Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors

Nagasaka, Susumu; Tanabe, Kenneth K.; Bruner, Janet M.; Saya, Hideyuki; Sawaya, Raymond; Morrison, Richard S.

doi:10.3171/jns.1995.82.5.0858

Cited by 34 publications

(19 citation statements)

References 30 publications

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“…These results are consistent with earlier studies showing that CD44s protein is the most dominant form of CD44 expressed in brain tumors. [35][36][37][38] On the other hand, CD44 cleavage product was clearly detected in 58% (32 of 55) of high-grade gliomas and 59% (10 of 17) of low-grade gliomas, suggesting its potential as a target for new diagnostic and therapeutic approaches. We and others have previously reported that CD44 cleavage promotes tumor cell migration in vitro.…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Cleavage of the CD44 Adhesion Molecule in Multiple Human Tumors

Okamoto

Tsuiki

Kenyon

et al. 2002

The American Journal of Pathology

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145

125

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Cell surface adhesion molecules are crucial for the development and/or pathogenesis of various diseases including cancer. CD44 has received much interest as a major adhesion molecule that is involved in tumor progression. We have previously demonstrated that the ectodomain of CD44 undergoes proteolytic cleavage by membrane-associated metalloproteases in various tumor cell lines. The remaining membranebound CD44 cleavage product can be detected using antibodies against the cytoplasmic domain of CD44 (anti-CD44cyto antibody). However, the cleavage of CD44 in primary human tumors has not been investigated. Using Western blots with anti-CD44cyto antibody to assay human tumor tissues, we show that the CD44 cleavage product can be detected in 58% (42 of 72) of gliomas but not in normal brain. Enhanced CD44 cleavage was also found in 67% (28 of 42) of breast carcinomas, 45% (5 of 11) of non-small cell lung carcinomas, 90% (9 of 10) of colon carcinomas, and 25% (3 of 12) of ovarian carcinomas. Tumors expressing a CD44 splice variant showed a significantly higher incidence of enhanced CD44 cleavage. CD44 is a widely distributed cell-surface adhesion molecule that is implicated in a diverse range of physiological and pathological processes, including lymphocyte homing and activation, cell-matrix interactions, cell migration, and the regulation of tumor growth and metastasis.1 The gene encoding the CD44 protein contains 20 exons of which up to 10 variant exons encoding a portion of the ectodomain are alternatively spliced in various combinations, thereby generating numerous CD44 splice variant isoforms (CD44v).1,2 The standard CD44 (CD44s) lacks all variant exons. All forms of CD44 are heavily glycosylated to varying degrees. The diversity of CD44 functions is compounded by its variable structure.3-5 The expression of CD44 or its variants has been shown to be associated with tumor progression; however, the data concerning CD44v forms is controversial for some tumors.1,6 -13 Thus, the exact role of CD44 in the progression of human tumors remains obscure and increased interest has been directed at elucidating the possible mechanisms by which CD44 plays a role in human tumors.The extracellular domain of a number of membrane proteins can be proteolytically cleaved on the extracytoplasmic side.14 The proteolytic cleavage of membrane proteins has recently emerged as a key mechanism underlying their functional regulation. 15 We have previously demonstrated a proteolysis-based model as one mechanism involved in the regulation of CD44 function. 16 -18 Our studies showed that CD44 is proteolytically cleaved at the ectodomain through membrane-associated metalloproteases in various cancer cell lines to produce a membrane-bound cleavage product of ϳ25 kd.16 This CD44 ectodomain cleavage was found to play a critical role in CD44-mediated tumor cell migration by regulating the dynamic interaction between CD44 and the extracel-

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Section: Discussionmentioning

confidence: 99%

Proteolytic Cleavage of the CD44 Adhesion Molecule in Multiple Human Tumors

Okamoto

Tsuiki

Kenyon

et al. 2002

The American Journal of Pathology

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145

125

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“…The interaction between glioma and brain ECM components is, however, extremely complex and remains poorly understood. The recent finding that the expression of CD44 directly correlates with the highly invasive behavior of gliomas (14) establishes CD44 protein expression and functions as potential central nervous system tumor markers (38,39). Accordingly, CD44-mediated HA binding at the cell surface of gliomas is thought to involve multivalent binding events affected by the size of the HA ligand, the quantity and density of cell surface CD44, and the activation state of CD44 (40).…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Annabi

