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PubMed1997

CD44 is an independent prognostic factor in early-stage cervical cancer.

The expression of specific cell-adhesion molecule CD44 isoforms (splice variants) is associated with metastatic spread and poor prognosis in human malignancies. The aim of this study was to evaluate whether CD44 isoform expression is a prognostic factor in early-stage cervical cancer. We used 4 different variant exon sequence-specific murine monoclonal antibodies to the CD44 isoforms CD44v3, CD44v5, CD44v6 and CD44v7-8 to study the prognostic value of CD44 splice variants in 200 cases of International Federation of Gynecology and Obstetrics (FIGO) stage-IB cervical cancer by immunohistochemistry. In the univariate analysis, the expression of CD44v3 (log-rank test, p = 0.03) and CD44v6 (log-rank test, p = 0.03) was correlated with poor overall survival. In the subgroup of patients without metastatic disease in the pelvic lymph nodes, expression of CD44v6 was correlated with poor disease-free and overall survival (log-rank test, p = 0.04 and p = 0.01, respectively). Multivariate analysis, correcting for the confounding variables pelvic lymph-node involvement, depth of invasion and histologic grading, revealed CD44v6 to be an independent prognostic factor for overall survival of patients with early-stage cervical cancer. The results of this study indicate that CD44v6 is an additional prognostic marker in surgically treated cervical cancer. The assessment of CD44 isoform expression could be of clinical value in deciding upon adjuvant therapy, resulting in a more individualized management of therapy.

Adult↗
PubMed1998

Cytosol concentrations of CD44 isoforms in breast cancer tissue.

The role of the adhesion molecule CD44 in the natural history of breast cancer is controversial. We investigated the CD44 isoform CD44v5 and CD44v6 concentrations in the cytosol of 90 breast cancer specimens, 9 fibroadenomas and 22 normal breast tissue specimens by means of ELISA. CD44v5 and CD44v6 cytosol concentrations were statistically significantly higher in breast cancer compared with fibroadenoma and normal breast tissue (Mann-Whitney U-test, p = 0.009 and p < 0.001, respectively). When CD44 isoforms were correlated with lymph node involvement, histological grading, histological type, tumor stage and age at diagnosis, we found no statistically significant correlation with any of the investigated clinico-pathological parameters. In univariate and multivariate analyses, CD44v5 and CD44v6 were of no prognostic relevance regarding disease-free survival in breast cancer patients (log-rank test, p = 0.16 and p = 0.08, respectively). Our results indicate that CD44 isoforms are increased in samples from tumors relative to normal tissue. Our data show that CD44v5 and CD44v6 isoform expression, although up-regulated by malignant transformation, is not required to acquire a metastatic phenotype in breast cancer. Furthermore, our data support the assumption that cytosolic CD44 isoforms are of no prognostic relevance for disease-free survival of breast cancer patients.

Adult↗
PubMed1999

Involvement of CD44 in matrix metalloproteinase-2 regulation in human melanoma cells.

CD44 is a family of cell-surface-adhesion proteins that are thought to play an important role in cancer invasion and metastasis. However, the specific mechanisms by which CD44 expression modulates invasion or metastasis are not well understood. In the current study, we have demonstrated that treatment of human melanoma cells with a CD44 MAb, F10-44-2, induces up-regulation of matrix metalloproteinase-2 (MMP-2) protein and mRNA. Moreover, treatment of melanoma cells with MAb F10-44-2 enhances their migration through gelatin-coated membranes and invasion through reconstituted basement membranes. Treatment of melanoma cells with several known CD44 ligands, including hyaluronate, extracellular-matrix proteins, and osteopontin, did not induce MMP-2 production. CD44 binding by F10-44-2 MAb results in induction of MMP-2 expression, which is associated with enhanced cell migration and invasion. These findings have several implications for investigations into tumor metastasis, development, and lymphocyte function.

