Regulation of the release and function of tumor cell-derived soluble CD44

CD44, a major receptor for glycosaminoglycan hyaluronan (HA), is a broadly distributed cell surface glycoprotein implicated in multiple functions, including tumor growth and dissemination. The affinity of surface CD44 for HA is subject to regulation at several levels. CD44 is found in multiple phases, including as an integral transmembrane protein and as soluble fragment of the extracellular domain found in the circulation and other body fluids. Transmembrane CD44 and its ability to interact with HA have been a focus of numerous studies in the past, but the function of soluble CD44 remains obscure. Interestingly, malignant diseases are often associated with an increase in the plasma level of CD44. The delineation of the HA binding capacity of tumor-derived soluble CD44 is an important step toward understanding the biological function of this molecule. In this study, we demonstrate that tumor cells activated to bind HA by cytokines rapidly release CD44 upon treatment with phorbol ester (PMA). The affinity for HA of the soluble CD44 released in response to PMA varied depending on the cytokine pretreatment. These results suggest that the function of tumor-derived soluble CD44, like the transmembrane form of the receptor, can be regulated.