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PubMed2001

Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid.

Proteolytic cleavage of the extracellular domain of CD44 from the surface of cells has been observed recently in different cell types. In cell culture supernatants of human melanoma cell lines a 70 kDa soluble CD44 protein (solCD44) was detected at concentrations of 250-300 ng/ml. Protease inhibitor studies revealed that serine proteases and metalloproteases are involved in the cleavage of CD44 from the surface of melanoma cells. To analyse a possible function of soluble CD44 a human malignant melanoma cell line was stably transfected with cDNAs encoding either wild type soluble CD44s or mutated forms with defective HA binding properties (CD44sR41A and CD44sR150A/R154A). Soluble CD44s almost completely inhibited hyaluronic acid binding by melanoma cells, whereas soluble CD44 mutated in the HA binding domain had no effect. When cultivated on hyaluronic acid, melanoma cell proliferation was induced by 30% for both the parental and the control transfected cells. This increase in proliferation was blocked completely in solCD44s-secreting transfectants, whereas solCD44sR41A and solCD44sR150A/R154A-secreting cells again showed hyaluronic acid-induced cell proliferation. These cell lines were subcutaneously injected into MF1 nu/nu mice to compare their growth as tumors in vivo. Compared to tumors derived from parental and control transfected cells, we observed a dramatic reduction of primary tumor growth with solCD44s expressing MM cells. Transfectants expressing solCD44s mutated in the HA binding domain in contrast developed fast-growing primary tumors. These results provide strong evidence that direct solCD44 interactions with hyaluronic acid interfere competitively with processes induced by hyaluronic acid binding to surface CD44. Autocrine, or drug-induced secretion of solCD44 by human melanoma cells may thus exert potent antitumoral effects in vivo.

Animals↗

PubMed1997

Interferons alpha/beta inhibit IL-7-induced proliferation of CD4- CD8- CD3- CD44+ CD25+ thymocytes, but do not inhibit that of CD4- CD8- CD3- CD44- CD25- thymocytes.

Type 1 interferons (IFN-alpha/beta) have recently been shown to inhibit interleukin-7 (IL-7)-induced growth and survival of early B-lineage cells. The CD3- CD4- CD8- (triple negative; TN) thymocytes from normal mice strongly proliferated upon stimulation with IL-7 in suspension, culture. Such an IL-7-induced proliferation was suppressed by the addition of IFN-alpha/beta, but a fraction of the TN thymocytes still showed proliferation. The IL-7-induced growth of TN thymocytes from acid mice, which lack the CD44- CD25- subpopulation, was completely inhibited by the addition of IFN-alpha/beta. The IL-7 induced proliferation of CD4- CD8- thymocytes from T-cell receptor (TCR) transgenic mice, the majority of which are CD3+ CD44- CD25-, was resistant to IFN-alpha/beta-mediated suppression. In fetal thymus organ cultures (FTOC), the addition of IL-7 greatly increased the population of CD4- CD8- CD44+ CD25+ thymocytes and IFN-alpha/beta inhibited this IL-7-driven expansion. In contrast, the addition of IL-7 markedly decreased the percentages of CD4- CD8- CD3- CD44- CD25- cells, and IFN-alpha/beta reversed the effect and increased the subpopulations of CD44- CD25+ and CD44- CD25-. Finally, IFN-beta mRNA was found to be expressed in the thymus. The data suggest that type I interferons inhibit IL-7-driven proliferation of TN thymocytes, but do not block the normal differentiation process.

Animals↗

PubMed2004

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy.

We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.

Animals↗

PubMed1997

Regulation of CD44-protein 4.1 interaction by Ca2+ and calmodulin. Implications for modulation of CD44-ankyrin interaction.

Erythrocyte membrane skeletal protein 4.1 isoforms have been identified in a variety of non-erythroid cells. However, interactions between protein 4.1 and its binding partners in non-erythroid cell membranes are poorly understood. In the erythrocyte membrane, protein 4.1 binds to the cytoplasmic domain of band 3 and, through this interaction, modulates ankyrin binding to band 3. The sequences LRRRY or IRRRY in band 3 mediate the interaction between band 3 and protein 4.1. The cytoplasmic domain of CD44, a transmembrane glycoprotein found in erythroid as well as non-erythroid cells, has internal sequences SRRRC and QKKKL. We wanted to determine if protein 4.1 binds to CD44 in a fashion analogous to its binding to band 3 and through this interaction modulates ankyrin binding to CD44. We report here that protein 4.1 binds to the cytoplasmic domain of CD44 with a dissociation constant on the order of 10(-7) M and that Ca2+ and calmodulin reduce the affinity of this interaction. Furthermore, although independent binding of both protein 4.1 and ankyrin to CD44 could be documented, binding of protein 4.1 prevented subsequent ankyrin binding. These studies have enabled us to identify a potentially important functional role for protein 4.1 in modulating ankyrin binding to CD44.