Antibodies, Monoclonal↗
PubMed2001

Hyaluronan synthases, hyaluronan, and its CD44 receptor in tissue around loosened total hip prostheses.

Aseptic loosening of prosthetic components, the most common long-term complication after total hip replacement (THR), is characterized by the formation of a synovial membrane-like interface tissue (SMLIT). It was hypothesized that the hyaluronan synthase (HAS)/hyaluronan (HA)/HA receptor CD44 signalling system is responsible for the synovial-like differentiation of the interface membrane. SMLIT was therefore compared with osteoarthritis (OA) synovial membrane by using reverse transcriptase polymerase chain reaction (RT-PCR) of HAS 1, 2 and 3, histochemical HA assay, and immunohistochemistry of CD44 and its non-HA ligands. All three isoforms of HAS were found in these samples. HA and CD44 were most abundant in the lining, but the signal was actually stronger in aseptic loosening than in OA (p<0.01). The non-HA CD44 ligands, collagen type VI, fibronectin, osteopontin, and MCP-1, had a similar distribution pattern in both tissues. These results confirm the synovial-like structure of the interface tissue lining. The pressure waves and movement of the HA-rich pseudosynovial fluid seem to drive HA into the implant-to-host interface, which itself also produces HA. HA may be responsible for the induction of a synovial-like lining at the interface through HA-CD44 signalling.

Adult↗
PubMed2001

CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation.

BACKGROUND: Recent studies have suggested a correlation between increased or decreased expression of CD44 variant molecules and tumor metastasis. CD44 expression in gallbladder carcinoma was examined and compared with tumor differentiation. METHODS: Eighty-three samples of gallbladder carcinoma, 17 gallbladder adenoma samples, and 66 normal control mucosa samples were stained immunohistochemically for CD44 standard form (CD44s), variant 3 (CD44v3), and variant 6 (CD44v6). RNA extracted from nine patients with carcinoma also was investigated with reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and Southern blot hybridization (SBH) for the CD44 gene. RESULTS: Normal gallbladder mucosa showed strong, membranous staining for CD44s but not for CD44v3 or CD44v6. In gallbladder tumors, CD44s was stained as strongly as it was in normal mucosa, but immunoreactivity for CD44v3 and CD44v6 also was significant. In well differentiated, advanced adenocarcinomas (n = 38), CD44s immunoreactivity was significantly lower in the invasive component than in the intramucosal component of the tumors (P = 0.0048). Immunoreactivity for CD44v3 and CD44v6 in moderately and poorly differentiated areas was significantly higher than in well differentiated areas (P < 0.0001 and P = 0.0378, respectively). RT-PCR and SBH signals for CD44v3 and CD44v6, including exons 7 and 10, were strong in carcinoma samples but weak in normal samples, in line with the results of immunohistochemistry. The prognosis of patients with gallbladder carcinoma was not associated significantly with altered expression of CD44s, CD44v3, or CD44v6. CONCLUSIONS: The current study demonstrated that CD44 variant overexpression in patients with gallbladder carcinoma was linked closely with histologic dedifferentiation rather than clinicopathologic factors, including prognosis.

Adenocarcinoma↗
PubMed2001

Reevaluation of the origin of CD44(high) "memory phenotype" CD8 T cells: comparison between memory CD8 T cells and thymus-independent CD8 T cells.

CD44(high)CD8 T cells in naive mice, which increase with age, and are often referred to as memory CD8 T cells. However, since thymus-independent CD8 T cells have also been shown to be CD44(high), the origin of the CD44(high)CD8 T cells in naive mice remains unclear. In this study, we compared the characteristics of memory CD8 T cells and thymus-independent CD8 T cells in TCR transgenic mice to clarify the origin of the CD44(high)CD8 T cells in naive normal mice. The memory and thymus-independent CD8 T cells showed differences in surface molecules, spontaneous cell death, cytokine production, and response to IL-2R binding of cytokines. Importantly, the "memory phenotype" CD8 T cells in naive normal mice showed similar characteristics to the thymus-independent CD8 T cells, but differed greatly from "true" memory CD8 T cells in the TCR transgenic mice. Therefore, we conclude that a significant part of the CD44(high) memory phenotype CD8 T cells in naive normal mice represents thymus-independent CD8 T cells, which may participate in age-related changes in immune responses.

