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At least 199 records · Page 11Linked to original sources
PubMed2006

CD44 disruption prevents degeneration of the capillary network in obstructive nephropathy via reduction of TGF-beta1-induced apoptosis.

CD44 is a glycoprotein that is involved in inflammation and cell-cell/cell-matrix interactions, is upregulated in the kidney upon injury, and leads to fibrosis through enhancement of TGF-beta1 signaling. Absence of CD44 prevents development of renal fibrosis in unilateral ureteral obstruction (UUO). A hallmark of development of renal fibrosis is the degeneration of the capillary network. This study shows that CD44 is upregulated on capillary endothelial cells during UUO. For elucidation of the role of CD44 on peritubular endothelial cells in UUO, capillary network degeneration was compared in CD44+/+ and CD44-/- mice. As expected, degeneration of the capillary network was observed in CD44+/+ mice during UUO, associated with increased endothelial apoptosis. However, in the absence of CD44, degeneration of the network is prevented as a result of a decrease in the rate of apoptosis in endothelial cells. The divergence in endothelial apoptosis is not correlated to differential vascular endothelial growth factor or thrombospondin-1 expression. For further investigation of capillary regression, CD44+/+ and CD44-/- peritubular capillary endothelial cell lines were established. With the use of these cells, it is shown that interaction between CD44 and its ligand hyaluronic acid enhances the proapoptotic effect of TGF-beta1 but not thrombospondin-1 on endothelial cells, contributing to the degeneration of the capillary network. Blocking interaction between hyaluronic acid and CD44 therefore may be a potential therapeutic opportunity to preserve the capillary network and prevent the development of fibrosis in chronic renal disease.

Animals↗
PubMed1996

De novo CD44 expression by proliferating mesangial cells in rat anti-Thy-1 nephritis.

CD44 is the major cell-surface receptor for hyaluronan, and cell-matrix interactions mediated by the CD44/hyaluronan receptor-ligand pair are involved in a variety of cellular functions, including cell migration. The aim of the study presented here was to examine the expression of CD44 and hyaluronan in the mesangial proliferative response in rat anti-Thy-1 nephritis. In normal rat kidney, CD44 is expressed by medullary tubules, some distal tubules and thick ascending limbs of Henle, dendritic-like cells around Bowman's capsule, and some interstitial cells. However, only occasional CD44+ cells were found within the glomerular tuft. In experimental nephritis, there was an early glomerular influx of CD44+ macrophages, which peaked on Day 4 after anti-Thy-1 antibody injection. A striking finding was de novo CD44 expression by mesangial cells. This CD44 expression was restricted to the transient period of mesangial cell proliferation as shown by double-staining with an antibody against the proliferating cell nuclear antigen. Immunohistochemistry staining also demonstrated hyaluronan deposition within segmental areas of proliferating CD44+ cells, suggesting a functional interaction between the CD44/hyaluronan receptor-ligand pair during mesangial cell proliferation. In vitro, rat mesangial cells were shown to express mRNA and protein for the 90-kd isoform of CD44. In addition, hyaluronan-dependent aggregation of CD44+ mesangial cells was specifically inhibited by an anti-CD44 antibody, demonstrating a functional interaction between hyaluronan and the CD44 expressed on the surface of rat mesangial cells. In conclusion, these data suggest that cell-matrix interactions mediated by the CD44/hyaluronan receptor-ligand pair are involved in mesangial cell proliferation in rat anti-Thy-1 nephritis.

Animals↗
PubMed2006

Involvement of endothelial CD44 during in vivo angiogenesis.

CD44, a cell-surface receptor for hyaluronan, has been implicated in endothelial cell functions, but its role in the formation of blood vessels in vivo has not been established. In CD44-null mice, vascularization of Matrigel implants and tumor and wound angiogenesis were inhibited. Leukocyte accumulation during tumor growth and wound healing in wild-type and CD44-null mice were comparable, and reconstitution of CD44-null mice with wild-type bone marrow did not restore the wild-type phenotype, suggesting that impairments in angiogenesis in CD44-deficient mice are due to the loss of endothelial CD44. Although the cell proliferation, survival, and wound-induced migration of CD44-null endothelial cells were intact, these cells were impaired in their in vitro ability to form tubes. Nascent vessels in Matrigel implants from CD44-null mice demonstrated irregular luminal surfaces characterized by retracted cells and thinned endothelia. Further, an anti-CD44 antibody that disrupted in vitro tube formation induced hemorrhage around Matrigel implants, suggesting that antagonism of endothelial CD44 undermined the integrity of the endothelium of nascent vessels. These data establish a role for CD44 during in vivo angiogenesis and suggest that CD44 may contribute to the organization and/or stability of developing endothelial tubular networks.

