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.
Soares
Raquel
R
IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal. raquel.soares@ipatimup.pt
Guo
Shanchun
S
Gärtner
Fátima
F
Schmitt
Fernando C
FC
Russo
Jose
J
D000313:Adrenal Medulla / Q000166:cytology; D000818:Animals; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology; D002417:Cattle; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D005786:Gene Expression Regulation; D006801:Humans; D007797:Laminin / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D020239:Receptor Cross-Talk; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D004965:Estrogen Antagonists; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C059485:matrigel; D000077267:Fulvestrant; D004958:Estradiol; D003094:Collagen; D066246:ErbB Receptors