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PubMed1996

Distribution of CD44 in the retina during development and the rds degeneration.

It was previously demonstrated that the 90 kDa cell adhesion molecule CD44 is localized to Müller cell apical microvilli which project into the interphotoreceptor matrix in the adult retina. For the current report, the distribution of CD44 was studied in developing normal BALB/c mouse retinas and in rds mutant mouse retinas of various ages. Using immunoperoxidase techniques, positive label for CD44 was first detected on Müller cell microvilli after 7 days postnatal in BALB/c retinas and the band of label widened as the microvilli elongated and the retina reached maturity. Labeling of the radiating Müller cell bodies within the retina was also observed during development, and this distribution of CD44 is most likely related to retinal cell differentiation and maturation which are taking place at this time. This label was not observed in mature retinas. In the rds mouse retina, a normal labeling pattern for CD44 was observed on Müller cell microvilli at early ages, prior to photoreceptor degeneration. During the time course of the degeneration, microvillar labeling was still seen, however labeling of the radiating Müller cell bodies within the retina increased dramatically. Following degeneration, the Müller cell microvilli appeared to have retracted or collapsed and the inner retinal labeling was not observed. Only a residual label remained at the level of the outer limiting membrane. The increased presence of CD44 within the rds retina during photoreceptor degeneration is likely due to an upregulation of CD44 synthesis by the Müller cells and/or to the transfer of CD44 from retracting microvilli into lower portions of the Müller cells.

Age Factors↗
PubMed1995

CD44 expression and modulation on human neuroblastoma tumours and cell lines.

The human CD44 cell surface glycoprotein has been involved in a variety of functions including lymphocyte homing, extracellular cell matrix attachment and tumour metastasis. A large family of variants or isoforms, generated by alternative splicing of a single gene, has been reported to be involved in the malignant process, by conferring metastatic potential to non-metastatic cells. Neuroblastoma is a tumour characterised by an aggressive and metastatic behaviour in advanced stages, with amplification of the MYCN protooncogene. In this report, we show that the CD44 standard molecule was highly expressed in the majority of tumours of stages 1-3, in all stage 4s and ganglioneuromas, but only in a subset of stage 4 tumours. A lack of CD44 expression was observed in all MYCN amplified stage 4 tumours, thus demonstrating a highly significant inverse relationship between MYCN amplification and CD44 expression in neuroblastoma. In addition, the expression of 4 different CD44 isoforms was measured on all specimens and was always found to be negative. Using neuroblastoma cell lines and MYCN expressing transfectants, we show that CD44 expression by neuroblastoma cell lines is not directly related to MYCN amplification, but is associated to the stage of differentiation or lineage, and to the tumorigenic properties of the cells. In addition, CD44 expression can be upmodulated parallel to differentiation or maturation as induced by retinoic acid, bromodeoxyuridine or phorbol ester. In contrast, cytokines such as IFN gamma, TNF alpha, or growth factors such as bFGF, SCF and TGF beta were ineffective in modulating CD44 expression.

Biomarkers, Tumor↗
PubMed2006

CD44-v6 expression in smooth muscle cells in the postnatal remodeling process of ductus arteriosus.

Closure of the ductus arteriosus (DA) is due to functional constriction followed by wall remodeling, with neointimal formation caused by proliferation and migration of smooth muscle cells (SMCs) from the media to subendothelium. CD44 is a surface cell proteoglycan family. Its isoform, CD44-v6, is only minimally expressed in SMCs in the media of normal arteries, but is highly expressed in SMCs in the intima and media of injured arteries (e.g., atherosclerosis). Twenty-two autopsy DA specimens, 11 from full-term babies (age range 2 days to 5 months) and 11 from premature babies (age range 3 days to 5 months), with varying degrees of ductal wall remodeling, were evaluated by immunohistochemistry using antiactin, antifibronectin-extradomain A, anti-leukocyte common antigen, anti-CD44, and anti-CD44-v6. In DA with wall remodeling, synthetic antifibronectin-extradomain A-positive SMCs were evident at the neointimal mounds, and the SMCs were highly positive for the CD44-v6 isoform, irrespective of gestational age at birth. Conversely, SMCs of either closed DAs or persistently patent DAs were CD44-v6 negative. In conclusion, the present data provide evidence that closure of DA involves synthetic SMCs highly positive for CD44-v6, and patent or closed DAs are populated by CD44-v6-negative SMCs.