Animals↗
PubMed1995

Induction of a hyaluronan receptor, CD44, during embryonal carcinoma and embryonic stem cell differentiation.

This paper describes the expression profile of the CD44 glycoprotein during differentiation of embryonal carcinoma (EC) and embryonic stem (ES) cells. We have recently shown that CD44 is expressed in discrete embryonic structures and, in view of this, we sought an in vitro differentiation model of development in which we could study more readily the structure and function of the CD44 molecule. The P19 EC and CGR8 ES cells were chosen as they have the capacity to develop down the cardiac muscle pathway and we have previously demonstrated that CD44 is expressed abundantly in the embryonic myocardium. The differentiation process in both cell types is accompanied by an induction of CD44 mRNA and protein. However, in differentiated cultures CD44 is not expressed in contractile cells, indicating that these P19 cells do not represent CD44-positive embryonic cardiomyocytes. Expression of CD44 is observed on fibroblast-like cells which appear to migrate over and out from the plated aggregates. Hyaluronan, the major ligand for CD44, is also associated with these CD44-positive fibroblast-like cells. It is suggested that expression of both receptor and ligand by the fibroblast cells is required for cell:matrix adhesion and cell motility. As CD44 is up-regulated in these cultures, P19 cells are now established as a useful model system to study the factors regulating expression of the CD44 gene.

Alternative Splicing↗
PubMed2004

Role of CD44 and hyaluronan in neutrophil recruitment.

Lymphocyte CD44 interactions with hyaluronan localized on the endothelium have been demonstrated to mediate rolling and regulate lymphocyte entry into sites of chronic inflammation. Because neutrophils also express CD44, we investigated the role of CD44 and hyaluronan in the multistep process of neutrophil recruitment. CD44(-/-) and wild-type control mice were intrascrotally injected with the neutrophil-activating chemokine, MIP-2, and leukocyte kinetics in the cremasteric microcirculation were investigated 4 h subsequently using intravital microscopy. Neither the rolling flux nor the rolling velocities were decreased in CD44(-/-) mice relative to wild-type mice. In vitro, neutrophils did not roll on the CD44 ligand hyaluronan, consistent with the in vivo data that CD44/hyaluronan did not mediate rolling. However, the number of adherent leukocytes in the venule was decreased by 65% in CD44(-/-) mice compared with wild-type mice. Leukocyte emigration was also greatly decreased in the CD44(-/-) mice. The same decrease in adhesion and emigration was observed in the wild-type mice given hyaluronidase. Histology revealed neutrophils as being the dominant infiltrating population. We generated chimeric mice that express CD44 either on their leukocytes or on their endothelium and found that CD44 on both the endothelium and neutrophils was important for optimal leukocyte recruitment into tissues. Of those neutrophils that emigrated in wild-type and CD44(-/-) mice, there was no impairment in migration through the interstitium. This study suggests that CD44 can mediate some neutrophil adhesion and emigration, but does not appear to affect subsequent migration within tissues.

Animals↗
PubMedDate not supplied

Recent advances in the regulation of CD44 expression and its role in inflammation and autoimmune diseases.

