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Cell and Tumor Biology |
Departments of 1 Chemical and Biomolecular Engineering and 2 Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland; Departments of 3 Dermatology and 4 Medicine, Brigham and Women's Hospital; 5 Harvard Skin Disease Research Center, Harvard Medical School; and 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Requests for reprints: Robert Sackstein, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Room 671, Boston, MA 02115. Phone: 617-525-5601; Fax: 617-525-5571; E-mail: rsackstein{at}rics.bwh.harvard.edu or Konstantinos Konstantopoulos, Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218. Phone: 410-516-6290; Fax: 410-516-5510; E-mail: kkonsta1{at}jhu.edu.
Metastasis of circulating tumor cells requires a multistep cascade of events initiated by adhesion of tumor cells to the vascular endothelium of involved tissues. This process occurs under the forces of blood flow and is promoted by adhesion molecules specialized to interact under shear conditions. The endothelial molecule E-selectin is a major mediator of these adhesive events, and there is strong evidence that E-selectin receptor-ligand interactions contribute to the formation of metastasis. However, little is known about the identity of E-selectin ligand(s) expressed on cancer cells. To address this issue, we did SDS-PAGE analysis of membrane proteins, metabolic inhibition studies, and blot rolling assays of LS174T, a colon carcinoma cell line known to interact with E-selectin under physiologic flow conditions. Our studies show that LS174T cells express the hematopoietic cell E/L-selectin (HCELL) glycoform of CD44, which functions as a high-affinity E-selectin glycoprotein ligand on these cells. However, in contrast to the HCELL glycoform on human hematopoietic progenitor cells, which expresses carbohydrate-binding determinant(s) for E-selectin primarily on N-glycans of standard CD44, the relevant determinant(s) on LS174T cells is expressed on O-glycans and is predominantly found on variant isoforms of CD44 (CD44v). Our finding that tumor-associated CD44 splice variant(s) express E-selectin ligand activity provides novel perspectives on the biology of CD44 in cancer metastasis.
This article has been cited by other articles:
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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]
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 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]
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S. N. Thomas, F. Zhu, R. L. Schnaar, C. S. Alves, and K. Konstantopoulos Carcinoembryonic Antigen and CD44 Variant Isoforms Cooperate to Mediate Colon Carcinoma Cell Adhesion to E- and L-selectin in Shear Flow J. Biol. Chem., June 6, 2008; 283(23): 15647 - 15655. [Abstract] [Full Text] [PDF]
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V. A. Resto, M. M. Burdick, N. M. Dagia, S. D. McCammon, S. M. Fennewald, and R. Sackstein L-selectin-mediated Lymphocyte-Cancer Cell Interactions under Low Fluid Shear Conditions J. Biol. Chem., June 6, 2008; 283(23): 15816 - 15824. [Abstract] [Full Text] [PDF]
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 C. Suzuki and N. Kojima A Cholesterol-independent Membrane Microdomain Serves as a Functional Counter-receptor for E-selectin at the Colo201 Cell Surface and Initiates Signalling on E-selectin Binding J. Biochem., July 1, 2007; 142(1): 55 - 64. [Abstract] [Full Text] [PDF]
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 P. Auguste, L. Fallavollita, N. Wang, J. Burnier, A. Bikfalvi, and P. Brodt The Host Inflammatory Response Promotes Liver Metastasis by Increasing Tumor Cell Arrest and Extravasation Am. J. Pathol., May 1, 2007; 170(5): 1781 - 1792. [Abstract] [Full Text] [PDF]
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S. L. Napier, Z. R. Healy, R. L. Schnaar, and K. Konstantopoulos Selectin Ligand Expression Regulates the Initial Vascular Interactions of Colon Carcinoma Cells: THE ROLES OF CD44V AND ALTERNATIVE SIALOFUCOSYLATED SELECTIN LIGANDS J. Biol. Chem., February 9, 2007; 282(6): 3433 - 3441. [Abstract] [Full Text] [PDF]
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 S. Gout, C. Morin, F. Houle, and J. Huot Death Receptor-3, a New E-Selectin Counter-Receptor that Confers Migration and Survival Advantages to Colon Carcinoma Cells by Triggering p38 and ERK MAPK Activation. Cancer Res., September 15, 2006; 66(18): 9117 - 9124. [Abstract] [Full Text] [PDF]
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M. M. Burdick, J. T. Chu, S. Godar, and R. Sackstein HCELL Is the Major E- and L-selectin Ligand Expressed on LS174T Colon Carcinoma Cells J. Biol. Chem., May 19, 2006; 281(20): 13899 - 13905. [Abstract] [Full Text] [PDF]
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 R. C. Fuhlbrigge, S. L. King, R. Sackstein, and T. S. Kupper CD43 is a ligand for E-selectin on CLA+ human T cells Blood, February 15, 2006; 107(4): 1421 - 1426. [Abstract] [Full Text] [PDF]
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