Ductus Arteriosus↗
PubMed2005

Expression of CD44 mRNA induced by interleukin-1beta in human cultured uterine cervical fibroblasts.

OBJECTIVE: Hyaluronic acid in the cervix plays an important role in the process of cervical ripening. CD44 is a receptor for hyaluronic acid. We investigated whether CD44 is related to cervical ripening by examining the expression of CD44 mRNA in human cultured cervical fibroblasts with or without inflammatory cytokines. STUDY DESIGN: CD44 mRNA expressions derived from cultured human uterine cervical fibroblasts in the presence or absence of interleukin-1beta (IL-1beta) (1-100 pg/ml) or interleukin-8 (IL-8) (1-100 ng/ml) were analyzed by the Northern blot analysis. The human CD44 cDNA probe was hybridized with three species of mRNA. Sizes of the mRNAs were 1.6, 2.2, and 5.0 kilobases (kb). RESULTS: Interleukin-1beta stimulated the expression of CD44 mRNA in a dose-dependent manner. Interleukin-8 did not stimulate the expression. CONCLUSIONS: It is concluded from the present study that human cervical CD44 mRNA expression is induced by interleukin-1beta. Accordingly, we deduce that the concentration of hyaluronic acid in the cervical tissue is increased because of the expression of CD44.

Cells, Cultured↗
PubMedDate not supplied

Differential expression of CD44 in canine melanocytic tumours.

CD44, the main cell surface receptor for hyaluronan (HA), is often overexpressed in tumour cells, and its presence has been related to cell proliferation and migration. Many of the functions of CD44 are mediated through its interaction with hyaluronan. This study investigated the expression of CD44 in CML-1 and CML-10c2 canine melanoma cell lines and melanoma biopsies, and the production of hyaluronan and versican by the canine melanoma cell lines. Versican is an extracellular proteoglycan that binds hyaluronan, forming a tridimensional pericellular coat surrounding the cells. Both canine melanoma cell lines expressed CD44 and produced HA, but only CML-1 produced versican. Cells expressing all three components (CD44, HA and versican) formed abundant extracellular matrices as demonstrated by a particle exclusion assay. CD44 was present within benign and malignant melanomas, but its expression was more intense in malignant melanomas (P < 0.01). In high CD44-expressing tumours, CD44 tended to be present in the periphery of malignant melanomas, whereas its expression was homogeneous in benign melanomas.

Animals↗
PubMedDate not supplied

Tubular CD44 expression in renal allograft biopsies.

CD44 is a type I transmembrane glycoprotein serving as a cell adhesion receptor, whose main ligand is hyaluronic acid, but also may interact with collagen, laminin, fibronectin, and osteopontin. This marker is involved in cell migration, homing, activation, metastasis, and inflammation. Tubular CD44 expression has been shown to correlate with scarring in renal diseases, but there is little data on allograft biopsies. This deficiency is important since experimental studies have shown that blockade of the CD44-hyaluronic acid interaction may prolong allograft survival. In an attempt to clarify the role of tubular CD44 expression in renal allografts, CD44 expression was determined immunohistochemically in 37 allograft and 10 implantation biopsies, as the percentage of tubules expressing this marker. For implantation biopsies the mean tubular CD44 expression was 6% +/- 14%; for allograft biopsies, 13% +/- 20% (P =.17, Mann-Whitney U). By the Spearman correlation test, CD44 expression did not correlate with Banff scores, but was moderately correlated with serum creatinine values at the time of biopsy (P =.017, r =.4). These findings suggest an important role of tubular CD44 expression in renal allografts. It appears to be induced by more than one pathway, resulting in a pattern of expression that correlated with renal function. However larger series are required before recommending the routine use of this marker.

Adult↗
PubMed2004

CD44 expression identifies astrocyte-restricted precursor cells.