Interaction of CD44, an adhesion molecule, with its extracellular matrix ligand, hyaluronan (HA), has been suggested to play a critical role in a number of biological manifestations, including cell migration, tumorigenesis, metastasis, and regulation of immune responses. CD44 comprises a large family of transmembrane glycoproteins that exhibit extensive molecular heterogeneity. This heterogeneity in size is generated by alternative RNA splicing of variable exons as well as by post-translational modifications. Most cell types express CD44 but do not bind HA. The biological functions of CD44, including the regulation of lymphocyte recruitment to the sites of inflammation, have been attributed to the generation of a functionally active, HA-adhesive phenotype. The molecular mechanisms underlying the regulation of CD44 expression and the generation of a functionally active HA-binding phenotype are not well understood. Recently, CD44-HA interactions have been reported to play a critical role in a number of autoimmune diseases in humans and experimental animal models. Initial studies have taken advantage of anti-CD44 antibodies which specifically block CD44-HA interactions. Administration of these antibodies in several experimental murine models of autoimmune diseases resulted in alleviation of inflammatory reactions. In addition, the generation of CD44-deficient animals has facilitated our understanding of the involvement of CD44 in inflammation and autoimmune diseases. This review will focus on the recent advances in the molecular mechanisms regulating CD44 expression, ligand binding, as well as the contribution of CD44 to the development of inflammation and autoimmune disorders.

Alternative Splicing↗
PubMedDate not supplied

Expression of the CD44 glycoprotein (lymphocyte-homing receptor) in untreated human breast cancer and its relationship to prognostic markers.

CD44 is a cell surface glycoprotein which has been suggested to be associated with aggressive histological features in breast cancer (BC). It has also been implicated in conferring metastatic potential to rat carcinoma cells. The aim of this study was to determine the potential value of CD44 as a prognostic/metastatic marker in BC by means of immunohistochemistry. The expression of the CD44 glycoprotein was investigated in tumours from 52 untreated female patients with BC, using the monoclonal antibody A3D8. 10 samples of normal breast tissue were randomly obtained and also investigated with respect to CD44 expression. DNA ploidy, the S-phase fraction (SPF) and oestrogen-(OR) and progesterone-receptor (PgR) contents in the tumours were determined and together with the prognostic markers of age, tumour size, tumour grade and lymph node status, correlated with CD44 expression in BC. Also, the distribution of CD44 tumour cell expression was compared with expression of the permeability drug resistance glycoprotein (P-gp) in this material. Expression of CD44 on carcinoma cells was observed in 21/52 cases (40%). Capillary endothelial reactivity of the tumours occurred in 42 cases (80%). Non-neoplastic epithelial breast tissue was positive in 2/10 (20%) samples and capillary vessels in 7/10 (70%). Carcinoma CD44 cell expression was not associated with age, tumour size, tumour grade, DNA ploidy, SPF, hormone-receptor contents or lymph node metastases. There was a statistical correlation between CD44 and P-gp expression in breast carcinoma cells which may suggest a connection between adhesion molecules and drug resistance. These findings do not support an association between CD44 expression and adverse prognostic features or lymph node metastases in BC. Capillary CD44 staining was a common feature in BC. There appeared to be an upward regulation in CD44 expression in BC compared with the normal breast tissue.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Altered patterns of CD44 epitope expression in human chronic and acute myeloid leukemia.

Abnormal expression of different isoforms of CD44 has been found to characterize many types of malignant cells although data for human acute and chronic myeloid leukemia is limited. In this study, we have identified significant, albeit variable, increases in these diseases of the frequency of both light density and CD34+ cells expressing two particular CD44 epitopes, neither of which is commonly found on normal human marrow cells. One of these epitopes is unique to exon v10-containing isoforms of CD44. The other is located in the common region of CD44 and was previously revealed on T cells only after their activation. Interestingly, another T cell activation-associated epitope was found to be expressed on a high proportion of normal marrow cells including the CD34+ subset and this remained the case for most of the primary leukemic samples evaluated. As expected, >90% of cells in all primary normal and leukemic samples expressed high levels of CD44, as shown by their reactivity with an antibody specific for the CD44 hyaluronan-binding site. To begin investigating how expression of the CD44 epitopes seen more commonly on leukemic than on normal CD34+ cells may be modulated, and to identify potentially associated effects on the hyaluronan-binding ability of the CD44 expressed, the effect of phorbol ester treatment on these properties of CD44 were examined. For these studies, a panel of five different human leukemic cell lines that were found to exhibit different patterns of CD44 expression and function in the absence of phorbol ester were used. Both the level and the hyaluronan-binding properties of CD44 could be stimulated in some, but not all, of these leukemic cell lines. Taken together, our findings indicate that CD44 expression is perturbed in a variety of leukemic populations suggesting a possible relationship to some of the pathogenetic features they share.

