[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

5. THE ROLE OF CD44 AS A HYALURONAN RECEPTOR DURING TUMOR PROGRESSION

Thus far, several potential functions for CD44 interaction with hyaluronan have been discussed. As illustrated in figure 2B, hyaluronan could serve as a ligand support for CD44-mediated cell locomotion. This hypothesis is attractive because many of the same types of tumor cells expressing CD44, also express hyaluronan-stimulatory-activity, i.e., a capacity to induce hyaluronan synthesis in advance of the cell migration. Together with a capacity to stimulate fibroblast collagenase activity, these induction mechanisms could function to prepare a pathway for migration. Alternatively, CD44-mediated endocytosis

may function to remove adjacent stromal hyaluronan that acts as a barrier, or again, represent part of the "rolling" mechanism of endocytosis-mediated locomotion (58, 70). CD44– hyaluronan interactions may result in the assembly of a protective pericellular matrix. Such matrices may serve as a protective barrier or function to reduce homotypic cell-cell adhesion or even cell-matrix interactions. Do any of these potential CD44-mediated interactions participate in tumor progression in vivo? CD44 is upregulated in many tumors, including CD44H as well as other CD44 variant isoforms. Hyaluronan synthesis and deposition are also upregulated. In other words, the two critical components are present but, does this represent two independent activities or, do CD44–hyaluronan interactions occur?

In a recent study by Auvinen et al., human benign breast lesions displayed hyaluronan localized within the stroma, with all epithelial elements being negative (71). In cases of malignant mammary carcinoma, hyaluronan staining intensity was significantly elevated. However, in addition to intense staining within the tumor-associated stroma, hyaluronan was also observed associated with some of the malignant adenocarcinoma cells, both at the tumor cell surface as well as within intracellular sites. If, the adenocarcinoma cells are not synthesizing hyaluronan (as is often the case (50, 72)), this data would suggest that the more aggressive cells are binding and/or internalizing tumor-associated hyaluronan. Somewhat similar results were obtained in a recent study of human colorectal cancer (42). Again, there was a trend for elevation in hyaluronan staining intensity associated with increase in tumor grade. However, analysis of patients with hyaluronan associated with, or bound to, cells of the tumor epithelium was correlated with a low survival rate. Furthermore, multivariate analysis demonstrated that, in patients without metastases, only intensity of hyaluronan associated with tumor epithelium was a predictive indicator of survival. Hints of tumor cell binding of hyaluronan can also be observed in mouse mammary carcinoma following metastatic colonization of mesenteric tissue (50) and lung epithelium (53) described above, and possibly, the infiltrating malignant cells depicted in figure 2D. Thus, the more aggressive and invasive the tumor, the more likely that cells of the tumor parenchyma will be observed staining strongly for hyaluronan. That this epithelial-asssociated hyaluronan is bound or internalized via CD44 interactions is likely as epithelial-derived tumor cells typically synthesize little hyaluronan. CD44-mediated endocytosis has been shown to be primarily mechanism responsible for intracellular accumulation of hyaluronan in malignant as well as normal cell types (57, 73, 74). Lastly, as described above, inhibiting CD44 interaction with ligands, via the secretion of soluble CD44, resulted in the near complete inhibition of lung metastases (53).

In summary, tumor progression is associated with an increase in expression of CD44 as well as the principal CD44 ligand, hyaluronan. Further, progression also appears associated with malignant cells staining strongly for hyaluronan, likely bound to the tumor cell surface via CD44. Although CD44 has the potential to participate in tumor progression via a variety of mechanisms (lymphocyte homing receptor, a proteoglycan, receptor for other ligands, etc), its function as a hyaluronan receptor is likely its critical role in this disease. Development of methods to selectively inhibit CD44 – hyaluronan interactions will go a long way in definitively establishing the functional link between these interactions and their role in tumor progression.