The precise lineage between neural stem cells and mature astrocytes remains poorly defined. To examine astrocyte development, we have characterized glial precursors from neural tissue derived from early embryonic ages. We show that CD44 identifies an astrocyte-restricted precursor cell (ARP) that is committed to generating astrocytes in vitro and in vivo in both rodent and human tissue. CD44+ cells arise later in development than neuronal-restricted precursors (NRPs) or tripotential glial-restricted precursors (GRPs). ARPs are distinguished from GRP and NRP cells by their antigenic profile and differentiation ability. ARPs can be generated from GRP cells in mass or clonal cultures and in vivo after transplantation, suggesting a sequential differentiation of neuroepithelial stem cells (NEPs) to GRPs to ARPs and then to astrocytes. The properties of ARPs are different from other astrocyte precursors described previously in their expression of CD44 and S-100beta and absence of other lineage markers. Using a CD44 misexpression transgenic mouse model (CNP-CD44 mouse), we show that CD44 overexpression in vivo and in vitro decreases the number of mature glia and increases the number of O4+/GFAP+ cells tenfold. Misexpression of CD44 in culture inhibits oligodendrocytes and arrests cells at the precursor state. In summary, our data provide strong evidence for the existence of a CD44+ ARP in the developing nervous system.

Animals↗
PubMed2005

Regulation of hyaluronan binding by F-actin and colocalization of CD44 and phosphorylated ezrin/radixin/moesin (ERM) proteins in myeloid cells.

Proinflammatory cytokines such as TNF-alpha up-regulate the expression of the cell adhesion molecule, CD44, and induce hyaluronan (HA) binding in peripheral blood monocytes (PBM). Here we show that in PBM, TNF-alpha induced cytoskeletal rearrangement, increased threonine phosphorylation of ERM proteins, and induced the redistribution and colocalization of phospho-ERM proteins (P-ERM) with CD44. In the myeloid progenitor cell line, KG1a, hyaluronan binding occurred in the pseudopod where CD44, P-ERM, and F-actin were highly localized. Hyaluronan binding correlated with high expression of both CD44 and P-ERM clustered in a single pseudopod. Disruption of polymerized actin reduced hyaluronan binding in both PBM and KG1a cells and abolished CD44 clustering and the pseudopod in KG1a cells. The pseudopod was not required for the clustering of CD44, the colocalization with P-ERM, or hyaluronan binding. However, treatment with a kinase inhibitor abolished ERM phosphorylation and reduced hyaluronan binding. Furthermore, expression of CD44 lacking the putative ERM binding site resulted in reduced hyaluronan binding. Taken together, these data suggest that CD44-mediated hyaluronan binding in human myeloid cells is regulated by P-ERM and the actin cytoskeleton.

Actins↗
PubMed2004

CD44 cross-linking induces integrin-mediated adhesion and transendothelial migration in breast cancer cell line by up-regulation of LFA-1 (alpha L beta2) and VLA-4 (alpha4beta1).

CD44, a widely expressed cell surface glycoprotein, plays a major role in cell-cell adhesion, cell-substrate interaction, lymphocyte homing, and tumor metastasis. For tumor metastasis to occur through the blood vessel and lymphatic vessel pathway, the tumor cells must first adhere to endothelial cells. Recent studies have shown that high expression of CD44 in certain types of tumors is associated with the hematogenic spread of cancer cells. However, the functional relevance of CD44 to tumor cell metastasis remains unknown. In this study, we investigated the mechanisms of CD44 cross-linking-induced adhesion and transendothelial migration of tumor cells using MDA-MB-435S breast cancer cell line. Breast cancer cells were found to express high levels of CD44. Using flow cytometric analysis and immunofluorescence staining, we demonstrated that cross-linking of CD44 resulted in a marked induction of the expression of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) by exocytosis. These results were also observed with the Hs578T breast cancer cell line. Furthermore, LFA-1- and VLA-4-mediated adhesion and transendothelial cancer cell migration were also studied. Anti-LFA-1 mAb or anti-VLA-4 mAb alone had no effect on adhesion or transendothelial cancer cell migration, but were able to inhibit both of these functions when added together. This shows that CD44 cross-linking induces LFA-1 and VLA-4 expression in MDA-MB-435S cells and increases integrin-mediated adhesion to endothelial cells, resulting in the transendothelial migration of breast cancer cells. These observations provide direct evidence of a new function for CD44 that is involved in the induction of LFA-1 and VLA-4 expression by exocytosis in MDA-MB-435S cells. Because these induced integrins promote tumor cell migration into the target tissue, it may be possible to suppress this by pharmacological means, and thus potentially cause a reduction in invasive capability and metastasis.

