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The metastatic breast cancer cell line, 4T1, abundantly expresses the oligosaccharide sialylated Lewis x (sLe x ). SLe x oligosaccharide on tumor cells can be recognized by E-and P-selectin, contributing to tumor metastatic process. We observed that both selectins reacted with this cell line. However, contrary to the E-selectin reactivity, which was sLe x dependent, P-selectin reactivity with this cell line was sLe x -independent. The sLe x -Neg variant of the 4T1 cell line with markedly diminished expression of sLe x and lack of sLe a , provided a unique opportunity to characterize Pselectin ligands and their contribution to metastasis in the absence of overlapping selectin ligands and E-selectin binding. We observed that P-selectin binding was Ca 21-independent and sulfation-dependent. We found that P-selectin reacted primarily with cell surface chondroitin sulfate (CS) proteoglycans, which were abundantly and stably expressed on the surface of the 4T1 cell line. P-selectin binding to the 4T1 cells was inhibited by heparin and CS glycosaminoglycans (GAGs). Moreover, Heparin administration significantly inhibited experimental lung metastasis. In addition, the data suggest that surface CS GAG chains were involved in P-selectin mediated adhesion of the 4T1 cells to murine platelets and human umbilical vein endothelial cells. The data suggest that CS GAGs are also the major P-selectin-reactive ligands on the surface of human MDA-MET cells. The results warrant conducting clinical studies on the involvement of cell surface CS chains in breast cancer metastasis and evaluation of various CS types and their biosynthetic pathways as target for development of treatment strategies for antimetastatic therapy of this disease. ' 2006 Wiley-Liss, Inc.Key words: P-selectin; chondroitin sulfate; breast cancer; cell-cell adhesion Breast cancer metastasis represents a terrible milestone associated with a poor prognosis. The multistep process of metastasis includes release of malignant cells from the primary neoplasm, migration of cancer cells into the blood circulation, interaction with platelets and leukocytes in circulation, adhesion to the vascular endothelium in distant organs and growth of the disseminated cancer cells within the vessels or within the tissue following extravasation.1-3 Each step in this process requires different types of interactions between cancer cells and the host microenvironment.A widely accepted hypothesis is that cancer cells exploit the adhesion molecules used by hematopoietic cells to migrate into distant organs. 4 In particular, the selectin family of adhesion molecules whose ligands, sialyl Lewis x (sLe x ) and sialyl Lewis a (sLe a ), are expressed at elevated levels on various cancer cells of human and murine origin 5-9 and play a significant role in cancer metastasis. The oligosaccharides sLe x and sLe a are the prime ligands for P-and E-selectin and many published works underscore the relative importance of interactions between sLe x/a and these vascular receptors in the hematogenous spread ...

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