Ankyrins↗

PubMed1998

Ratio of CD44 epithelial variant to CD44 hematopoietic variant is a useful prognostic indicator in gastric and colorectal carcinoma.

BACKGROUND: The CD44 is a cell adhesion molecule that is present as numerous isoforms created by mRNA alternative splicing. Expression of variant isoforms of CD44 is associated with tumor growth and metastasis. The aim of this study was to evaluate whether CD44 isoform expression is a prognostic factor in gastric and colorectal cancer. METHODS: We performed a polymerase chain reaction analysis following reverse transcriptase treatment for CD44 expression in fresh surgical specimens obtained from 25 colon carcinomas and 30 gastric carcinomas and matched adjacent normal mucosa. We determined the epithelial variant/hematopoietic variant (E/H) ratio (the amount of the CD44 epithelial variant transcript relative to the CD44 hematopoietic variant transcript) in cancer tissues and examined it for correlations with clinicopathological parameters and survival rate. RESULTS: The E/H ratio in tumor tissue was significantly higher than that in adjacent non-cancerous mucosa. In gastric and colorectal cancer tissues, there was no significant relationship between E/H ratio and clinicopathological parameters. However, patients who died due to tumor recurrence had a higher E/H ratio than surviving patients with colorectal cancer. In gastric cancer, patients with high E/H tumors had a shorter survival time than those with low E/H tumors. CONCLUSIONS: Our results suggest that the E/H ratio is a useful indicator of prognosis in gastric and colorectal carcinoma.

Adult↗

PubMed1994

The significance of CD44 in human pancreatic cancer: II. The role of CD44 in human pancreatic adenocarcinoma invasion.

In our previous report (1), we showed the high expression of CD44 in human pancreatic adenocarcinomas cells. Pancreatic cancer aggressively invades surrounding tissues by penetrating basement membrane barriers. To examine the relation between the biological characteristics of human pancreatic adenocarcinoma cells and CD44 expression, we studied the function of CD44 in cell proliferation and cell invasion using a Matrigel basement membrane. The proliferation of human pancreatic adenocarcinoma cells was not affected by anti-CD44 antibody. On the contrary, invasion of the cells was suppressed by anti-CD44 antibody. This result suggests that the CD44 molecule plays an important role in pancreatic cancer cell invasion of the basement membrane.

Adenocarcinoma↗

PubMed1997

Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation.

CD44 is a broadly distributed polymorphic glycoprotein that serves as the principal cell-surface receptor for hyaluronate. Although CD44-mediated cell interaction with hyaluronate has been implicated in a variety of physiologic events, including cell-cell and cell-substrate adhesion, cell migration, proliferation, and activation, as well as hyaluronate uptake and degradation, the biologic role of CD44 in vivo in various tissues remains to be determined. In the present work we have developed transgenic mice that express an antisense CD44 cDNA driven by the keratin-5 promoter. These mice lack detectable CD44 expression in skin keratinocytes and corneal epithelium and display abnormal hyaluronate accumulation in the superficial dermis and corneal stroma, distinct morphologic alterations of basal keratinocytes and cornea, and defective keratinocyte proliferation in response to mitogen and growth factors. These alterations are reflected by a decrease in skin elasticity, impaired local inflammatory response and tissue repair, delayed hair regrowth, and failure of the epidermis to undergo hyperplasia in response to carcinogen. Our observations indicate that two major functions of CD44 in skin are the regulation of keratinocyte proliferation in response to extracellular stimuli and the maintenance of local hyaluronate homeostasis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1994

Expression of integrins and CD44 isoforms in non-Hodgkin's lymphomas: CD44 variant isoforms are preferentially expressed in high-grade malignant lymphomas.