Breast Neoplasms↗
PubMed2004

CD44 promotes resistance to apoptosis in human colon cancer cells.

Overexpression of CD44, especially its variant isoforms, occurs consistently in colon cancer, as compared to autologous normal colon, and this change occurs also in most other types of cancer. One of the basic features of malignant transformation is the acquisition of resistance to apoptosis. In this study, we asked whether the expression of CD44 and some of its variant isoforms commonly found in colon cancer participate in resistance to apoptosis and what are the mechanisms involved. A human colon cancer cell line, SW620, which does not express CD44 was stably transfected with standard, v3-10, and v8-10 containing isoforms of CD44. Mock-transfected and CD44-transfected cells were exposed to etoposide to induce apoptosis. Apoptotic and concomitant changes relevant to the mechanisms of apoptosis were monitored by flow cytometry, DNA fragmentation, and immunoblot analyses. It was observed that resistance to apoptosis induced by etoposide is promoted by CD44 expression in SW620, and this resistance is better sustained by the full variant isoform, v3-10. Concomitant alterations in caspase 9, caspase 3, Bcl-xl, and Bak indicated that the resistance to apoptosis in this model involved the mitochondrial pathway. The differential response of CD44 transfectants was associated with a downregulation of pRb and phosphorylated AKT. The results of this study are consistent with the conclusion that expression of variant CD44 isoforms which is characteristic of colon cancer, and most other types of cancer, confers a selective advantage to resist apoptosis, thereby promoting cell transformation into a malignant phenotype, in conjunction with other anti-apoptotic factors.

Adenocarcinoma↗
PubMed2005

Upregulation and dephosphorylation of cofilin: modulation by CD44 variant isoform in human colon cancer cells.

Colon cancer is among the leading causes of cancer death in North America. Dysregulation of the crypt homeostasis is evident in the early stage of colon cancer. Moreover, cytoskeletal rearrangement of actin also plays a crucial role in morphological changes during apoptosis. CD44, an adhesion and anti-apoptotic molecule is overexpressed in colon cancer and is known to interact with certain cytoskeletal proteins. In this study, we used the human colon cancer cell line SW620, which does not express CD44 but stably transfected with standard, 3-10v and 8-10v variant isoforms of CD44. By two-dimensional isoelectric focusing (2DIEF), we found an increasing concentration of a 21-kDa protein in SW620 colon cancer cells transfected with CD44 3-10v, as compared to cells transfected with an empty vector. Mass spectrometry (MS) and proteomic analysis of this protein identified the peptide fragment (YALYDATYETK) of 11 amino acids in length spanning residue 82 to 92 of cofilin, a widely distributed 21-kDa actin-modulating protein. Western blot analysis of lysates from cells expressing CD44 variant isoforms 3-10v had increased level of expression of cofilin compared to vector control consistent with our finding by 2DIEF. Also, immunocytochemistry showed that cofilin expression in colonic epithelial cells was greater in cells transfected with CD44 3-10v, as compared to vector controls. We observed that the phosphorylated form of cofilin is downregulated in cells expressing the 3-10v isoform of CD44 both by Western blot and immunocytochemistry. Cofilin expression is thus mechanistically associated with CD44 expression and its 3-10v isoform. Dephosphorylation of cofilin could bring about directional motility of cells that could have important implications to the proliferation and motility of colonic epithelial cells in cancer.

Actin Depolymerizing Factors↗
PubMed2000

Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer.

In colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms, which contain a site for HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.

Colorectal Neoplasms↗
PubMed2000

Perturbation of hyaluronan interactions by soluble CD44 inhibits growth of murine mammary carcinoma cells in ascites.

