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PubMed1999

Altered expression of CD44 and variant isoforms in human adenocarcinoma of the endocervix during progression.

OBJECTIVE: Altered expression of the CD44 family of cell adhesion molecules has been associated with tumor progression and metastasis. The aim of this study was to investigate the expression of the gene products of CD44 standard (CD44s) and several alternatively spliced variants (CD44v4, v6, v7, and v9) in adenocarcinoma of the endocervix and to correlate the degree of their expression with disease progression. METHODS: Immunohistochemical staining for CD44s and CD44v4, v6, v7, and v9 was performed on formalin-fixed, paraffin-embedded endocervical specimens. Seventeen cases of adenocarcinoma in situ (AIS) and 22 cases of invasive adenocarcinoma of the endocervix were included in this study, and the immunoreactivity was compared with that of normal endocervical epithelium. RESULTS: (1) In the normal endocervical mucosa, immunoreactivity for CD44s and the splice variants was lacking or was confined to only the basal portion of the glandular epithelium along the basement membrane; (2) CD44s was diffusely expressed along the entire cytoplasmic membrane, including the luminal surface of the tumorous glands in 94% of AIS and 95% of invasive adenocarcinomas; (3) a significantly stronger expression of CD44s was observed in invasive adenocarcinomas than in AIS; (4) in contrast to all other splice variants, CD44v9 demonstrated an increased expression in nearly all in situ and invasive lesions compared to the normal tissue; (5) CD44v4 and v6 were expressed only in a small proportion of invasive adenocarcinomas and were near totally absent in the in situ lesions; and (6) CD44 v7 was totally absent in all normal, in situ, and invasive lesions studied. CONCLUSIONS: It appears that neoplastic transformation of endocervical epithelium is associated with qualitative and quantitative changes in the expression of CD44 standard molecule and some CD44 splice variants.

Adenocarcinoma↗
PubMed2000

E-Cadherin and CD44 expression in cervical intraepithelial neoplasia: comparison between HIV-positive and HIV-negative women and correlation with HPV status.

AIMS: We aimed to compare the expression patterns of E-cadherin and CD44 isoforms in cervical intraepithelial neoplasia (CIN) between patients with or without infection by the human immunodeficiency virus (HIV). METHODS: An immunohistochemical analysis using the monoclonal antibody HECD-1 against E-cadherin and the monoclonal antibodies 2C5, binding to CD44s and all the variants encoded by exons 3 to 10, 3G5, specific for CD44v3 and 2F10, and specific for CD44v6, was performed in formalin-fixed, paraffin-embedded samples of 138 CIN (74 from HIV-negative and 64 from HIV-positive patients). RESULTS: In HIV-negative patients, the mean percentages (+/-SD) of E-cadherin-positive cells in CIN of grades I, II, and III were, respectively, 33% +/- 4, 63% +/- 5, and 91% +/- 9. The difference was statistically significant between the three groups of tumors (P < 0.0001). In HIV-negative patients, the mean percentages (+/-SD) of CD44-positive cells in CIN of grades I, II, and III were, respectively, 37% +/- 7, 57% +/- 8, and 90% +/- 11. The difference was statistically significant between the three groups of tumors (P < 0.0001). No difference in E-cadherin and CD44 expressions was noted between HIV+ and HIV- women. Further analysis showed no relation between E-cadherin or CD44 expression and the HPV status and CD4 T cell serum levels. CONCLUSION: Our study confirms that alterations in E-cadherin and CD44 expression in CIN depend on the histological grade but suggest nondirect involvement and are not related to HIV and immune status.

Adult↗
PubMed2002

Anti-CD44 monoclonal antibody (IM7) induces murine systemic shock mediated by platelet activating factor.