Animals↗
PubMed1998

Antisense inhibition of chondrocyte CD44 expression leading to cartilage chondrolysis.

OBJECTIVE: To better define critical functions of the hyaluronan receptor CD44 in cartilage. METHODS: Articular chondrocytes and cartilage tissue slices were treated with CD44 sequence-specific antisense phosphorothioate oligonucleotides. CD44 expression was probed by immunofluorescence microscopy, enzyme-linked immunosorbent assay, and Western blotting. RESULTS: Antisense oligonucleotides demonstrated a dose- and time-dependent inhibition of CD44 protein expression; negative controls showed no effect. Similar to osteoarthritic cartilage, antisense-treated cartilage slices displayed a near-total loss of stainable proteoglycan-rich matrix. CONCLUSION: CD44 expression is needed for maintenance of cartilage homeostasis.

Animals↗
PubMed2006

Hyaluronan and its receptor CD44 in the heart of newborn and adult rats.

The extracellular matrix is a dynamic space and a prerequisite for the function of cardiomyocytes. We have previously reported on the distribution of the glycosaminoglycan hyaluronan (HYA) and its cellular receptor CD44 in the vascular system. In newborn rats, HYA and its receptor were colocalized, but in the adult animals, no such colocalization was observed. Furthermore, the distribution of both HYA and CD44 differed between newborn and adult animals. In this study, the distribution of HYA and its receptor CD44 is explored in the heart. Hearts from newborn and adult rats were stained for visualization of HYA and CD44 using histochemistry and immunohistochemistry. HYA stained the interstitium of the myocardium heterogeneously. Strong staining was seen in the heart valves of both newborn and adult animals. CD44 staining was sparse in hearts from both newborn and adult animals. There are no major changes in the distribution of HYA in the myocardium during the postnatal development in contrast to the blood vessels. Thus, the structure of the interstitium does not change after birth when the heart starts to grow mainly through cardiomyocyte hypertrophy rather than hyperplasia. The abundance of HYA in the heart valves is probably related to their unique physiological properties to withstand repetitive mechanical stress.

Aging↗
PubMed2003

G1 domain of aggrecan cointernalizes with hyaluronan via a CD44-mediated mechanism in bovine articular chondrocytes.

OBJECTIVE: To determine whether aggrecan fragments bound to hyaluronan (HA) can be retained and internalized by articular chondrocytes and whether these events are dependent on HA and its receptor, CD44. An additional objective was to determine whether partial degradation of aggrecan is a prerequisite for internalization. METHODS: Binding and internalization of a variety of fluorescein isothiocyanate (FITC)- or biotin-labeled HA/proteoglycan probes were investigated on normal bovine articular cartilage chondrocytes, bovine articular chondrocytes transfected with a dominant-negative construct of CD44, or COS-7 cells transfected with wild-type CD44. The probes were defined as being internalized by the presence of label associated with the cells following extensive trypsinization of the cell surface. RESULTS: Biotinylated aggrecan fragments bound to FITC-HA were cointernalized in bovine articular chondrocytes or COS-7 cells transfected with CD44. Intracellular vesicles containing FITC-HA colocalized with a fluorescent probe for lysosomes. The internalization of the aggrecan fragments was dependent on the presence of HA as well as the presence of functional CD44. Intact aggrecan/FITC-HA complexes bound to the cell surface but were not internalized. However, following brief trypsin digestion of the aggrecan/HA complex, the remaining proteoglycan fragments were bound and internalized. CONCLUSION: Partially degraded aggrecan fragments (e.g., aggrecan G1 domains bound to HA) can be internalized by articular chondrocytes via a mechanism involving HA/CD44-mediated endocytosis. Further, the presence of an intact aggrecan monomer bound to HA inhibits the internalization of HA as well as HA-bound fragments.

