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Journal of Cell Science 114, 3463-3477 (2001)
© 2001 The Company of Biologists Limited

RESEARCH ARTICLE

CD44-dependent lymphoma cell dissemination: a cell surface CD44 variant, rather than standard CD44, supports in vitro lymphoma cell rolling on hyaluronic acid substrate and its in vivo accumulation in the peripheral lymph nodes

Shulamit B. Wallach-Dayan1, Valentin Grabovsky2, Jürgen Moll3,*, Jonathan Sleeman3, Peter Herrlich3, Ronen Alon2 and David Naor1,{ddagger}

1 The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, 91120 Israel
2 Department of Immunology, The Weizmann Institute, Rehovot, 76100 Israel
3 Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Karlsruhe D-76021, Germany
* Present address: Pharmacia & Upjohn, via Pasteur 10, 1-20014 Nerviano (Milan), Italy

{ddagger}Author for correspondence (e-mail: naord{at}md2.huji.ac.il)

Accepted June 25, 2001

Cell motility is an essential element of tumor dissemination, allowing organ infiltration by cancer cells. Using mouse LB lymphoma cells transfected with standard CD44 (CD44s) cDNA (LB-TRs cells) or with the alternatively spliced CD44 variant CD44v4-v10 (CD44v) cDNA (LB-TRv cells), we explored their CD44-dependent cell migration. LB-TRv cells, but not LB-TRs or parental LB cells, bound soluble hyaluronic acid (HA) and other glycosaminoglycans (GAGs), and exclusively formed, under physiological shear force, rolling attachments on HA substrate. Furthermore, LB-TRv cells, but not LB-TRs cells or their parental LB cells, displayed accelerated local tumor formation and enhanced accumulation in the peripheral lymph nodes after s.c. inoculation. The aggressive metastatic behavior of i.v.-injected LB-TRV cells, when compared with that of other LB-transfectants, is attributed to more efficient migration to the lymph nodes, rather than to local growth in the lymph node. Injection of anti-CD44 monoclonal antibody or of the enzyme hyaluronidase also prevented tumor growth in lymph nodes of BALB/c mice inoculated with LB-TRv cells. The enhanced in vitro rolling and enhanced in vivo local tumor growth and lymph node invasion disappeared in LB cells transfected with CD44v cDNA bearing a point mutation at the HA binding site, located at the distal end of the molecule constant region. These findings show that the interaction of cell surface CD44v with HA promotes cell migration both in vitro and in vivo, and they contribute to our understanding of the mechanism of cell trafficking, including tumor spread.

Key words: Adhesion molecules, CD44, Cell motility, Cell rolling, Hyaluronic acid, lymphoma cells


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© The Company of Biologists Ltd 2001