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Angiogenesis, Metastasis, and Cellular Microenvironment

Thombospondin-1 Disrupts Estrogen-Induced Endothelial Cell Proliferation and Migration and Its Expression Is Suppressed by Estradiol¹

Cancer Research Unit, VA Medical Center, Kansas City, MO and Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS

Requests for reprints: Sushanta K. Banerjee, Cancer Research Unit, Research Division 151, VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128. Phone: (816) 861-4700x7057; Fax: (816) 922-3320. E-mail: sbanerjee2{at}kumc.edu

The natural hormone 17ß-estradiol (17ß-E2) is known to induce tumor angiogenesis in various target organs by activating positive regulators of angiogenesis. In this study, we show for the first time that in human umbilical vein endothelial cells (HUVECs), 17ß-E2 transiently down-regulates the expression and secretion of a potent negative regulator of angiogenesis, thrombospondin-1 (TSP-1). This inhibitory effect of 17ß-E2 is mediated through nongenomic estrogen receptor (ER)/mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) 1/2 and c-Jun NH₂-terminal kinase (JNK)/stress-activated protein kinase (SAPK) signaling pathways, because this effect can be abolished by a pure ER antagonist (ICI 182,780) and inhibitors of downstream signaling proteins of MAPK signaling cascades, including MAPK kinase 1/2 and ERK1/2 inhibitor and JNK/SAPK inhibitor. To understand the functional role(s) of TSP-1 during estradiol-induced angiogenesis, we examined the growth and migration of endothelial cells in different experimental environments. Using a recombinant protein, we show that increments of TSP-1 protein concentration in culture medium significantly reduce the migration and proliferation of HUVECs stimulated by 17ß-E2. Together, these studies suggest that TSP-1 can be considered an important negative factor in understanding the increased angiogenesis in response to estrogens.

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