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PubMed1997

[Cellular adhesion molecule (CD44) in ovarian tumors].

OBJECTIVE: To investigate a method of detecting adhesion molecule (CD44) contents in ovarian tumors and its clinical significance. METHODS: In 106 patients with ovarian tumors (50 benign and 56 malignant), the adhesion molecule (CD44) contents in peripheral blood lymphocytes (PBL) and in neoplastic tissues were analysed (quantitatively by using flow cytometric-immunological method). RESULT: (1) The CD44 contents in the PBL of the patients with malignant tumor were obviously higher than those of patients with benign tumors (P<0.05) and than those of the control (P < 0.01); (2) Within the group of patients with malignant tumors, the CD44 contents in the neoplastic tissues were higher than those in the PBL (0.01 < P < 0.05); There was no significant difference in CD44 contents among the different histopathological types, whether benign or malignant; (4) The CD44 contents in the PBL decreased gradually after surgery. CONCLUSION: To analyse the CD44 contents in PBL and neoplastic tissues by flow cytometry may be an important method or parameter to differentiate benign ovarian tumors from malignant tumors and to discover recurrence of metastasis of malignant tumors in early stage.

Cell Adhesion Molecules↗

PubMed1998

[The prognostic factors of pancreatic cancer--adhesion molecule CD44].

The prognosis for pancreatic cancer is extremely poor, because there are usually invasion of surrounding tissues and metastases to lymph nodes, liver or peritoneum at the time of diagnosis. Many studies from the molecular-biological stand point have demonstrated this poor prognosis. However, the mechanisms underlying these invasive and metastatic capabilities have not yet been clarified. We reviewed several reports for prognostic factors of pancreatic cancer in molecular-biological examinations, and introduced our recent study on the adhesion molecule CD44. The CD44 variant 6 (v6) molecule has been noted as a marker for tumor metastasis and prognosis in several tumors. We examined whether or not v6 is a useful marker for evaluating the prognosis of pancreatic cancer patients. In addition, we attempted to assess the clinicopathological implications for pancreatic cancer of the variant 2 (v2) isoform using a recently developed monoclonal antibody against a v2 epitope. The expression of CD44 v6 and v2 was observed only in tumor cells, if at all. The expression of CD44 v6 and v2 was correlated with decreased overall survival. A significant correlation was obtained between CD44 v2 and vessel invasion. These results suggest that CD44 v2 and CD44 v6 may be useful markers of a poor prognosis.

Cell Adhesion Molecules↗

PubMed1998

Functional and clinical relevance of CD44 variant isoform expression on B-cell chronic lymphocytic leukemia cells.

BACKGROUND AND OBJECTIVE: Recent studies have shown that expression of adhesion molecules of the Ig superfamily, of integrins and of selectins allows definition of high vs low risk B-cell chronic lymphocytic leukemia (B-CLL). The proteoglycan CD44 is an adhesion molecule that may be expressed as a standard form of 85-95 KD or as several variant isoforms. The presence of certain CD44 variant (v) isoforms on neoplastic cells indicates poor prognosis in epithelial and lymphoid malignancies, as it is associated with tumor progression and metastasis. DESIGN AND METHODS: The expression of CD44 v3, 4, 5, 6, 7, 9 and 10 was analyzed in cells from 85 B-CLL patients. Indirect immunofluorescence and flow cytometry were used to identify CD44v. Functional studies were performed by analysis of adhesion to hyaluronate (HA), one CD44 ligand, and HA-induced Ca2+ influx. A variety of statistical methods were used to define phenotypic and functional differences between the various clones, to calculate survival curves, and for multivariate analyses. RESULTS: In 17/85 B-CLL (20%), one or more CD44v were detectable by indirect immunofluorescence, whereas in 68/85 cases (80%) this technique yielded negative results. However, moAb "mixes" against CD44v and patching of surface molecules on B-CLL cells have shown that all B-CLL clones express CD44v. This has been confirmed by Western blot in a number of cases. Thus, two groups of patients whose cells bear CD44v at high or low density, are distinguished. Functions of the two clonotypes were investigated, namely their adhesion to a CD44 ligand and hyaluronate (HA), and effect on HA-induced Ca2+ influx. Cells expressing high density CD44v adhere to HA-coated substrates more efficiently than cells with low density CD44v. In all clones, HA-signaling via CD44 yields Ca2+ influx. This indicates that CD44 mediates activatory signals following interaction with the ligand. INTERPRETATION AND CONCLUSIONS: The clinical relevance of these findings has been ascertained. The 17/85 cases whose cells bore high density CD44v had significantly worse prognostic features than those of patients with low density CD44v, namely more advanced disease stage, LDT < 12 months and therapy requirement. Moreover, the median survival in the former group of patients was < 5 years as opposed to > 12 years in the latter. Therefore, analysis of CD44v expression provides indications of biological and clinical relevance also in low grade lymphoproliferative disorders.

