[Frontiers in Bioscience 3, d604-615, July 1, 1998]
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THE ROLE OF CD44 AS A CELL SURFACE HYALURONAN RECEPTOR DURING TUMOR INVASION OF CONNECTIVE TISSUE

Warren Knudson

Department of Biochemistry, Department of Pathology, Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612-3864

Received 4/27/98, Accepted 5/15/98

2. INTRODUCTION

The articles in this series focus on the role and significance of CD44 in tumor progression and metastasis. CD44 is a cell surface, single-pass transmembrane glycoprotein. CD44 is expressed by a wide variety of cell types; from dermal fibroblasts to transitional epithelial cells, lymphocytes to macrophages, articular chondrocytes to neural glial cells (1, 2). As with the diversity of CD44-expressing cell types, the purported functions for CD44 are also diverse. Through an interaction with the lining adhesion molecule mucosal vascular addressin, CD44 functions as a homing receptor, targeting lymphocytes to the high endothelial venules of the peripheral lymph node (3, 4). As such, CD44 has been designated by other names including; In[Lu]-related p80, Pgp-1, Hermes antigen, HUTCH-1 and H-CAM (5). In other cells, CD44 functions as a "part time" proteoglycan expressing a chondroitin sulfate or heparan sulfate glycosaminoglycan side chain (6, 7). Although intriguing, it is not clear whether the critical aspect of the glycosaminoglycan addition is to modify a functional aspect of CD44 or provide a unique glycosaminoglycan-related role. By far the greatest interest in CD44 has been in relation to its function as a binding protein (i.e., "receptor") for the extracellular matrix macromolecule hyaluronan (a.k.a., hyaluronic acid, hyaluronate). The distal extracellular domain of CD44 contains a B loop motif, homologous to the functional binding domain present on other hyaluronan binding proteins e.g., aggrecan and link protein (1, 7). Although hyaluronan is considered the principal CD44 ligand, other macromolecules have been described that exhibit specific binding to CD44 including; chondroitin, chondroitin sulfate and collagen types I and VI (5, 8). These observations have yielded at least one additional designation for CD44 as the extracellular matrix receptor type III (ECM-III). The interaction of CD44 with the latter ligands have been considered of low affinity (and thus of less importance). This may be somewhat misleading as, in actual fact, the monovalent interaction of CD44 with hyaluronan is also of somewhat low affinity. In studies where it has been carefully examined, the binding affinity (Km) of solubilized hyaluronan receptor derived from SV-3T3 cells (representative of monovalent binding of hyaluronan to CD44) was 7.5 times lower than the Km observed on intact membranes (conditions that allow for multivalent interactions) (9). Data such as these led to the suggestion that the apparent high affinity for CD44/hyaluronan binding (~10-9 M) is due to multivalent binding of hyaluronan to several CD44 receptor sites (together with the high molecular mass and regular repeating structure of hyaluronan). Thus, hyaluronan/CD44 interactions have been considered to be of most importance physiologically. This physiological significance has been confirmed from studies suggesting hyaluronan/CD44 interactions are directly involved in various hyaluronan-dependent cellular functions such as cell migration, matrix assembly, matrix:cell signaling and matrix endocytosis (1).

The question remains, why the interest in CD44 in tumor progression and metastasis? There are perhaps two reasons. First, using monoclonal antibodies to screen for epitopes present on a metastatic pancreatic carcinoma cell line (but not present on the non-metastatic cell line), Gunthert et al., isolated a novel isoform of CD44--an alternatively spliced isoform termed CD44v6 (10). When an antibody specific to the variant CD44 isoform (CD44v6) was co-injected with the metastasizing cells, metastatic growth of the pancreatic carcinoma was inhibited and host survival was prolonged (11). Interest in CD44 variant isoforms peaked when it was found that non-metastatic tumor cells transfected with CD44v6 metastasized efficiently to lymph nodes (10). Since these, now seminal observations, numerous studies have documented the prevalence as well as diagnostic/prognostic value of CD44 variant isoforms in human cancer (e.g., (12-14)).

A second line of interest in CD44 relates more to the ligand hyaluronan. Several tumors, particularly those of human solid cancers as will be discussed below, are often enriched in hyaluronan (15). There has always been a question of whether the increase in tumor-associated hyaluronan provides an advantageous role in tumor progression or an inhibitory role. As data became available that tumor cell expression of CD44 was also upregulated as compared to cells of their tissue of origin (as illustrated in an immunostained section of human breast carcinoma, figure 2A), a possible link began to emerge. Further, tumor cells not only express a receptor capable of interacting with hyaluronan but also exhibit a capacity to stimulate or direct the neo-synthesis of hyaluronan. In this review, the focus will be on this linkage, namely, between tumor cell expression of CD44 and the aberrant levels of hyaluronan that accumulate within tumor tissue. Are they related and do they serve to facilitate tumor progression and metastasis?