The cell adhesion molecule CD44 plays an important role in progression of autoimmune diseases or cancer. Administration of anti-CD44 monoclonal antibodies (mAbs) have been reported to have anti-inflammatory or anti-cancer activity. However, our evidence shows that intravenous administration of the anti-CD44 IgG2b mAb IM7 induces systemic shock in mice. To examine the character of systemic shock, the cutaneous excess vascular permeability was evaluated. Administered mAb markedly increased vascular permeability but its F(ab')(2) fragments did not induce a reaction. The platelet-activating factor (PAF) specific antagonist Y-24180 was effective in preventing IM7-induced extravasation, whereas anti-histaminergic and anti-serotonergic agents were not. Y-24180 also ameliorated hematocrit elevation and hypotension in mice treated with IM7. These results indicate that IM7-induced systemic shock is mediated by PAF. Because IM7 also binds human CD44, anti-CD44 immunotherapy using IM7 may be applied to the clinical treatment of autoimmune diseases or cancer. This study describes potential triggering pathways for shock that must be avoided through modification of the immunotherapy.

Anaphylaxis↗
PubMed1996

Expression of CD44 splice variants in human skin and epidermal tumours.

Splice variants of the adhesion molecule CD44 (CD44v) are important in the lymphatic spread of rat carcinoma cells. In several human tumours expression of CD44v correlates with tumour progression. However, little is known about the physiological functions of distinct variant exons. Here we report on the immunohistological evaluation of CD44 expression in normal human skin and epidermal tumours which do not metastasise, or do so vary rarely. Frozen tissues were stained with a panel of monoclonal antibodies, recognizing epitopes of the CD44 standard isoform, as well as of variant exons v5, v6, v7, v7-v8 and v10. Stratum basale and spinosum as well as the root shaft of hairs reacted strongly with the whole panel of anti-CD44 antibodies. Stratum corneum, acinar cells of sebaceous and eccrine sweat glands stained with anti-CD44v5, anti-CD44v6 and anti-CD44v7, but not with anti-CD44v10, the latter recognizing the "epithelial isoform" (CD44v8-v10) of CD44. Ductal cells of glands and apocrine glands did not express CD44v. Compared with its expression in normal human skin, CD44v expression was reduced in basal cell carcinoma and squamous cell carcinoma of the skin. This was particularly true of CD44v10. The expression of CD44v in normal skin and dermal appendages indicates that not all combinations of variant exons are involved in tumour progression. Since the epithelial isoform is particularly downregulated in basal cell carcinoma and squamous cell carcinoma of the skin, it is unlikely that exons v8-v10 play a role in tumour progression. Rather, they may be of functional importance in maintenance of the epidermal structure.

Animals↗
PubMed1990

Identification of mRNA that encodes an alternative form of H-CAM(CD44) in lymphoid and nonlymphoid tissues.

The cluster of differentiation 44 (CD44), hereafter referred to as H-CAM(CD44), represents a novel class of polymorphic (Mr 80,000-215,000) cell adhesion molecules that are involved in cell-cell and cell-matrix adhesion events in a variety of organ systems. We report the detection of distinct mRNAs, in both hematopoietic and nonhematopoietic human cell lines, that encode H-CAM(CD44) with different cytoplasmic domains. Genomic Southern blot analyses indicate that the exons encoding these two cytoplasmic domains are located on the same approximately 16 kilobase (kb) Eco RI restriction fragment. Restriction endonuclease and Southern blot analyses performed on polymerase chain reaction (PCR) amplification copies of these mRNAs confirm that their sequences correspond with previously reported cDNA sequences. A consensus splice donor site which is conserved in human, baboon, and mouse mRNAs that encode a molecule with an elongated cytoplasmic domain (H-CAM-L) is utilized to generate a distinct but low-abundance mRNA species that encodes H-CAM(CD44) with a truncated cytoplasmic domain of only three amino acids (H-CAM-S). Estimations of the relative abundance of these mRNA species in B-lymphoblastoid cells using the PCR amplification technique exhibit average H-CAM-L/H-CAM-S ratios ranging between 100 and 200. Therefore, H-CAM (CD44)-mediated adhesive events may be regulated through a differential capacity of H-CAM-L and H-CAM-S to interact with the cytoskeleton and to participate in intracellular signaling events.

Base Sequence↗
PubMed1995

Involvement of CD44 and its variant isoforms in membrane-cytoskeleton interaction, cell adhesion and tumor metastasis.