Low- and high-grade malignant non-Hodgkin's lymphomas have been investigated by immunohistochemistry for their expression of various integrins and CD44 isoforms. Comparison with the expression patterns obtained in non-malignant adult lymph nodes revealed the following differences: alpha 6 and beta 4 integrins were expressed in several high-grade malignant lymphomas to a lower degree than in both the low-grade malignant lymphomas and the normal lymph nodes; all other integrins (alpha 2, alpha 4, alpha 5, alpha v, beta 1, beta 2, beta 3, and beta 7) did not exhibit significant differences in the expression levels between malignant and non-malignant tissues. The standard isoform of CD44 (CD44s) was highly expressed in all lymphoid tissues. Using CD44 exons-specific monoclonal antibodies, CD44 variant isoforms were not detected in non-malignant lymph nodes and were detected only rarely in low-grade malignant lymphomas. In contrast, high-grade malignant lymphomas expressed several CD44 variant isoforms, which included the products from the variant exons 3v, 6v, and 9v, but not 4v. Specifically, detection of exon 3v and 6v products indicates a more aggressive phenotype.

Adult↗

PubMed1999

Alternatively spliced CD44 isoforms containing exon v10 promote cellular adhesion through the recognition of chondroitin sulfate-modified CD44.

Correlations have been noted between the expression of certain alternatively spliced CD44 isoforms and the metastatic propensity of various histologically distinct tumor cell types. The precise mechanism by which particular CD44 isoforms contribute to the metastatic process is, however, unclear. In the present study we demonstrate that CD44R2, a CD44 isoform highly expressed on activated and transformed hemopoietic cells, can recognize and bind a common determinant present on CD44H and CD44R1. Importantly, CD44H lacked this activity. Pretreatment of TIL1 cells expressing CD44H or CD44R1 with chondroitinase ABC inhibited adhesion to CD44R2, suggesting that the unique inserted region present within the CD44R2 molecule, encoded by exon v10, mediates cell adhesion by potentiating the recognition of chondroitin sulfate moieties presented in association with other CD44 molecules. These data help explain the differential involvement of v10-containing CD44 isoforms in tumor metastasis.

Adjuvants, Immunologic↗

PubMed1997

Regulation of CD44 isoform expression and CD44-mediated signaling in human dendritic cells.

Dendritic cells (DCs) express CD44, a cell surface receptor for the extracellular matrix ligand hyaluronate, involved in cell-cell interactions and cell migration. Besides the "standard" form of CD44, a variety of splice variants contain an additional extracellular region encoded by 10 "variable" exons termed v1 to v10. The standard form of CD44 as well as variants containing exon v6 (CD44v6) are known to play important roles in the immune system, yet largely unexplored in the DC lineage. In this study, we examined the regulation of CD44 isoforms in human DCs derived from monocytes cultivated in the presence of GM-CSF and IL-4. We found that v3, v6 and v9 variants are all up-regulated upon TNF-alpha stimulation of DCs. In addition, we show that stimulation of DCs using anti-CD44 mAbs can induce DC agregation, up-regulation of accessory molecule expression and secretion of cytokines. A mAb directed against CD44v6 variants was shown to mediate some of these effects.

Antibodies, Monoclonal↗

PubMed1994

Hyaluronan and CD44 in psoriatic skin. Intense staining for hyaluronan on dermal capillary loops and reduced expression of CD44 and hyaluronan in keratinocyte-leukocyte interfaces.

The distributions of hyaluronan (HA) and its presumptive receptor, CD44, were studied in skin samples from 13 psoriasis vulgaris patients, using an HA-specific probe (HABC), and monoclonal antibodies, respectively. The general distribution of HA and CD44 in psoriatic lesional epidermis resembled that in normal epidermis. However, areas of epidermis invaded by leukocytes showed a local depletion of HA and CD44, particularly at the contact areas of keratinocytes to lymphocytes and neutrophils. Removal by cellular uptake or extracellular degradation of CD44 and HA may be required for tight adherence between a keratinocyte and a leukocyte. On the dermal side, the tips of the prolonged dermal papillae in psoriatic lesions were intensively stained with HABC. The dilated capillaries and the space below the tip basal lamina, in particular, were heavily covered with HA. Occasionally, a similar intense staining was seen around an enlarged capillary in uninvolved psoriatic skin. CD44-positive leukocytes were found around the affected capillaries. The accumulation of HA in the dermal papillae may support the growth of psoriatic lesions, since HA stimulates the growth of capillaries as well as attracting inflammatory cells.

Adult↗

PubMed1992

The complex CD44 transcriptional unit; alternative splicing of three internal exons generates the epithelial form of CD44.

