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

Cell motility is an essential element of tumor dissemination, allowing orga n infiltration by cancer cells. Using mouse LB lymphoma cells transfected w ith standard CD44 (CD44s) cDNA (LB-TRs cells) or with the alternatively spl iced 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 (GA GS), and exclusively formed, under physiological shear force, rolling attac hments on HA substrate. Furthermore, LB-TRv cells, but not LB-TRs cells or their parental LB cells, displayed accelerated local tumor formation and en hanced accumulation in the peripheral lymph nodes after s.c. inoculation. T he aggressive metastatic behavior of i.v.-injected LB-TRV cells, when compa red with that of other LB-transfectants, is attributed to more efficient mi gration to the lymph nodes, rather than to local growth in the lymph node. Injection of anti-CD44 monoclonal antibody or of the enzyme hyaluronidase a lso 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 CD4 4v cDNA bearing a point mutation at the HA binding site, located at the dis tal end of the molecule constant region. These findings show that the inter action 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 c ell trafficking, including tumor spread.