Biomarkers, Tumor↗

PubMed2002

Prediction of distant metastasis by using reverse transcriptase-polymerase chain reaction for epithelial and variant CD44 mRNA in the peripheral blood of patients with colorectal cancer.

BACKGROUND: Reverse transcriptase-polymerase chain reaction (RT-PCR) has been used to identify small numbers of tumor cells. Molecular detection is thought to provide useful information for the clinical management of postoperative adjuvant therapy regimens. OBJECTIVE: To use RT-PCR to identify messenger RNA (mRNA) coding for carcinoembryonic antigen, epithelial and variant CD44, and matrix metalloproteinase 7 in the portal venous and peripheral blood of patients with colorectal carcinoma to predict live or distant metastasis. DESIGN: Prospective consecutive series. SETTING: University hospital. PATIENTS AND METHODS: Portal venous and peripheral blood samples were obtained from 22 patients with colorectal cancer during surgical manipulation. Using complementary DNA primers specific for carcinoembryonic antigen, CD44, and matrix metalloproteinase 7, RT-PCR was performed to detect tumor cells. MAIN OUTCOME MEASURE: The clinical significance of RT-PCR for epithelial and variant CD44 mRNA in peripheral blood. RESULTS: During 3 years of follow-up, 2 patients whose peripheral blood had carcinoembryonic antigen and CD44 variant mRNA also had distant metastases (lung or spleen). Expression of epithelial and variant CD44 mRNA in peripheral blood was more highly correlated with the clinical cancer stage than with expression of carcinoembryonic antigen and matrix metalloproteinase 7. CONCLUSIONS: Molecular detection of epithelial and variant CD44 mRNA in the peripheral blood may help determine distant metastases in patients with colorectal carcinoma. Molecular detection in the peripheral blood at surgical treatment suggests that systemic hematogenic tumor cell dissemination is an early event of distant metastasis.

Carcinoembryonic Antigen↗

PubMed1999

Down-regulation of CD44 standard and variant isoforms during the development and progression of uterine cervical tumours.

To clarify the possible role of CD44 in the development or progression of uterine cervical tumours, an immunohistochemical investigation was carried out on 125 cases of cervical intraepithelial neoplasia (CIN), 78 invasive squamous cell carcinomas (ISCC), 61 cervical adenocarcinomas (AC), nine adenosquamous carcinomas (ASq), and 15 carcinomas with co-existent SCC and AC components, as well as 87 samples of normal cervix. A combination of reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) was also applied to 16 cervical carcinomas and 24 normal cervical specimens. Immunoreactivity for CD44s, CD44v3, and CD44v6 did not alter during the progression of CIN, while significantly decreased expression was observed in ISCC, associated with invasive features in some tumours. Reduced levels of CD44 expression in AC were also found, compared with normal cervical glandular epithelia. The average immunoreactivity scores for CD44s, CD44v3, and CD44v6 were significantly higher in ISCC than in AC, in line with the RT-PCR/SBH assay results. However, CD44 scores did not correlate with any clinicopathological factors or with survival in ISCC or AC. The ASq and AC CD44 scores were similar, while staining patterns in mixed tumours were dependent on the morphological phenotype, suggesting a close association between CD44 expression and the cell types. The results suggest that whereas CD44 is down-regulated during cervical tumourigenesis, positivity may not be useful as a consistent prognostic indicator.

Adenocarcinoma↗

PubMed1997

CD44 immunostaining of thyroid fine-needle aspirates differentiates thyroid papillary carcinoma from other lesions with nuclear grooves and inclusions.