Biomarkers, Tumor↗
PubMedDate not supplied

High CD44 expression on human mesotheliomas mediates association with hyaluronan.

PURPOSE: Malignant pleural mesothelioma is a rare malignancy with major environmental implications regarding passive asbestos exposure. We have conducted an immunohistochemical and functional study to address three questions: (1) What is the representation of CD44 on tumor cells as detected by immunohistochemistry? (2) Do cultured cell lines derived from malignant pleural mesothelioma tissue express the same CD44 phenotypes as the original tumors, and can they serve as a model for the study of CD44 in mesotheliomas? (3) What is the functional status of the CD44 expressed on mesotheliomas, with regard to hyaluronan anchorage? MATERIALS AND METHODS: Thirty-seven samples of pleural mesothelioma were obtained from patients entered on phase I/II protocols conducted in the Surgery Branch of the National Cancer Institute since 1991. The diagnosis was confirmed in all 37 patients by means of a battery of immunohistochemical tests for markers differentiating malignant pleural mesothelioma from adenocarcinoma. Tumor-positive lymph nodes and distant metastases were also examined in six of the patients. Cell lines, established from tumor tissue of six of the patients described above, were used in these experiments. Four (H2596, H2461, H2373, H2452) were derived from primary solid tumors and two (HP-1 and HP-3) were derived from effusions. RESULTS: Immunohistochemical staining with a monoclonal antibody (H4C4) that recognizes a constant region of human CD44 demonstrated that 34 (92%) of the malignant pleural mesotheliomas examined expressed CD44 on 50% to 100% of their cells. The extent of CD44 expression was apparently related to histologic subtype with the highest expression seen in epithelioid mesotheliomas and the least in sarcomatoid tumors. Tumor cell lines established from the primary tumors or effusions of six of the malignant pleural mesothelioma patients showed high expression of the hematopoietic form of CD44. Four of these cell lines exhibited strong attachment to hyaluronan in an in vitro attachment assay, indicating that their CD44 was functional with respect to hyaluronan anchorage. Hyaluronan attachment was specific in that it could be abolished by preincubation with epitope-specific anti-CD44 antibodies or soluble substrate or by hyaluronidase treatment of attachment surfaces. CONCLUSIONS: We conclude that CD44 is highly expressed on human mesotheliomas, that cell lines adequately represent tumor expression, and that CD44 mediates association with hyaluronan, a major component of pleural fluid.

Antibodies, Monoclonal↗
PubMed1997

Expression of CD44 and variant isoforms in cultured human retinal pigment epithelial cells.

PURPOSE: CD44 is a major hyaluronic acid receptor that exists as a number of isoforms, generated by alternative splicing of 9 "variant" exons in humans (v2 to v10) and 10 exons in rodents. Little is known about the expression and function of CD44 in human retinal pigment epithelium (RPE) cells. Therefore, the authors determined whether human RPE cells express CD44, and whether the expression differs depending on the proliferative status of the cells. METHODS: Human RPE cells were harvested from normal donor eyes and propagated in culture. Total RNA was extracted from cultured cells. mRNA expression of CD44 was determined by reverse transcription-polymerase chain reaction (RT-PCR), followed by cloning and sequencing of the PCR products, and by Southern hybridization. CD44 cell surface expression was measured by flow cytometry. Western hybridization and immunohistochemistry were used to determine the CD44 immunoreactivity of cultured human RPE cells and normal human RPE cells in situ. RESULTS: The standard form of CD44 mRNA and variant isoforms containing exon v6 or v10 were expressed in cultured human RPE cells. CD44 mRNA and protein levels were increased in proliferating human RPE cells compared with density-arrested counterparts. Addition of 1 microM retinoic acid enhanced the cell density-induced downregulation of CD44 mRNA, but did not significantly affect the CD44 cell surface protein expression. As previously reported, CD44 immunoreactivity was not detected in normal human RPE cells in situ. CONCLUSIONS: Cultured human RPE cells express CD44 standard form and variant isoforms containing exon v6 or v10, which are preferentially expressed by proliferating human RPE cells.