We have utilized the polymerase chain reaction (PCR) to isolate a 3.5 kilobase pair (kb) genomic fragment that encodes the additional extracellular domain unique to the epithelial isoform of CD44 (CD44E). Nucleotide sequence was determined for this complete region and sequence comparison to our previously determined CD44R1 and CD44R2 cDNA sequences revealed the R region to be comprised of three exons of 102 bp, 90 bp, and 204 bp. Northern blot analysis of CD44 expressing cell lines confirmed the presence of CD44R1 transcripts and indicates that the epithelial domain may be inserted through alternative splicing into all CD44 transcript classes. Southern blot analysis of the CD44E genomic fragments is consistent with a single copy per human haploid genome. The data presented here further supports our model of the human CD44 transcriptional unit as a single gene complex that utilizes an invariant 5' initiation site, alternative internal and 3' end splicing, and multiple poly (A) sites to generate through RNA processing a diverse number of human CD44 isoforms.

Amino Acid Sequence↗

PubMed1995

Homotypic cell aggregation via conformational change of CD44 molecule induced by anti-CD44 monoclonal antibodies.

The homotypic cell aggregation of leukocytes is an unique adhesive event which is caused by cellular activation. Anti-CD44 monoclonal antibody (mAb) induces homotypic cell aggregation of hematopoietic cell lines expressing CD44, but the mechanism of homotypic cell aggregation is poorly understood. We used four mAbs against CD44: TL-1 which was newly developed and seemed to react with a non-hyaluronate binding site, OS/37 and BU52 which recognized a hyaluronate binding site, and Hermes-3 which recognized a non-hyaluronate binding site. TL-1 treatment induced strong homotypic cell aggregation in several types of cell lines including a B cell line from a patient with leukocyte adhesion deficiency syndromes (LAD) and normal peripheral blood lymphocytes (PBL). OS/37 and BU52 also induced weak homotypic cell aggregation. None of these anti-CD44 mAbs-induced homotypic cell aggregations was blocked by antibodies against LFA-1, ICAM-1, VLA-4, or L-selectin. Interestingly, the TL-1-induced homotypic cell aggregation was blocked by Hermes-3 or OS/37, but not by BU52. BU52-induced homotypic cell aggregation was blocked by Hermes-3 or OS/37, but not by TL-1. OS/37-induced homotypic cell aggregation was blocked by Hermes-3, TL-1 or BU52. The blocking experiments with anti-metabolic agents revealed that the induced homotypic cell aggregation was energy-dependent and associated with intracytoplasmic actin filaments. This homotypic cell aggregation did not require de novo protein synthesis, because it was not affected by pretreatment with either cycloheximide or actinomycin D. FACS analysis revealed that TL-1 binding did not affect the intensity of expression of the CD44 molecule on the cell surface.

Animals↗

PubMed2005

Chemotaxis towards hyaluronan is dependent on CD44 expression and modulated by cell type variation in CD44-hyaluronan binding.

The accumulation of the extracellular matrix glycosaminoglycan hyaluronan by tumours and tumour-associated stroma promotes cancer cell invasion and metastasis. Using the Dunn chamber chemotaxis assay, we demonstrate for the first time that high molecular mass hyaluronan acts as a soluble chemoattractant promoting the directional migration of MDA-MB-468 and MDA-MB-231 breast cancer cells. Moreover, chemotaxis towards hyaluronan, but not foetal bovine serum, can be abrogated following treatment of the cells with siRNA oligonucleotides to downregulate CD44 expression. These data indicate that CD44 is the principal receptor mediating this response and that CD44 expression is not a general requirement for cell migration and gradient sensing, rather it elicits a ligand-specific response. However, expression of CD44 alone is not sufficient to drive chemotaxis towards hyaluronan, as NIH-3T3 fibroblasts were unable to respond to a hyaluronan gradient even when transfected with high levels of human CD44. For NIH-3T3 cells to bind exogenous hyaluronan, it was necessary to both increase the level of receptor expression and remove a hyaluronan pericellular matrix. Together, these studies reveal a direct mechanism for promoting cell invasion into the hyaluronan-rich matrix and predict that in the complex multicellular environment in vivo, multiple mechanisms exist to regulate the ability of a cell to respond to a chemotactic hyaluronan gradient.

Animals↗

PubMed2003

Monoclonal antibodies with defined recognition sequences in the stem region of CD44: detection of differential glycosylation of CD44 between tumor and stromal cells in tissue.