BACKGROUND: Although nuclear grooves and inclusions are considered to be characteristic cytologic features of thyroid papillary carcinoma, a variety of other thyroid lesions may on occasion display these features in fine-needle aspiration specimens. METHODS: The authors evaluated the immunocytochemical staining of 16 fine-needle aspirations of thyroid papillary carcinoma and 14 aspirations of thyroid lesions confirmed to be other than papillary carcinoma but that included cells with nuclear grooving and/or inclusions, comprised of multinodular goiter (four cases), follicular adenoma (two cases), Hurthle cell adenoma (two cases), pure thyroiditis (three cases), and thyroiditis with nodular hyperplasia (three cases). CD44 previously has been shown to be selectively expressed in thyroid papillary carcinoma. RESULTS: Of 16 surgically confirmed cases of thyroid papillary carcinoma featuring nuclear grooves and inclusions on fine-needle aspiration, 14 (88%) stained intensely for CD44 in a membranous pattern. Of the 14 nonpapillary thyroid carcinoma cases, only 1 (7%), a Hürthle cell adenoma, featured membranous CD44 staining. The difference in the proportion of cases with CD44 staining between the two groups was statistically significant (chi-square test, P < 0.001). CONCLUSIONS: The authors conclude that immunostaining for CD44 can readily be performed on thyroid fine-needle aspiration specimens and that, for specimens featuring nuclear grooves and inclusions, the presence or absence of staining for CD44 may be of value in the distinction between thyroid papillary carcinoma and other lesions that may share some of the cytologic features of papillary carcinoma.

Adult↗

PubMed1996

Altered expression of CD44 isoforms in squamous-cell carcinomas and cell lines derived from them.

CD44 is a transmembrane glycoprotein that binds hyaluronan, extracellular matrix proteins and growth factors. Multiple isoforms of CD44 are generated by alternative splicing of 10 separate exons (V1-V10). Expression of the variable exons has been correlated with tumour progression and metastasis in a range of cell types. However, multiple CD44 isoforms are expressed by normal stratified squamous epithelia, such as the epidermis and the lining of the oral cavity. The purpose of our study was to examine CD44 expression in squamous-cell carcinomas (SCC). By immunofluorescence we found reduced expression of one or more of the variant exons in a series of 13 oral SCC, with loss being most common in poorly differentiated tumours. Of the exons we examined, V3 was lost most frequently, but otherwise there was no consistent pattern as to which exons (V4/5, 6, 8) were missing. We also studied CD44 expression in a range of SCC lines, using Western blotting and semi-quantitative RT-PCR. All lines showed reduced expression of the terminal differentiation marker involucrin. Two lines showed selective loss of the largest forms of CD44 and one failed to express any of the variant exons. These cell lines, therefore, provide a useful experimental model with which to study the biological significance of exon loss in SCC.

Alternative Splicing↗

PubMed1996

Immunohistochemical detection of adhesion molecule CD44 splice variants in lymph node metastases of cervical cancer.

Expression of specific cell adhesion molecule CD44 isoforms (splice variants) has been shown to be associated with poor prognosis in human cervical cancer. We used 3 different variant exon sequence-specific murine monoclonal antibodies (MAbs) to epitopes encoded by exons v5, v6 and v7-v8 of human variant CD44 to study the expression of CD44 splice variants in 35 primary squamous-cell carcinomas of the cervix and pelvic lymph node metastases by means of immunohistochemistry. Primary tumors showed expression of CD44 splice variants CD44v5, CD44v6 and CD44v7-8 in 93%, 73% and 33% of cases, respectively. Lymph node metastases expressed CD44v5, CD44v6 and CD44v7-8 in 83%, 53% and 21% of cases, respectively. Tumors with expression of CD44v6 in pelvic lymph node metastases showed metastatic spread to 2 or more pelvic lymph nodes significantly more often compared to patients without expression of splice variant CD44v6. Patients suffering from tumors with lymph node metastases expressing splice variant CD44v6 had a poorer recurrence-free survival compared to patients without CD44v6 expression in lymph node metastases, but this trend was not statistically significant. Expression of CD44 splice variants containing epitopes encoded by exon v6 in primary tumors and pelvic lymph node metastases of cervical cancer patients is consistent with a prominent role of CD44 in the process of metastasis formation.

Adult↗

PubMed2000

Interaction between CD44 and the repeat domain of ankyrin promotes hyaluronic acid-mediated ovarian tumor cell migration.