Blotting, Western↗
PubMed1996

CD44 expression in dysplastic epithelium and squamous-cell carcinoma of the esophagus.

The molecular events involved in the development of esophageal dysplasia and carcinoma are poorly understood. We examined the expression of CD44, a cell-adhesion molecule, in normal and dysplastic epithelia and in squamous-cell carcinoma (SCC) of the esophagus. A monoclonal antibody (MAb) which recognized all CD44 isoforms and 2 MAbs specific to the CD44v3 and CD44v6 splice variants were used to detect CD44 isoforms in 50 archival specimens. A semi-quantitative scoring system based on the extent and intensity of the immunostaining was used to quantify CD44 expression. In normal epithelium, expression of CD44 was strongest in the basal-cell layer and weak or absent in surface cells. Expression of CD44 was increased in dysplastic epithelium as compared with normal epithelium. The extent of this increase correlated directly with the severity of dysplasia. CD44 was expressed in all SCCs, but the extent and intensity of immunostaining varied with areas of tumor differentiation. The well-differentiated components showed greater CD44 expression than the moderately and poorly differentiated components. The patterns of expression of CD44v3 and CD44v6 were strikingly similar to that of total CD44 in normal, dysplastic and malignant esophageal epithelia. Thus, changes in expression of these splice variants likely account to some extent for the changes in total CD44 expression observed in the dysplastic and malignant transformation of the esophagus. Our results suggest that changes in the expression of CD44 may be involved in the development of esophageal dysplasia as well as SCC.

Carcinoma, Squamous Cell↗
PubMed1996

CD44 protein levels and its biological activity are regulated in Balb/c 3T3 fibroblasts by serum factors and by transformation with the ras but not with the sis oncogene.

CD44s (standard isoform) levels and hyaluronan-binding activity were investigated in Balb/c 3T3 cells and their derivatives transformed with ras or sis oncogenes as a function of serum concentration in the medium. 3T3 cells contained low levels of CD44 and did not bind hyaluronan when grown in medium containing 0.5 or 10% serum. In 5% serum, however, the cells had much higher levels of CD44 and were able to bind hyaluronan. CD44 levels also increased in 3T3 cells restimulated with either 5 or 10% serum after prior maintenance in low serum. In cells restimulated with 5% serum, high levels of CD44 were sustained for at least 72 hr. In cells restimulated with 10% serum, however, the increase in CD44 levels reverted by 48 hr. Transformation of 3T3 cells with ras (but not with sis) oncogene rendered CD44 levels insensitive to serum modulation: ras-transformed cells contained high levels of CD44 and bound hyaluronan at all serum concentrations and at all time points tested. Sis-transformed cells behaved like 3T3 cells in these modulatory changes. Platelet-derived growth factor (PDGF), when supplementing 0.5% serum, mimicked the effects of serum on the levels and hyaluronan-binding capacity of CD44 in 3T3 cells and the CD44-upregulating activity of serum was neutralized by incubation with anti-PDGF antibodies. These data demonstrate that serum factors, specifically PDGF, mediate regulation of CD44 levels in BAlb/c 3T3 cells and that transformation of 3T3 cells by ras renders CD44 expression insensitive to the modulating effects of serum in vitro. These results correlate with the metastatic capacity of these cells in vivo.

3T3 Cells↗
PubMed1993

Antibody-induced activation of the hyaluronan receptor function of CD44 requires multivalent binding by antibody.