CD44s (standard form of CD44) is a transmembrane glycoprotein whose external domain displays extracellular matrix adhesion properties by binding both hyaluronic acid (HA) and collagen. The cytoplasmic domain of CD44s interacts with the cytoskeleton by binding directly to ankyrin. It has been shown that post-translational modifications, such as phosphorylation (by protein kinase C), acylation (by acyl-transferase) and GTP-binding enhanced CD44's interaction with cytoskeletal proteins. Most importantly, the interaction between CD44s and the cytoskeletal protein, ankyrin, is required for the modulation of CD44s cell surface expression and its adhesion function. Recently, a number of tumor cells and tissues have been shown to express CD44 variant (CD44v) isoforms. Using RT-PCR and DNA sequence analyses, we have found that unique CD44 splice variant isoforms are expressed in both prostate and breast cancer cell lines and carcinomas. Most importantly intracellular ankyrin is preferentially accumulated underneath the patched/capped structures of CD44 variant isoform in both breast and prostate cancer cells attached to HA-coated plates. We propose that selective expression of CD44v isoforms unique for certain metastatic carcinomas and their interaction with the cytoskeleton may play a pivotal role in regulating tumor cell behavior during tumor development and metastasis.

Animals↗
PubMed2002

CD44 variant exons in leukemia and lymphoma.

CD44 is a cell surface glycoprotein expressed on different cell types that functions in lymphocyte activation and homing, extracellular matrix adhesion and cellular migration. CD44 is encoded by a single gene composed of at least 20 exons. The standard CD44 protein (CD44S or CD44H) is the hematopoietic form of CD44 in lymphoid cells. Variant isoforms (designated from v1 to v10) are formed by addition of new exons to the extracellular domain. High levels of CD44v6 expression has been observed in some tumors and are associated with metastatic spread. The aim of the present study was to investigate and evaluate expression of the CD44v6 and v6-containing variants as a possible marker in chronic myeloid leukemia and lymphoma by reverse transcription-polymerase chain reaction. CD44 exon v6 was detected in all patients and all individuals in the control group. CD44v6-v10 mRNA was observed in 25 patients but in none of the subjects in the control group. CD44v6/v9-10, CD44v6-v7, CD44v6/v10 transcripts were detected in 11, 6, and 2 patients, respectively. CD44v6-7/v9-10 transcripts were not observed in either the patients or the healthy individuals. We conclude that CD44v6-v10 expression may be associated with hematologic malignancies.

Adult↗
PubMed1999

Irregular expression of hyaluronan and its CD44 receptor is associated with metastatic phenotype in laryngeal squamous cell carcinoma.

The distributions of hyaluronan (HA) and its CD44 receptor were studied in 24 normal, 27 dysplastic samples of laryngeal epithelium and in 172 squamous cell carcinomas (LSCC), using a specific probe prepared from cartilage proteoglycan (bHABC, biotinylated hyaluronan binding complex) and a monoclonal antibody (Hermes 3). HA and CD44 were expressed similarly in all normal and about 90% of dysplastic and neoplastic laryngeal epithelia. In the normal epithelium HA and CD44 were homogeneously distributed throughout the epithelium, whereas the most superficial layers were negative. This was in contrast to the picture in dysplastic epithelium and well-differentiated invasive carcinomas, which were entirely HA and CD44 positive. Local areas with a low signal for HA and CD44 were present in 11% and 22% of the samples with dysplasia, and in 27% and 28% of those with carcinoma, respectively. The presence of this staining irregularity was associated with poor differentiation of the carcinoma, a significantly elevated mitotic index and a high frequency of nodal spreading and metastases. Furthermore, the irregular staining showed a trend towards poor disease-free survival, suggesting that an altered metabolism of HA is a common feature in LSCC and is associated with an aggressive growth pattern.

Carcinoma, Squamous Cell↗
PubMed1998

Expression of CD44 in rat liver allografts during rejection.