Aggrecans↗
PubMed1995

Hyaluronan binding by CD44 is regulated by a phosphorylation-independent mechanism.

CD44 is an adhesion receptor for which the major characterized ligand is the extracellular matrix glycosaminoglycan, hyaluronan. This interaction underlies CD44-mediated cell attachment, cell migration, and matrix remodelling during development and wound healing. Truncation of the CD44 cytoplasmic domain does not prevent cell surface expression of this hyaluronan receptor but it dramatically impairs ligand binding. In this study we have examined the role of phosphorylation in regulating this function by mutating the target serine residues to either neutral amino acids with the aim of creating a phosphorylation-incompetent molecule, or to acidic residues to mimic a fully phosphorylated CD44. In transfected AKR1 cells the behavior of both the neutral and acidic mutants was indistinguishable from wild-type CD44, indicating that there is a phosphorylation-independent mechanism involved in regulating hyaluronan binding.

Amino Acid Sequence↗
PubMed1995

Expression of CD44 splice variants in human cutaneous melanoma and melanoma cell lines is related to tumor progression and metastatic potential.

Expression of CD44, particularly of certain splice variants, has been linked to tumor progression and metastasis formation in a number of different animal and human cancers. Because human cutaneous melanoma is among the most aggressive human cancers, we explored expression of CD44 isoforms (CD44v) in lesions of melanocytic tumor progression. In addition, by RT-PCR and FACS analysis we assessed CD44v RNA species and cell surface expression of CD44v in cultured melanocytes isolated from human foreskin and in a panel of 2 non-, 2 sporadically and 2 highly metastatic human melanoma cell lines. We observed that all melanocytic lesions examined showed strong uniform expression of standard CD44 (CD44s) epitopes. We did not detect CD44v6 expression in the melanocytic lesions. However, CD44 isoforms containing v5 or v10 were differentially expressed. V5 was expressed in 16%, 0%, 20%, 67% and 58% of common nevi, atypical nevi, early primary melanomas (< or = 1.5 mm), advanced primary melanomas (> 1.5 mm) and metastases, respectively, and hence was related to tumor progression. In contrast, CD44v10 was expressed in all common nevi, whereas part of the atypical nevi and most primary melanomas and metastases lacked v10. CD44v RNA patterns were closely similar in cultured melanocytes and all melanoma cell lines. Melanocytes expressed high levels of CD44s but no CD44v, whereas all melanoma cell lines expressed CD44v at the surface. Interestingly, expression of v5 was strongly increased in the highly metastatic cell lines. Our results suggest a role for CD44 variant domains, particularly v5 and v10, in human melanocytic tumor progression.

Base Sequence↗
PubMed1994

Hyaluronan receptor (CD44) expression and function in human peripheral blood monocytes and alveolar macrophages.

CD44 glycoproteins are present on the surfaces of many hematopoietic cells and in some cases can bind hyaluronan, a major component of the extracellular matrix. In the present study, we have found that newly explanted human peripheral blood monocytes (PBMs) exhibit a major CD44 band of 85 kDa, whereas autologous alveolar macrophages (AM phi) express multiple isoforms ranging from 85 to 200 kDa. Within 4 h in culture, PBMs began expressing new CD44 isoforms of 120, 150, and 180 kDa. Newly explanted AM phi specifically bound [3H]hyaluronan (135 cpm/microgram protein), but newly explanted PBMs did not. However, in vitro cultured PBM progressively acquired the ability to bind [3H]hyaluronan and exhibited specific binding of hyaluronan similar to that of AM phi (113 cpm/microgram protein) after 4 days in culture. In both case, the binding of [3H]hyaluronan was specifically inhibited by the addition of monoclonal antibody directed against CD44. AM phi readily degraded [3H]hyaluronan and reached a plateau after 4 days in culture (115 cpm/microgram protein). Newly explanted PBM exhibit no hyaluronan degradation and only a small degradative activity after 4 days in culture (6 to 11 cpm/microgram protein). Thus, CD44 expression and function appear to change as PBM mature in vitro resembling more that found in AM phi.

