent investigation from our laboratory demonstrated unusual resistance of Spalax to cancer either naturally occurring or induced by chemical carcinogens (2). Moreover, normal fibroblasts isolated from Spalax inhibit growth and kill broad spectrum of cancer cells either via direct co-cultivation or via conditioned medium (2). The vasculature is one of the tumor microenvironment components, and angiogenesis plays a pivotal role in tumor progression and development of metastatic lesion. We thus addressed the question whether secreted factors of Spalax fibroblasts may influence angiogenesis in vitro. Tube formation assay was used to compare effects of conditioned medium (CM) of Spalax and mouse fibroblasts on HUVEC (human umbilical vein endothelial cells) migration and formation of tube-like structures in 3D extracellular matrix. Tube formation was stimulated by mouse CM; nonetheless, it was significantly inhibited when HUVEC cells were exposed to Spalax CM. Secretome analysis of Spalax fibroblasts CM revealed increased level of multiple proteins with anti-angiogenic activity. Since mesenchymal stem cells may contribute to tumor angiogenesis, we investigated the effect of CM of adipose-derived stromal cells (ADSC) isolated from Spalax adipose tissue on HUVEC tube formation. Preliminary results did not show effect of Spalax ADSC CM on tube formation compared to untreated HUVEC. We conclude that Spalax fibroblasts inhibit tube formation in vitro in paracrine manner. Future studies will include the role of Spalax fibroblasts or its CM on intratumoral vessel formation by using xenographt model.

1. Shams, I., et al., 2005. FASEB J 19, 307-309.
2. Manov, I., et al., 2013. BMC Biol 11, 91.