As CD44 is believed to be a homing receptor involved in lymphoid trafficking and inflammatory responses, it is expected to be closely linked to transplant rejection. In this study, the expression of CD44 during liver transplant rejection was compared with the expression of lymphocyte-function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), which play an essential role in cell interactions and the initiation of immune responses. Male Brown Norway (BN) and Lewis (LEW) rats were used as donors and recipients, respectively. Orthotopic liver transplantation (OLTX) was done using the cuff technique of Kamada and Calne. Animals were killed on days 3, 5, and 7 after OLTX, and a piece of tissue from each of the liver grafts was obtained. Immunohistochemical staining was used to investigate the expression of CD44, ICAM-1, and LFA-1. CD44 was strongly expressed in portal areas of the rejected liver, and LFA-1 and ICAM-1 were expressed mainly on sinusoids and hepatocytes. These findings indicate that CD44 is closely involved in lymphocyte infiltration, which is dominant in portal areas, and that lymphocyte infiltration during the rejection process may involve a homing mechanism.

Animals↗
PubMed1992

Hyaluronate binding and CD44 expression in human glioblastoma cells and astrocytes.

CD44 is an integral membrane glycoprotein of approximately 90 kDa which has been implicated in the binding of hyaluronate to the cell surface. The expression of CD44 in astrocytes was investigated by means of indirect immunofluorescence on cultured cells. The vast majority of these cells were found to express CD44. Western blot analysis of these cells revealed a highly polydisperse species having an M(r) corresponding to 74-86 kDa. In order to visualize hyaluronate-binding cells, living cultures were probed with fluorescein-conjugated hyaluronate (FI-HA). Some astrocytes were able to bind FI-HA, provided that they were first treated with hyaluronidase. Streptomyces hyaluronidase, which is hyaluronate-specific, was effective in exposing the hyaluronate-binding capacity of these cells. This leads one to conclude that hyaluronate is bound to the surface of these cells and that it masks their capacity to bind hyaluronate. Provided that they were first treated with hyaluronidase, the U-87 MG (glioblastoma-astrocytoma), U-373 MG (glioblastoma), and Hs 683 (glioma) cell lines were also able to bind FI-HA. The U-138 MG (glioblastoma) cell line was unable to bind FI-HA, with or without prior hyaluronidase treatment. A quantitative assay was developed with the use of [3H]hyaluronate ([3H]HA). This revealed the binding to be highly specific, inasmuch as the addition of unlabeled hyaluronate, but not other glycosaminoglycans, was effective in inhibiting the binding of the [3H]HA. An anti-CD44 monoclonal antibody, 50B4, was able to inhibit the binding of the [3H]HA to the U-373 MG cell line. In this cell line, then, CD44 functions as a hyaluronate receptor and one may infer that this is also the case in some astrocytes.

Antibodies, Monoclonal↗
PubMed1994

Bromelain protease F9 reduces the CD44 mediated adhesion of human peripheral blood lymphocytes to human umbilical vein endothelial cells.

The thiol protease bromelain has been shown to remove T-cell CD44 molecules from lymphocytes and to affect T-cell activation. We investigated the effect of a highly purified bromelain protease F9 (F9) on the adhesion of peripheral blood lymphocytes (PBL) to human umbilical vein endothelial cells (HUVEC). Preincubation of the lymphocytes with F9 reduced the adherence to about 20% of unstimulated and to about 30% of phorbol-dibutyrate (P(Bu)2) stimulated lymphocytes. Using flow cytometry, both crude bromelain and protease F9 reduced the expression of CD44, but not of LFA-1, on PBL. F9 was about 10 times more active than crude bromelain; at 2.5 micrograms/ml of F9 about 97% inhibition of CD44 expression was found. A mAb against CD44 was tested and found to block the F9-induced decrease in PBL-binding to HUVEC. The results indicate that F9 selectively decreases the CD44 mediated binding of PBL to HUVEC.

Antibodies, Monoclonal↗
PubMed1990

Expression of CD44 confers a new adhesive phenotype on transfected cells.