The adhesion molecule, CD44, interacts with ankyrin within its cytoplasmic domain and binds to hyaluronic acid (HA) at its extracellular domain. In this study, we focused on the functional domain in ankyrin (in particular, the ankyrin repeat domain [ARD]) responsible for CD44 binding and its role in regulating HA-mediated ovarian tumor cell function. Using recombinant fragments of ankyrin (e.g., ARD and subdomain 1 [S1, aa1-aa217], subdomain 2 [S2, aa218-aa381], subdomain 3 [S3, aa382-aa612], and subdomain 4 [S4, aa613-aa834]) and in vitro binding assays, we determined that the S2 but not S1, S3, or S4 of ARD is the primary ankyrin binding region for CD44. Microinjection of antiglutathione S-transferase (GST)-tagged S2 or GST-tagged ARD fusion protein into CD44-positive ovarian tumor cells (e.g., SKOV3 cell line) promotes ankyrin association with CD44 in plaque-like structures and membrane projections. Additionally, we demonstrated that transfection of SKOV3 cells with S2cDNA or ARD cDNA results in an upregulation of HA-mediated tumor cell migration. Taken together, we believe that the S2 of the ARD plays a pivotal role in the direct binding to CD44 and promotes the cytoskeleton activation required for HA-mediated function such as ovarian tumor cell migration.

Amino Acid Sequence↗

PubMed2000

Intracellular osteopontin is an integral component of the CD44-ERM complex involved in cell migration.

Osteopontin (OPN) is a secreted glycoprotein with mineral- and cell-binding properties that can regulate cell activities through integrin receptors. Previously, we identified an intracellular form of osteopontin with a perimembranous distribution in migrating fetal fibroblasts (Zohar et al., J Cell Physiol 170:88-98, 1997). Since OPN and CD44 expression are increased in migrating cells, we analyzed the relationship of these proteins with immunofluorescence and confocal microscopy. A distinct co-localization of perimembranous OPN and cell-surface CD44 was observed in fetal fibroblasts, periodontal ligament cells, activated macrophages, and metastatic breast cancer cells. The co-localization of OPN and CD44 was prominent at the leading edge of migrating fibroblasts, where OPN also co-localized with the ezrin/radixin/moesin (ERM) protein ezrin, as well as in cell processes and at attachment sites of hyaluronan-coated beads. The subcortical location of OPN in these cells was verified by cell-surface biotinylation experiments in which biotinylated CD44 and non-biotinylated OPN were isolated from complexes formed with hyaluronan-coated beads and identified with immunoblotting. That perimembranous OPN represents secreted protein internalized by endocytosis or phagocytosis appeared to be unlikely since exogenous OPN that was added to cell cultures could not be detected inside the cells. A physical association with OPN, CD44, and ERM, but not with vinculin or alpha-actin, was indicated by immunoadsorption and immunoblotting of cell proteins in complexes extracted from hyaluronan-coated beads. The functional significance of OPN in this complex was demonstrated using OPN-/- and CD-/- mouse fibroblasts which displayed impaired migration and a reduced attachment to hyaluronan-coated beads. These studies indicate that OPN exists as an integral component of a hyaluronan-CD44-ERM attachment complex that is involved in the migration of embryonic fibroblasts, activated macrophages, and metastatic cells.

Animals↗

PubMed2000

Osteogenic protein 1 stimulates cells-associated matrix assembly by normal human articular chondrocytes: up-regulation of hyaluronan synthase, CD44, and aggrecan.

OBJECTIVE: To determine the effects of osteogenic protein 1 (OP-1) on hyaluronan (HA), CD44, and aggrecan biosynthesis as well as the contribution of these molecules in promoting matrix assembly by human articular chondrocytes. METHODS: Normal human chondrocytes were cultured with or without OP-1 treatment. Changes in the relative expression of messenger RNA (mRNA) for HA synthases 2 and 3 (HAS-2 and HAS-3), CD44, and aggrecan were determined by competitive quantitative reverse transcriptase-polymerase chain reaction. Accumulation of HA was characterized by indirect staining, CD44 by flow cytometry, and aggrecan biosynthesis by 35SO4 incorporation. RESULTS: OP-1 stimulated the expression of HAS-2, CD44, and aggrecan mRNA in a time-dependent manner, resulting in increased expression of HA, CD44, and aggrecan. Prominent increases in HA-rich cell-associated matrices were also observed. CONCLUSION: OP-1 stimulates not only the synthesis of matrix macromolecules such as aggrecan, but also the synthesis of other molecules required for matrix retention, namely, HA and CD44.

Aggrecans↗

PubMed2004

Inhibition of interleukin-1beta-stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage.

