CD44 is the principal cell surface receptor for hyaluronic acid (HA), a ubiquitous ECM polysaccharide which profoundly influences stromal and infiltrating cell behavior and plays a major role in the maintenance of tissue homeostasis. HA accumulation is increased during periods of cell proliferation as in inflammation, tissue remodeling and regeneration, development and invasion by malignancy. CD44-HA interaction is therefore believed to regulate multiple cellular responses as a results of tumor formation in vivo and that this effect is CD44-HA interaction dependent. The applicant has observed expression of the intracellular domain of CD44 is required for tumor cell migration on HA and have shown that glycosylation provides a potent regulatory mechanism for CD44-HA interaction, affecting both the standard form of CD44 (CD44H) and differentially spliced exons encoding a segment of the membrane proximal domain. The applicant will determine the mechanisms by which glycosylation regulates CD44-HA interaction and identify specific carbohydrate groups which enhance or inhibit binding. Studies will extend these experiments to examine the effects of disrupting tumor cell CD44-ECM HA interaction using soluble recombinant CD44 and anti CD44 antibodies. Specifically, the applicant will address the role of CD44 in tumor cell adhesion to host tissue endothelium and stroma as well as in tumor angiogenesis. Finally, the applicant has developed a transgenic mouse model which has tissue specific CD44 deficiency in the skin. Availability of this model will provide the possibility to address the physiologic function of CD44 in HA metabolism, regulation of tissue homeostasis, inflammation and tumorigenesis.
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