The function of the CD44 glycoprotein as an adhesion molecule was directly tested by transformation of a CD44 cDNA into mouse fibroblasts. This cDNA was expressed as a heavily modified cell surface protein reactive with monoclonal antibodies that recognize glycoproteins now identified in primates as CD44. Independent transfectants exhibited a new self-adhesive phenotype, forming large aggregates when placed in suspension. In variants derived from a clone of cells, aggregation competence segregated with expression of the transfected gene. This CD44-mediated adhesion was blocked specifically by monoclonal antibodies binding one immunologically defined region of CD44. Nontransfected L cells did not self-aggregate but were capable of adhering to the transfectants, indicating that at least one ligand for this adhesion molecule is expressed by mouse fibroblasts.

Animals↗
PubMed1991

Sequence of the bovine CD44 cDNA: comparison with human and mouse sequences.

CD44 is a cell-surface glycoprotein involved in leukocyte adherence, T-cell activation and lymphocyte homing. We have isolated and sequenced a cDNA clone which encodes for bovine CD44. The predicted amino acid sequence of bovine CD44 has an overall high similarity with that of human and mouse CD44, 79.5 and 73.2%, respectively. In all three species, CD44 has a similar transmembrane region and cytoplasmic tail. In addition, all of the cysteine residues and a majority of the putative N-linked glycosylation sites in the extracytoplasmic domain are conserved between bovine, human and mouse. All three species have an area of low interspecies similarity within the extracytoplasmic domain. This area has a similarity of 34% between bovine and human, 27% between bovine and mouse, and 35% between human and mouse. The location of this area of low similarity is conserved between species.

Amino Acid Sequence↗
PubMed1994

Analyses of monoclonal antibodies reactive with porcine CD44 and CD45.

Twenty-six monoclonal antibodies (mAbs), assigned to the CD44/CD45 section of the First International Swine CD Workshop, were compared for their reactivity against a selected group of target cells by one- and two-color flow cytometric analysis. Based on staining and reactivity patterns the 26 mAbs were assigned to six groups, group F1 mAbs were designated CD44 mAbs; and groups F2 and F3 as CD45 mAbs. With the information available, a CD designation could not be given to the mAbs in groups F4, F5 or F6 consisting of four, three and four mAbs each, respectively. The reactivity of all six mAbs in group F1 (MAC35, 25-32, PORC24A, H22A, BAG40A, and BAT31A) was blocked by soluble porcine CD44. One mAb in this group (MAC325) reacted with a cell surface protein with a molecular weight of 80 kDa and was designated as CD44; the other five mAbs were designated as wCD44 because no molecular weight was known. Blocking experiments utilizing a cross reactive anti-human CD44 (mAb Z062) allowed the definition of the wCD44a epitope recognized by mAbs PORC24A and H22A. The group F2 mAbs (74-9-3; MAC323; K252.1E4; and 2A5) were designated as CD45 based on their broad reactivity pattern with lymphoid and myeloid cells and their ability to immunoprecipitate three polypeptides with an apparent molecular weight of 226, 210 and 190 kDa. The F3 mAbs (MAC327; MAC326; 3a56 and -a2) were designated as CD45R based on their restricted reactivity against lymphoid and myeloid target cells, and their ability to immunoprecipitate either two polypeptides with an apparent molecular weight of 226 and 210 kDa (mAbs MAC327 and MAC326) or a single polypeptide with an apparent molecular weight of 210 kDa (mAbs-a2 and 3a56). Sequential immunoprecipitation analyses confirmed the relatedness of the F2 and F3 group mAbs. The work conducted for this first workshop led to the definition of six mAbs specific for CD44, four mAbs specific for CD45, and four mAbs specific for CD45R which should prove to be very valuable reagents for the study of the porcine immune system.

Animals↗
PubMed1996

Expression of CD44 splice variants in metastatic and non-metastatic mouse tumour cell lines.

Different splice variants of the CD44 cell-surface molecule have been linked to metastasis formation in several animal and human cancers. We have used metastatic CSML-100 and non-metastatic CSML-0 mouse adenocarcinoma cell lines to determine whether variant CD44 molecules could be implicated in the different behaviour of these cells. Two CD44 splice variants containing exons v7-v10 and v8-v10 were detected in the non-metastatic CSML-0. Two other mouse cell lines, the normal mammary gland NMuMG and the mammary pre-neoplastic CL-S1 were also found to express these exons. A short (hematopoietic) CD44 isoform was expressed in the metastatic CSML-100 and three other mouse mammary tumour cell lines. Overexpression of v7-v10 and v8-v10 CD44 variants in CSML 100 cells did not decrease their metastatic potential.

