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J. Biol. Chem., Vol. 283, Issue 23, 15647-15655, June 6, 2008

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Carcinoembryonic Antigen and CD44 Variant Isoforms Cooperate to Mediate Colon Carcinoma Cell Adhesion to E- and L-selectin in Shear Flow^*

Susan N. Thomas, Fei Zhu, Ronald L. Schnaar, Christina S. Alves, and Konstantinos Konstantopoulos¹

From the Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218 and the Departments of Pharmacology and Neuroscience, The Johns Hopkins University, Baltimore, Maryland 21205

Selectin-mediated adhesion of tumor cells to platelets, leukocytes, and endothelial cells may regulate their hematogenous dissemination in the microvasculature. We recently identified CD44 variant isoforms (CD44v) as functional P-, but not E- or L-, selectin ligands on colon carcinoma cells. Moreover, an 180-kDa sialofucosylated glycoprotein(s) mediated selectin binding in CD44-knockdown cells. Using immunoaffinity chromatography and tandem mass spectrometry, we identify this glycoprotein as the carcinoembryonic antigen (CEA). Blot rolling assays and flow-based adhesion assays using microbeads coated with CEA immunopurified from LS174T colon carcinoma cells and selectins as substrate reveal that CEA possesses E- and L-, but not P-, selectin ligand activity. CEA on CD44-knockdown LS174T cells exhibits higher HECA-452 immunoreactivity than CEA on wild-type cells, suggesting that CEA functions as an alternative acceptor for selectin-binding glycans. The enhanced expression of HECA-452 reactive epitopes on CEA from CD44-knockdown cells correlates with the increased CEA avidity for E- but not L-selectin. Through the generation of stable knockdown cell lines, we demonstrate that CEA serves as an auxiliary L-selectin ligand, which stabilizes L-selectin-dependent cell rolling against fluid shear. Moreover, CEA and CD44v cooperate to mediate colon carcinoma cell adhesion to E- and L-selectin at elevated shear stresses. The novel finding that CEA is an E- and L-selectin ligand may explain the enhanced metastatic potential associated with tumor cell CEA overexpression and the supportive role of selectins in metastasis.

Received for publication, January 22, 2008 , and in revised form, March 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 CA101135 (NCI) (to K. K.). This work was also supported by a National Science Foundation graduate research fellowship (to S. N. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218. Tel.: 410-516-6290; Fax: 410-516-5510; E-mail: kkonsta1{at}jhu.edu.

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				S. N. Thomas, R. L. Schnaar, and K. Konstantopoulos Podocalyxin-like protein is an E-/L-selectin ligand on colon carcinoma cells: comparative biochemical properties of selectin ligands in host and tumor cells Am J Physiol Cell Physiol, March 1, 2009; 296(3): C505 - C513. [Abstract] [Full Text] [PDF]

				C. S. Alves, S. Yakovlev, L. Medved, and K. Konstantopoulos Biomolecular Characterization of CD44-Fibrin(ogen) Binding: DISTINCT MOLECULAR REQUIREMENTS MEDIATE BINDING OF STANDARD AND VARIANT ISOFORMS OF CD44 TO IMMOBILIZED FIBRIN(OGEN) J. Biol. Chem., January 9, 2009; 284(2): 1177 - 1189. [Abstract] [Full Text] [PDF]