Abstract
Abstract The purposes of the study: Colorectal (CRC) tumors depend on mediators in the tumor microenvironment, such as vascular endothelial growth factor, to promote angiogenesis. Norrin is a ligand that binds to the cell surface Frizzled-4 receptor, stimulating canonical Wnt signaling, and is known to mediate blood vessel growth in the eye and ear. We investigate here the role of Norrin secreted by colon cancer cells in endothelial cell growth and motility as well as the expression of the Norrin signaling pathway components in the CRC tumor microenvironment. Experimental procedures: Primary human umbilical vein endothelial cells (HUVEC) expressing green fluorescent protein and a HUVEC-derived endothelial cell line, EAhy926 were utilized for in vitro angiogenesis assays measuring cell motility and in vitro angiogenesis. Experiments were performed with and without the addition of Norrin-containing conditioned medium from a transfected CRC cell line CaCO2 and with and without blocking anti-Norrin antibodies. Tissue specimens from human CRC patients were evaluated with a double signal amplification system to define the expression of Norrin, Frizzled-4, LRP5 and TSPAN12 in tumor blood vessels. Summary of data: Blocking generated by the endothelial cells themselves Norrin reduced endothelial cell motility, branch point number during in vitro angiogenesis (1/sq. mm), and the network length (mm/sq. mm) during in vitro angiogenesis. Norrin conditioned medium produced by CRC cell line CaCO2 transfected with Norrin expression construct increased endothelial cell motility. Colorectal tumors express Norrin protein. Endothelial cells in the colorectal tumor blood vessels contain all of the components of the Norrin signaling pathway needed for the endothelial cells to respond to Norrin in the tumor microenvironment. Statement of the conclusions: This study presents both in vitro and in vivo data that colorectal tumors use Norrin protein as an alternative mechanism that promotes angiogenesis in the CRC tumor microenvironment. Citation Format: Kestutis Planutis, Marina Planoutene, Randall F. Holcombe. Norrin controls colon cancer angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1002. doi:10.1158/1538-7445.AM2014-1002
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