CD44 can function as a receptor for hyaluronan (HA). However, many cell lines and normal hematopoietic cells that express CD44 do not constitutively bind HA. A monoclonal antibody (mAb) specific for CD44 (IRAWB 14) has been described previously which induces CD44-mediated binding of HA rapidly (seconds to minutes) in some cell lines and in normal murine T cells. Of 16 CD44-specific mAb tested in the present study, only 3 exhibited this activity. Monovalent Fab fragments were prepared from two IgG2a antibodies that induce HA binding (IRAWB 14 and IRAWB 26) and used to determine whether multivalent binding was required for induction of HA receptor function. Fab from both antibodies had a tendency to form multivalent aggregates. After addition of iodoacetamide to prevent further aggregation, multimeric and monovalent forms were separated by gel filtration. This made it possible to compare the inducing activity of monovalent and multivalent antibody fragments of identical composition in the absence of Fc determinants. Multimeric forms were very active at inducing binding of fluorescein-conjugated HA (Fl-HA). Monovalent Fab fragments of both antibodies had 20- to 50-fold lower binding activity than intact antibody or multimer. IRAWB 26 Fab monomers were completely inactive in the induction of HA-binding. The observed weak inducing activity of IRAWB 14 Fab monomer could be attributed to very low levels of contaminating multimer. Induction of HA binding could also be achieved by using anti-immunoglobulin to cross-link Fab monomers of IRAWB 26. Thus, multivalent binding was required for the activation of HA binding by CD44-specific antibody, suggesting that the distribution of CD44 molecules on the cell surface is important for HA receptor function. In kinetic studies, induction of HA receptor function occurred simultaneously with antibody binding at 0 degrees C (ice water bath). Furthermore, antibody could induce HA binding in paraformaldehyde-fixed cells, which were permeable to propidium iodide and trypan blue, suggesting that intracellular signaling mechanisms were not involved in induction of receptor function. We conclude, therefore, that these CD44-specific antibodies are inducing HA binding by directly influencing the distribution of CD44 on the cell surface. The possibility of a concurrent change in CD44 conformation is not ruled out. We discuss possible mechanisms by which CD44 might be activated to bind HA in vivo.

Animals↗
PubMed2000

Adhesion of lymphoid cells to CD44-specific substrata: the consequences of attachment depend on the ligand.

Interactions between cell-surface adhesion receptors and immobilized specific substrata can exert profound effects on cell morphology. Using phase-contrast microscopy, we show that CD44-expressing mouse lymphoid cells display a spread morphology when adhering to CD44-specific monoclonal antibody (mAb) immobilized on plastic. This spread morphology is different from that of these same cells when adhering to immobilized hyaluronan, the natural ligand of CD44. Morphometric measurements, in combination with intracellular actin staining and fluorescence microscopy, revealed that the adhesion of lymphoid cells to hyaluronan required essentially no cytoskeletal reorganization and resulted in no fundamental change in morphology. On the other hand, cells adhering to immobilized CD44-specific mAb rearranged their actin structure and established multiple membrane contact sites (spread). Cell spreading on antibody, but not attachment to hyaluronan, was inhibited by cytoskeleton-disrupting agents. Transfection of CD44-negative lymphoid cells with full-length and tailless CD44 enabled these cells to bind to both immobilized hyaluronan and mAb. However, the transfectant lacking the cytoplasmic tail of CD44 spread only transiently on the antibody-coated surface. Our results suggest that CD44 may mediate lymphocyte attachment to its carbohydrate ligand hyaluronan by mechanisms broadly similar to those used by selectins. When immobilized CD44-specific antibody is the ligand, however, CD44 may regulate the activity of the cytoskeleton by mechanisms broadly similar to those used by integrins. In the latter case, the cytoplasmic domain of CD44 contributes to cell spreading.

Actins↗
PubMed2000

Clear cell carcinoma of the ovary: characterization of its CD44 isoform repertoire.

OBJECTIVE: CD44 is a cell surface receptor implicated in tumor metastases. We have previously shown that there is a loss of CD44 splice control in clear cell carcinoma (CCCa) of the ovary. Our aim is to characterize the expression of CD44-3v, -5v, -7v, and -10v in clear cell ovarian tumors and to determine their prognostic value. METHODS: Twenty-two cases of ovarian CCCa were studied for CD44-3v, -5v, -7v, and -10v expression by immunocytochemistry. RESULTS: The primary tumors showed expression of CD44-3v, -5v, -7v, and -10v in 44, 55, 61, and 39% of the cases, respectively. We were able to compare the expression of CD44 in the primary tumor and metastatic sites from the same patient in 7 cases (metastatic sites n = 16). We observed decreased immunoreactivity of CD44-3v, -5v, -7v, and -10v in 67, 100, 93, and 92% of the sites, respectively. CD44-3v and -10v expression was absent in 100% of the nonaffected contralateral ovaries while -7v and -10v were expressed in 1/11 (9%) of them. When CD44-10v was not expressed in the primary tumor, only 18% of the women recurred or died of disease; in contrast, of the cases where it was present, 71% of the women recurred or died of disease (P = 0.049). CONCLUSIONS: There is aberrant alternative mRNA splicing in the development of CCCa of the ovary when compared to the contralateral nonaffected ovary. The expression of CD44-10v correlates with survival. Larger series are needed to further understand the role of CD44 isoforms in ovarian cancer metastases.

