17 beta -estradiol-mediated vessel assembly and stabilization in tumor angiogenesis requires TGF beta and EGFR crosstalk.

It is widely established that angiogenesis is required during tumor progression. Emerging data, suggests that estrogens can mediate endothelial proliferation and differentiation. We investigated the role of estrogens in the formation and stabilization of capillary-like structures, and identified 17 beta -estradiol-driven pathways involved in vessel assembly. We show that estrogens induce MCF7 breast cancer cells to secrete TGF beta 1. In addition, TGF beta cross talks with EGFR signaling pathway with concomitant up-regulation of EGFR ligand, TGF alpha, promoting cord-like formations in HUVEC cultures. The action of 17 beta -estradiol was not restricted to endothelium, since 17 beta -estradiol also stimulated recovery and migration of a smooth muscle cell line (FLTR) to injured areas again by the cross talk between these two signaling pathways. Finally, given the relevant role of 17 beta -estradiol in vessel stabilization, co-cultures of HUVEC and FLTR cells were established in the presence of 17 beta -estradiol or TGF beta 1. By blocking TGF beta or EGFR signaling, we demonstrate that 17 beta -estradiol promoted vessel stabilization through the interplay of TGF beta 1 and EGFR signaling transduction pathways. Our data suggest that estrogen mediates endothelial cell stabilization and vessel assembly. These vessel protective effects involve TGF beta 1 and EGFR signaling transduction pathways.