Adult↗
PubMed2000

Recognition of human activated CD44 by tumor vasculature-targeted antibody.

TES-23 monoclonal antibody (MAb), which targets rat CD44H on tumor vascular endothelial cells (TEC), dominantly reacted to human activated CD44 rather than human inactive CD44. TES-23 MAb reacted to HT-1080 fibrosarcoma cells almost comparably to anti-human CD44 MAb and moderately to HUVEC; however, it hardly reacted to PBMC. The binding of soluble hyaluronate to HT-1080 cells and HUVEC was clearly noted, but not to PBMC. In addition, stimulation with phorbol 12-myristate 13-acetate induced soluble hyaluronate binding of MOLT-4 human T lymphoma cells and relatively increased the reactivity of TES-23 MAb. Our results suggest that TES-23 MAb can potentially recognize human activated CD44 and hence might be potentially useful for the treatment of human solid tumors containing TEC that express activated CD44.

Animals↗
PubMed2001

RalA mediates v-Src, v-Ras, and v-Raf regulation of CD44 and fibronectin expression in NIH3T3 fibroblasts.

Oncogenic transformation of fibroblasts by v-Src and v-Ras is often associated with downregulation of fibronectin (FN) and increased expression of CD44, a receptor for hyaluronan. Both v-Src and v-Ras as well as v-Raf activate phospholipase D through the small GTPase, RalA, an important mediator of transformation and tumorigenesis in vivo. We have therefore investigated whether RalA is involved in the downregulation of FN and overproduction of CD44 upon oncogenic transformation. We report here that compared to untransfected cells NIH3T3 cells transformed by v-Src, v-Ras, or v-Raf have reduced levels of FN and increased levels of CD44. Moreover, the ability to form extracellular FN fibrils was significantly reduced in the oncogene-transformed cells compared to parental controls. Coexpression of the dominant negative S28N-RalA mutant restored the levels of CD44 and FN and the capacity of v-Src-, v-Ras-, and v-Raf-expressing cells to form extracellular FN fibrils, to those observed in NIH3T3 cells. The data presented here show a novel regulatory role for RalA, which is required for tumor formation in transformed NIH3T3 cells, in mediating the signal transduction pathway activated by v-Src, v-Ras, and v-Raf, that leads to FN downregulation and CD44 overexpression.

3T3 Cells↗
PubMed1999

Regulation of CD44-hyaluronan interactions in Burkitt's lymphoma and Epstein-Barr virus-transformed lymphoblastoid B cells by PMA and interleukin-4.

In this study, we investigated the regulation of CD44-hyaluronan (HA) interactions in a panel of EBV+ Burkitt's lymphoma (BL) and lymphoblastoid B cell lines (B-LCL) generated by in vitro EBV transformation of normal human B cells. The results show that among B cell mitogens, phorbol 12-myristate 13-acetate (PMA) alone induced strong HA recognition in EBV+ BL-30/B95-8 cells. Among the cytokines that affect B cell growth and differentiation, IL-4 alone induced HA recognition in BL-30/B95-8 cells. Attempts to delineate the molecular mechanism for this increased HA adhesion in BL-30/B95-8 cells revealed an enhanced expression of CD44 H, isoforms containing V3, V6, and V9 exons, alterations in the splicing pattern of the V4 exon, and the increased electrophoretic mobility of the CD44 H protein. In contrast, the ability to recognize HA was not observed in B-LCL cells stimulated with either PMA or IL-4, even though these cells respond to IL-4, as observed by upregulation of CD23 expression. The molecular pathways that regulate CD44 expression and CD44-mediated HA binding may be selectively inactivated in B-LCL cells. These results may have implications with respect to the generation and spread of B cell tumors.

