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CD44 on LS174T Colon Carcinoma Cells Possesses E-Selectin Ligand Activity

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.

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