Thibeault

Moumdjian

et al. 2004

Journal of Biological Chemistry

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Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesteroldepleting agent ␤-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.The principal molecules that have been identified in the normal brain extracellular matrix (ECM) 1 are hyaluronan (HA; also known as hyaluronic acid, hyaluronate) and chondroitin sulfate (1, 2). HA is an important glycosaminoglycan constituent believed to be implicated in angiogenesis, the formation of new blood vessels from preexisting vasculature. Although the serum level of HA is already used as an indicator of progressive malignant disease (3), its effects on in vivo angiogenesis and endothelial cell (EC) function are complex and have been reported to depend on HA concentration and molecular size (4, 5). Accordingly, whereas high molecular weight HA was shown to inhibit EC functions (6), low molecular weight HA stimulated EC proliferation, tubulogenesis (6, 7), and neovascularization (8). Moreover, small HA polymers efficiently regulated CD44 cell surface functional expression and promoted tumor cell migration (9). Astrocytic tumors of the central nervous system express CD44 among other cell adhesion receptors of the integrin or immunoglobulin superfamily. Although HA is the principal ligand of CD44, other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate, whereas mucosal addressin, serglycin, osteopontin, and the class II invariant chain represent ECM-unrelat...

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“…CD44s is the most abundant form of CD44 while other specific splice variants are found in only low amounts or not at all, which may contribute to the usually nonmetastatic behavior of malignant gliomas [28][29][30]. However, interactions of CD44s with hyaluronate as well as with basal lamina proteins such as laminin, fibronectin and collagen IV have been suggested to be an essential contributor to the invasive character of primary brain tumors [9,18,19,21,31,32] giving CD44s a central role in glioma tumor cell invasion along vessels which are a main route for neoplastic cell invasion reflected by the finding that laminin, collagen IV and fibronectin are potent stimulators of glioma cell motility [6,7,17,33,34].…”

Section: Discussionmentioning

confidence: 99%

Expression of Adhesion Factors and Degrading Proteins in Primary and Secondary Glioblastomas and Their Precursor Tumors

Tews

Nissen²

1998

Invasion Metastasis

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In tumor tissue specimens of 27 primary and 17 secondary glioblastomas and the precursor lesions, the immunohistochemical expression patterns of the membrane protein CD44s, the basal lamina proteins laminin, collagen IV, and fibronectin, the lectin galectin-3 recognizing tenascin and N-CAM as well as of the matrix-degrading enzymes matrix metalloproteinase MMP-2 and MMP-9, and cathepsin D were studied. Besides expression of basal lamina proteins in vessels, all glioblastomas and the precursor lesions showed strong immunoreactivity of CD44s, tenascin, galectin-3, and N-CAM which were restricted to solid tumor masses. Present in solid tumor areas, MMP-2, MMP-9 and cathepsin D were also strongly expressed by single tumors cells invading adjacent brain tissue at the infiltrative margin. Neither the expression pattern in primary and secondary glioblastomas nor in the precursor tumors revealed significant differences. There was also no intraindividual constant expression pattern during glioma progression or correlation with malignancy. Restricted expression of CD44s, galectin-3, tenascin and N-CAM in solid tumor masses seems to contribute to homotypic tumor cell adhesion while single tumor cells abolish this expression profile and acquire invasive activities by expression of cathepsin D, MMP-2 and MMP-9.

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Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors

Cited by 34 publications

References 30 publications

Proteolytic Cleavage of the CD44 Adhesion Molecule in Multiple Human Tumors

Proteolytic Cleavage of the CD44 Adhesion Molecule in Multiple Human Tumors

Hyaluronan Cell Surface Binding Is Induced by Type I Collagen and Regulated by Caveolae in Glioma Cells

Expression of Adhesion Factors and Degrading Proteins in Primary and Secondary Glioblastomas and Their Precursor Tumors

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