B-Lymphocytes↗
PubMed1999

Adhesion proteins in the biology of breast cancer: contribution of CD44.

One of the most important features of tumor cell invasion is the ability to establish or modulate adhesion to other cells or to an extracellular matrix, a process mediated by a large number of adhesion proteins. This review examines how CD44 participates in malignant transformation and progression of the breast epithelium. CD44 is a family of cell adhesion glycoproteins generated by alternative splicing of up to 10 variant exons. Discrete CD44 isoforms are overexpressed in different human cancers, including breast cancer. Recent studies, including our own, have shown that CD44 is involved in two of the three steps of the invasive cascade: adhesion to the extracellular matrix and motility. The overexpression of one of the CD44 variants, CD44v6, is a significant component in the malignant transformation of the breast epithelium and its use as a prognostic marker is presently investigated.

Animals↗
PubMed1997

The expression patterns of standard and variant CD44 molecules in normal uterine cervix and cervical cancer.

CD44 is a cell-surface glycoprotein postulated to play a role in tumor-cell metastasis. We have examined the expression of the standard CD44 (CD44s), and alternative spliced variants of CD44 containing variant exons v6, v9, and v1O (CD44v6, CD44v9, and CD44v10 respectively) in 9 samples of normal cervix, 6 samples of cervical intraepithelial neoplasia (CIN), and 11 samples with invasive cervical carcinomas. RT/PCR demonstrated the presence of CD44s in all samples of normal cervix and those with invasive carcinomas. CD44v6 was also found in all normal cervical samples and in 9 tissue samples of invasive carcinomas. The results also suggested that some tumor specimens had several higher molecular transcripts containing exon v6 compared to specimens of normal cervix. Immunohistochemistry detected the presence of CD44s and the absence of CD44v10 in both epithelial and stromal cells in all specimens. In contrast, CD44v6 and CD44v9 were stained positive in epithelial cells but were absent in stromal cells. The intensity of CD44v6 and CD44v9 staining was strongest in normal cervical epithelium followed by CIN, invasive squamous cell carcinoma, and adenocarcinoma. In the malignant samples, heterogeneity in staining intensity among different clusters of tumor cells was observed. Furthermore, poorly differentiated and undifferentiated carcinomas from patients having poor prognosis did not stain at all. This study suggests that variant CD44 molecules may serve an important function in the cell contact of cervical epithelial cells, and that cervical epithelium acquires heterogeneity in the expression of CD44 adhesion molecules during carcinogenesis, which may be related to tumor metastasis.

Cervix Uteri↗
PubMed1997

Immunohistochemical detection of CD44 splice variant expression in premalignant lesions of the cervix and benign cervical epithelium.

The expression of specific CD44 splice variants in malignant tumors has been shown to be associated with metastasis and poor prognosis. In previous studies we have detected aberrant expression of the transmembranous cell adhesion molecule CD44 in cervical cancer. Therefore, we now focus on its role in intraepithelial dysplastic lesions of the cervix. Forty-five cervical intraepithelial neoplasias (CIN), grades I to III, were investigated immunohistochemically for three different splice variants of CD44 (v5, v6, and v7-8). A negative correlation of CD44v5 (Kendall correlation coefficient r = -0.25, P < 0.05) expression with the grade of CIN was found. In normal squamous epithelium of the cervix, the staining reaction of CD44v5 was confined to the basal and the parabasal cell layers. In dysplastic lesions a diffuse and weaker staining pattern of the entire epithelium was observed. Our data suggest a loss of CD44v5 epitope during dysplastic transformation. It seems that expression of CD44 splice variants is not a continuous process in the natural history of cervical cancer, and the pattern of CD44 splice variant expression is changed during carcinogenesis.

Cervix Uteri↗