Alternative Splicing↗
PubMed1996

Soluble forms of CD44 and CD54 (ICAM-1) cellular adhesion molecules are released by human prostatic cancer cell lines.

We have identified that human prostatic cancer cell lines DU145, PC3, ND1, ALVA31 and JCA1 released soluble CD44 molecules and DU145, PC3 and ND1 released soluble CD54. Both soluble and surface CD44 were not found in LNCaP, and both forms of CD54 were not expressed in LNCaP and JCA1. CD54 was found to be highly expressed on cell surface in ALVA31, but these cells did not release soluble CD54. Expression of both cell surface and soluble forms were examined after treatment of cells with IFN-gamma, TGF-beta 1, or culturing in serum-free media. The concentration of soluble CD54 in supernatants changed to small extent after treatment with TGF-beta 1 and increased after treatment with IFN-gamma or in serum-free media. Cell surface expression of CD54 however, changed only minimally after treatment. The levels of cell surface and soluble CD44 also changed minimally after treatment with IFN-gamma and TGF-beta 1 but decreased in serum-free media and this was accompanied by marked elevation of soluble CD44 in supernatants. These data indicate that soluble CD44 might be released from cell surface by shedding whereas alternative splicing is the most likely mechanism of soluble CD54 release.

Cell Adhesion Molecules↗
PubMed1995

Quantitative and qualitative changes in CD44 and MEL-14 expression by T cells in C57BL/6 mice during aging.

Aging is associated with a decrease in the functional activity of T cells. We have explored age-related alterations in CD44 and MEL-14 expression by spleen cells bearing the Thy1.2, CD4 or CD8 antigens in C57BL/6 mice at 2, 8, 15 and 23 months of age. The membrane expression of CD44 and MEL-14 molecules can be used to distinguish naive (CD44low, MEL-14high) from preactivated/memory (CD44high, MEL-14low) T cells. Our results show that the proportion of CD4+ splenic cells begins to decrease at an intermediate age (8-month-old mice), whereas the proportion of CD8+ cells remains unaltered. The proportion of CD4+ and CD8+ splenic cells with the CD44high memory phenotype was increased at an early stage of aging (in 8-month-old mice) without a concomitant change in MEL-14 expression. In older mice, MEL-14 expression decreased on CD4+ but not on CD8+ subsets. Recent studies have reported that following activation, the expression of CD44 molecules containing additional, so-called variable exons can be detected. By PCR, we observed an increase in CD44 transcripts containing the v6 or v7 variable exons in murine lymph nodes at the age of 15 months. Our results suggest that v6- or v7-containing variants of CD44 may be involved in the development of memory cells. Taken together, these results suggest that the trafficking of memory T cells in aging may be altered by quantitative and/or qualitative differences in the expression of molecules involved in lymphocyte recirculation.

Aging↗
PubMed2006

Angiogenic potential of CD44+ CD90+ multipotent CNS stem cells in vitro.

Although it is now clear that several subpopulations of neural stem cells (NSCs) exist during early development and adulthood, the angiogenic potential of NSCs remains a subject of debate. Here, we report that CD44(+) CD90(+) cells isolated from primary neurospheres can form vascular-tube structures in vitro. NSCs isolated from the mouse embryonic cortex formed neurospheres when cultured in serum-free medium containing 20ng/ml basic fibroblast growth factor (bFGF). CD44(+) CD90(+) cells were enriched from the neurospheres using an EPICS ALTRA flow cytometer, and antibodies against CD44 and CD90. The purified CD44(+) CD90(+) cells generated neurospheres, and differentiated into neurons and astrocytes. When the cells were inoculated into collagen gels and cultured with 20% fetal bovine serum plus bFGF for 7 days, vascular tube-like structures were formed. These results indicate that CD44(+) CD90(+) cells have the ability to generate neurospheres and to form vascular tubes.

Animals↗