OBJECTIVE: To investigate the mechanism of the inhibitory action of hyaluronan (HA) on interleukin-1beta (IL-1beta)-stimulated production of matrix metalloproteinases (MMPs) in human articular cartilage. METHODS: IL-1beta was added to normal and osteoarthritic (OA) human articular cartilage in explant culture to stimulate MMP production. Articular cartilage was incubated or preincubated with a clinically used form of 800-kd HA to assess its effect on IL-1beta-induced MMPs. Levels of secreted MMPs 1, 3, and 13 in conditioned media were detected by immunoblotting; intracellular MMP synthesis in chondrocytes was evaluated by immunofluorescence microscopy. Penetration of HA into cartilage tissue and its binding to CD44 were analyzed by fluorescence microscopy using fluoresceinated HA. Blocking experiments with anti-CD44 antibody were performed to investigate the mechanism of action of HA. RESULTS: Treatment and pretreatment with 800-kd HA at 1 mg/ml resulted in significant suppression of IL-1beta-stimulated production of MMPs 1, 3, and 13 in normal and OA cartilage explant culture. Fluorescence histocytochemistry revealed that HA penetrated cartilage tissue and localized in the pericellular matrix around chondrocytes. HA-binding blocking experiments using anti-CD44 antibody demonstrated that the association of HA with chondrocytes was mediated by CD44. Preincubation with anti-CD44 antibody, which suppressed IL-1beta-stimulated MMPs, reversed the inhibitory effect of HA on MMP production that was induced by IL-1beta in normal and OA cartilage. CONCLUSION: This study demonstrates that HA effectively inhibits IL-1beta-stimulated production of MMP-1, MMP-3, and MMP-13, which supports the clinical use of HA in the treatment of OA. The action of HA on IL-1beta may involve direct interaction between HA and CD44 on chondrocytes.

Antibodies, Blocking↗

PubMed1990

The ontogeny of human lymphocyte recirculation: high endothelial cell antigen (HECA-452) and CD44 homing receptor expression in the development of the immune system.

In the present report we have studied the expression of a lymphocyte homing receptor, the CD44 antigen, and of HECA-452, a high endothelial-specific antigen, during the development of the human immune system. We found that prothymocyte immigrants of the thymus already expressed the CD44 antigen. Similarly, the first peripheral T lymphocytes in fetal lymph nodes, tonsils and gut-associated lymphoid tissue were also CD44+. Cortical thymocytes and germinal center cells were CD44-. CD44 antigen expression was, thus, not limited to mature recirculating lymphocytes. This suggests that CD44 may not only be involved in recirculation of mature lymphocytes but also in the migration of prothymocytes to their site of maturation, i.e. the thymus. High endothelial venules (HEV) were not demonstrable at the early onset of lymphocyte immigration into the developing lymphoid organs. However, when large-scale influx of lymphocytes occurred, it paralleled HEV development. HECA-452 antigen expression preceded the morphological transformation of endothelium into a HEV phenotype. Expression of this antigen therefore, independently reflected the specialized nature of high endothelium. In a patient with complete DiGeorge's syndrome normal HEV developed, indicating that the presence of T lymphocytes is not a requirement for HEV development. Interestingly, a subpopulation of venules located in the thymic medulla near the cortico-medullary junction expressed the HECA-452 antigen. These vessels, which had flat or intermediately high endothelium, are probably involved in lymphocyte migration to the thymus.

Antibodies, Monoclonal↗

PubMed1997

Complex CD44 splicing combinations in synovial fibroblasts from arthritic joints.

CD44 is a broadly expressed cell surface glycoprotein which is the major cell surface receptor for the glycosaminoglycan, hyaluronan. In humans, alternative splicing of up to 9 variant exons (v2-v10) into CD44 mRNA, together with post-translational modification via glycosylation and chondroitin sulfate attachment has the potential of generating a large number of CD44 isoforms. Insertion of these various exons has the potential to change the functional capacities of the molecule and has implications in disease. We have analyzed CD44 splice variant expression in cultured VCAM-1-positive synovial fibroblasts isolated from patients with osteo- or rheumatoid arthritis and from normal synovium. Rheumatoid and osteoarthritic tissue express CD44 splice variants at the cell surface level. At the mRNA level exons v3, v6, v7, v8, v9 and v10 were detected in different splicing combinations. Rheumatoid tissue showed high expression, osteoarthritic tissues showed great variation. In contrast, non-inflamed tissue showed no splicing events. Our results indicate that the nature of CD44 splice variant expression may be linked to the inflammatory state of the synovial joint.