CD44 is an enigmatic cell adhesion molecule acting as a major receptor for hyaluronan and playing roles in many biological and pathological processes such as lymphocyte homing, T-cell activation, wound healing, angiogenesis, and metastatic spread of tumor cells. However, the complexity of the molecule, with its alternatively spliced variants, extensive glycosylation, and processing by different proteases, has hampered detailed analysis. In this study, we prepared four monoclonal antibodies (285-2F12, 284-43F1, 268-1F5, and 294-6F2) and one polyclonal antibody (C6) that recognize defined sequences in the stem region of CD44H. Interestingly, two of the monoclonal antibodies, 268-1F5 and 294-6F2, failed to recognize the CD44 expressed in five of the seven human tumor cell lines examined by Western blotting. Treatment of the samples with a combination of neuraminidase and O-glycosidase as well as the expression of mutants with site-directed mutations at possible modification sites rendered the CD44 reactive to the antibodies. Thus, the reactivity of the antibodies is sensitive to O-glycosylation presumably near the recognition sites. Glycosylation of CD44 that affects reactivity to the antibodies was found to be regulated differentially between tumor and stromal cells in two breast and three oral carcinoma tissues. Antibody 268-1F5 reacted to the tumor cells, but not to the cells in the surrounding stroma. On the other hand, the reactivity of 294-6F2 to the cells was opposite between the two tumor types. Thus, these sets of antibodies are useful to detect and analyze the as-yet-unknown roles of site-specific glycosylation of CD44, particularly in tumors.

Amino Acid Sequence↗

PubMed1990

Homotypic cell aggregation induced by anti-CD44(Pgp-1) monoclonal antibodies and related to CD44(Pgp-1) expression.

The present study shows that a mAb (H4C4) developed against human peripheral blood adherent cells has the unusual property of inducing in vitro homotypic aggregation of several types of hemopoietic cells and cell lines. The Ag recognized by mAb H4C4 is a 85-kDa glycoprotein that corresponds to the human Ag CD44 (equivalent to murine Pgp-1), as determined by protein purification, immunologic cross-reactivity studies, and tryptic fragment sequencing. In addition to H4C4, other mAb directed against some, but not all, epitopes of CD44(Pgp-1) were capable of inducing cell aggregation. This process was temperature sensitive and was almost totally abrogated by cytochalasin B but was unaffected by sodium azide, colchicine, EGTA, trifluoperazine, or staurosporin. A role for CD44 (Pgp-1) in cell-to-cell adhesion was further indicated by an inverse relationship observed between spontaneous aggregation of some hemopoietic cell lines and cell-surface expression of CD44(Pgp-1). These observations provide evidence for a fundamental role of CD44(Pgp-1) in cellular aggregation phenomena with an involvement of the cytoskeleton.

Amino Acid Sequence↗

PubMed2002

A genetic marker within the CD44 gene confirms linkage at 11p13 in African-American families with lupus stratified by thrombocytopenia, but genetic association with CD44 is not present.

Systemic lupus erythematosus (SLE) is complicated from both a clinical and genetic standpoint. We have stratified SLE families by the presence of thrombocytopenia, which is associated with increased mortality among SLE patients, and found genetic linkage at chromosome 11p13 in African-American families. In the present study we have evaluated CD44, a gene very close (0.5 cM) to the peak LOD score marker, as a candidate gene. Using a newly identified short DNA repeat within the CD44 gene, we find a LOD score of 2.7, which confirms linkage within this genetic interval. However, using a panel of four single nucleotide markers spanning the CD44 gene, we find no genetic association with SLE. Therefore, these data further suggest an SLE susceptibility gene at 11p13, but also imply that an ancestral mutation in the CD44 gene does not account for the linkage.

Black People↗

PubMed2006

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation.

Cancer progression is associated with enhanced directional cell migration, both of the tumour cells invading into the stroma and stromal cells infiltrating the tumour site. In cell-based assays to study directional cell migration, phorbol esters are frequently used as a chemotactic agent. However, the molecular mechanism by which these activators of protein kinase C (PKC) result in the establishment of a polarized migratory phenotype is not known. Here we show that CD44 expression is essential for chemotaxis towards a phorbol ester gradient. In an investigation of CD44 phosphorylation kinetics in resting and stimulated cells, Ser316 was identified as a novel site of phosphorylation following activation of PKC. PKC does not phosphorylate Ser316 directly, but rather mediates the activation of downstream Ser316 kinase(s). In transfection studies, a phosphorylation-deficient Ser316 mutant was shown to act in a dominant-negative fashion to impair chemotaxis mediated by endogenous CD44 in response to a phorbol ester gradient. Importantly, this mutation had no effect on random cell motility or the ability of cells to migrate directionally towards a cocktail of chemoattractants. These studies demonstrate that CD44 functions to provide directional cues to migrating cells without affecting the motility apparatus.

Amino Acid Sequence↗