INTERACTION BETWEEN CD44 AND HYALURONATE IS DIRECTLY IMPLICATED IN THE REGULATION OF TUMOR-DEVELOPMENT

CD44 is implicated in the regulation of tumor growth and metastasis bu t the mechanism by which expression of different CD44 isoforms determi nes the rate of primary and secondary tumor growth remains unclear. In the present study we use a human melanoma transfected with wild-type and mutant forms of CD44 to determine which functional property of the CD44 molecule is critical in influencing tumor behavior. We show that expression of a wild-type CD44 isoform that binds hyaluronic acid aug ments the rapidity of turner formation by melanoma cells in vivo, wher eas expression of a CD44 mutant, which does not mediate cell attachmen t to hyaluronate, fails to do so. The importance of CD44-hyaluronate i nteraction in tumor development is underscored by the differential inh ibitory effect of soluble wild-type and mutant CD44-Ig fusion proteins on melanoma growth in vivo. Whereas local administration of a mutant, nonhyaluronate binding, CD44-Ig fusion protein has no effect on subcu taneous melanoma growth in mice, infusion of wild-type CD44-Ig is show n to block tumor development. Taken together, these observations sugge st that the tumor growth promoting property of CD44 is largely depende nt on its ability to mediate cell attachment to hyaluronate.