Alternative Splicing↗

PubMed2003

Malignant peripheral nerve sheath tumor cell invasion is facilitated by Src and aberrant CD44 expression.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies that arise within peripheral nerves. These tumors occur with increased incidence in patients with neurofibromatosis type 1 (NF1), exhibiting increased Ras activity due to loss of the NF1 gene product, neurofibromin, and abnormal expression of the epidermal growth factor receptor (EGFR). We previously found that MPNSTs express increased levels of the CD44 family of transmembrane glycoproteins that have been implicated in tumor cell invasion and metastasis. In two MPNST cell lines, we have found that elevated CD44 expression and cell invasion are dependent on Src kinase activity but are independent of mitogen-activated protein kinases (MAPK) kinase (MEK) activity. In contrast, inhibition of Src kinase activity has no influence on MPNST cell proliferation. Reduction of CD44 levels, using antisense oligonucleotides, results in reduced MPNST cell invasion in vitro, suggesting that Src contributes in part to MPNST cell invasion by increasing CD44 levels. At least some of this increased CD44 expression results from elevated EGFR levels through a Src-dependent mechanism, consistent with the notion that EGFR promotes constitutive Src activation in MPNSTs. These data indicate that Src and CD44 are putative targets for the treatment of MPNST invasion and metastasis.

Enzyme Inhibitors↗

PubMed2004

CD44 overexpression by oligodendrocytes: a novel mouse model of inflammation-independent demyelination and dysmyelination.

The CD44 transmembrane glycoprotein family has been implicated in cell-cell adhesion and cell signaling in response to components of the extracellular matrix but its role in the nervous system is not understood. CD44 proteins are elevated in Schwann cells and oligodendrocytes following nervous system insults, in inflammatory demyelinating lesions, and in tumors. Here, we tested the hypothesis that elevated CD44 expression influences Schwann cell and oligodendrocyte functions by generating transgenic mice that express CD44 under the control of the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) promoter. These mice failed to develop peripheral nerve or CNS tumors. However, they did develop severe tremors that were associated with CNS dysmyelination and progressive demyelination. Loss of CNS myelin was not due to alterations in early oligodendrocyte precursor differentiation, proliferation, or survival. Myelination in the PNS appeared normal. In no instance was there any evidence of an inflammatory response that could account for the loss of CNS myelin. These findings suggest that CNPase-CD44 mice are a novel model for noninflammatory progressive demyelinating disease and support a potential role for CD44 proteins expressed by glial cells in promoting demyelination.

Animals↗

PubMed1992

Differential expression of the CD44 molecule in human brain tumours.

Expression of the CD44 molecule was examined in a variety of human brain tumours, brain metastases and normal brain. Immunohistological staining with several CD44 antibodies demonstrated differential expression of the CD44 molecule among different brain tumour types. CD44 was strongly expressed in high-grade gliomas and weakly expressed in meningiomas, medulloblastomas and normal brain. Northern blot analysis revealed the presence of 3 major CD44 mRNAs of 1.6, 2.2, and 5.0 kb in glioblastomas and a mRNA of 5.6 kb in meningiomas. CD44 expression was also detected by flow cytometric analysis on cultured cells derived from a variety of human brain tumours including glioblastomas and meningiomas.

Brain Neoplasms↗

PubMed1994

Expression of alternatively spliced forms of the CD44 extracellular-matrix receptor on human lung carcinomas.

Expression of isoforms of the CD44 hyaluronan receptor/lymph-node endothelial receptor by human tumour cells is thought to play a role in tumour growth and metastasis. These isoforms which vary in the length of the extracellular domain are generated by differential RNA splicing that involves the 10 alternative exons (v1 to v10) encoding the membrane proximal region of the molecule. Several tumours have been shown to over-express CD44 containing the v6 exon, and this, together with other evidence, has led to the suggestion that v6 may play a causative role in tumour metastasis. In this report we have compared the expression of CD44 isoforms between different lung tumour lines, including SCLC, squamous-cell carcinoma, adenocarcinoma and mesothelioma, using both RT-PCR and fluorescent antibody staining with a panel of CD44 exon-specific monoclonal antibodies (MAbs). Our results show large differences in vCD44 expression between individual tumour lines. Little or no vCD44 containing the metastasis-associated v6 exon was detected in most tumours, including the highly metastatic SCLC lines. Indeed, the SCLC lines and some squamous-cell carcinomas contained only very low levels of either vCD44 or CD44H, indicating that CD44 expression may not always correlate with tumour development or dissemination. One of the squamous-cell carcinomas studied (HOTZ) was found to express a complex mixture of CD44 splice variants similar to the immortalized normal bronchial epithelial line BEAS-2B. Cloning and sequencing of vCD44 from the HOTZ cell line yielded several splice variants that have also been identified on leukaemic cells, normal keratinocytes and activated peripheral-blood lymphocytes.

Alternative Splicing↗