Adenocarcinoma, Clear Cell↗
PubMed1996

CD44 isoform expression in the diffuse neuroendocrine system. II. Benign and malignant tumors.

The membrane glycoprotein CD44 may be associated with aggressive behavior, dissemination, and poor prognosis of a variety of human tumors. In order to extend our knowledge on the expression and significance of CD44 in cells of the dispersed neuroendocrine system we investigated a spectrum of 134 neuroendocrine tumors, including pituitary adenomas, medullary thyroid carcinomas, parathyroid adenomas, pheochromocytomas, neuroblastomas, small-cell lung carcinomas, and bronchopulmonary, pancreatic, and gastrointestinal neuroendocrine tumors immunohistochemically for CD44 standard and variant exon-encoded gene products (CD44v3, -v4, -v5, -v6, -v9). Furthermore, we compared protein expression with that of CD44 mRNA by reverse-transcriptase PCR and Southern blot hybridization in a subset of tumors. Our results show that CD44 expression is correlated with the "histogenetic origin" of the appropriate neuroendocrine neoplasm. Endoderm-derived tumors generally express 3'-end CD44 variant exon-containing isoforms, whereas neural crest-derived tumors rarely are positive for CD44. Furthermore, we provide evidence that CD44 expression is not correlated with metastatic disease or a particular hormonal phenotype but exhibits an association with the degree of cellular differentiation. Thus, CD44 is not useful as marker for malignancy or prognosis. The number of patients with clinical follow-up data in our study was too small to allow definite conclusions about a possible correlation between CD44 expression and prognosis. But CD44 may help to better classify neoplasms with an unclear neuroendocrine phenotype.

Biomarkers, Tumor↗
PubMed2004

Effect of CD44 suppression by antisense oligonucleotide on attachment of human trabecular meshwork cells to HA.

The effects of suppression of CD44 by CD44-specific antisense oligonucleotide on attachment of human trabecular meshwork cells to hyaluronic acid (HA) were observed and the possible relationship between CD44 and primary open-angle glaucoma (POAG) investigated. CD44-specific antisense oligonucleotide was delivered with cationic lipid to cultured human trabecular meshwork cells. The expression of CD44 suppressed by CD44-specific antisense oligonucleotide was detected by RT-PCR and Western blotting. The effect of CD44 suppression by specific antisense oligonucleotide on attachment of trabecular meshwork cells to HA was measured by MTT assay. Results showed that expression of CD44 was suppressed by CD44-specific antisense oligonucleotide. Antisense oligonucleotide also suppressed the adhesion of human trabecular meshwork cells to HA in a concentration dependent manner. It was concluded that attachment of human trabecular meshwork cells to HA was decreased when CD44 was suppressed by specific antisense oligonucleotide. CD44 might play a role in pathogenesis of POAG by affecting the adhesion of trabecular meshwork cells to HA.

Cell Adhesion↗
PubMed2006

CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex.

The macrophage migration inhibitory factor (MIF) receptor (CD74) was cloned recently, but the signaling mechanism is not evident. We hypothesized that signaling requires an additional molecule such as CD44, which activates nonreceptor tyrosine kinases. We utilized the CD74- and CD44-deficient COS-7/M6 cell to create stable transfectants expressing CD74, CD44, and a truncated CD44 lacking its intracytoplasmic signaling domain. CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. MIF binding was associated with the serine phosphorylation of CD74 and CD44. Investigations that used siRNA or kinase inhibitors indicate that MIF-induced ERK1 and ERK2 activation through CD44 required the Src tyrosine kinase. Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction.

Animals↗