CD44 and its role in tumour progression and metastasis

Abstract

THE NATURE of the transmembrane glycoprotein molecule CD44 [l] and the role it plays in tumour development and progression are matters which are rapidly becoming of interest not only to basic researchers but also to cancer clinicians and pathologists. Initially identified and studied in many cell systems, CD44 was known by several synonyms, including phagocytic glycoprotein1 (Pgp-1) [2], extracellular matrix receptor III (ECM-III) [3], and HUTCH-l [4]. When these individual molecules were shown to be the same [C61, the name CD44 was assigned at the Third International Workshop on Leukocyte Differentiation Antigens [7]. Resolution of the cDNA sequence [8] revealed considerable homology with the cartilage link proteins involved in adhesion between hyaluronate and other proteoglycans in the extracellular matrix [9]. Subsequently, CD44 was found to have at least two functions, as a receptor for the glycosaminoglycan hyaluronate [lo] and as a lymphocyte homing receptor [ 11, 121. It was this latter role in the normal recirculation of lymphocytes that led, initially by analogy, to interest in the possible role of CD44 in regulating tumour cell dissemination. The standard or haemopoietic form of CD44 (CD44s), which is found predominantly on haemopoietic cells, is synthesised as a 37kD core protein which can be modified extensively by glycosylation and by addition of chondroitin sulphate [8, 13, 141. Epithelial cells produce a larger core protein form of CD44, CD44E, which is generated by alternative RNA splicing [8]. At present the ligand for CD44E remains unknown though, in direct contrast to CD44s, it has been shown not to facilitate binding to hyaluronate [15, 161. The discovery that alternative RNA splicing could lead to the generation of a larger epithelial isoform of CD44 was rapidly followed by the exciting findings of Gunthert et al. [ 171. A molecule expressed only on metastatic rat pancreatic carcinoma cells, compared with their benign counterparts, was shown to be another variant of CD44, designated CD44v or phleta-1. This variant was also generated by alternative splicing of the RNA, resulting in the addition of 162 amino acids into the same site as that used to generate CD44E [ 171. Subsequent investigations have revealed that the extensive isoform heterogeneity of CD44 is in fact a consequence of splicing choice from 10 variant exons [18, 191. Many of these variants have been shown to be expressed by a range of human tumour cell lines [20] suggesting that the association between isoform expression and metastatic behaviour, initially deter-