Hyaluronan accumulates in ascites during intraperitoneal proliferation of TA3/St murine mammary carcinoma cells and at sites of their invasion of the peritoneal wall. To determine whether hyaluronan is functionally involved in these events, ascites tumor formation was compared in mice injected intraperitoneally with stable transfectants of TA3/St cells that overexpress soluble CD44, a hyaluronan-binding protein, versus in mice injected with transfectants expressing mutated soluble CD44 that does not bind hyaluronan. The soluble CD44 transfectants temporarily grew at a reduced rate within the peritoneal cavity, then went into G(1) arrest and were subsequently cleared from the peritoneum. However, transfectants overexpressing mutant soluble CD44 that does not bind hyaluronan exhibited similar ascites accumulation, growth rates, and cell-cycle profiles in vivo to wild-type and vector-transfected TA3/St cells, all of which continued to grow until the tumors became fatal. The soluble CD44-transfected TA3/St cells also failed to attach to and form tumors in the peritoneal wall. When grown in vitro in soft agar, the soluble CD44 transfectants exhibited a dramatic reduction in colony formation compared to wild-type, vector-transfected, and mutant soluble CD44-transfected TA3/St cells. Thus, perturbation of hyaluronan interactions by soluble CD44 has a direct effect on the growth characteristics of these tumor cells, leading to inhibition of anchorage-independent growth in vitro and ascites growth in vivo.

Animals↗
PubMed2003

Motility of colon cancer cells: modulation by CD44 isoform expression.

The invasion of cancer cells at primary tumor sites and their migration during metastatic spread require the expression of cell adhesion and motility proteins. Whether accelerated cell motility is necessary in these two processes is not universally accepted. In this study we took advantage that CD44, a cell adhesion protein, has different metastatic potentials depending on its splicing isoforms to examine how they affect cell motility. We established stable transfectants of standard and variant isoforms of CD44 in SW620 cells, a human colon carcinoma cell line that does not express CD44. The morphology of the cells varied according to the CD44 isoform expressed, but actin filament distribution remained unchanged. Using the wound assay in a two-dimensional in vitro cell motility system, we found that the expression of standard CD44 increases cell motility, whereas CD44 isoforms containing an exon sequence associated with metastatic dissemination has a slowing effect. Cell proliferation was also decreased by the expression of variant CD44 isoforms. Overall, colon cancer cells expressing variant CD44 isoforms had slower cell motility, possibly due to alterations in their cell adhesion properties. In conclusion, this study suggests that, contrary to common models, the metastatic phenotype is associated with a slow rate of cell migration when tested in vitro.

Actins↗
PubMed1998

Expression of CD44 (HCAM) in small lymphocytic and mantle cell lymphoma.

Small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL) are small B-cell lymphomas that share many morphological and immunophenotypic features, both expressing the T-cell antigen CD5. Because of this, there is speculation that these two lymphomas may have a common origin, both arising from the mantle zone of the lymph node. CD44 (HCAM), a glycoprotein "homing receptor," has been reported as a marker of small B-cell lymphomas for determining behavior as well as the nodal cell of origin. Intensity of CD44 expression also has been correlated with dissemination of lymphoma. We studied 50 cases with classic features of SLL (30 cases) or MCL (20 cases). Immunophenotypic analysis was performed on paraffin sections. All cases of MCL and SLL were CD20 positive; CD5 was expressed in 19 of 25 (76%) SLL and 11 of 15 (73%) MCL. Cyclin D1 was expressed in 11 of 17 (76%) MCL and no cases of SLL. CD43 coexpression was seen in 27 of 29 (93%) SLL and 17 of 19 (89%) MCL. CD23 was positive in 25 of 28 (89%) SLL and 2 of 20 (10%) MCL. Bcl-2 was positive in 18 of 22 (82%) SLL and 15 of 16 (94%) MCL. CD44 was positive with moderate to strong intensity in 11 of 30 SLL and 15 of 20 MCL. Peripheral blood involvement did not correlate with CD44 immunoreactivity. MCL tended to have intense CD44 immunoreactivity, whereas SLL tended to show weaker CD44 intensity. This trend in the intensity of CD44 in MCL suggests that CD44 may be helpful in distinguishing SLL from MCL and possibly elucidating the origin of these CD5-positive B-cell neoplasms.

Adult↗
PubMed1997

Differential expression of CD44 splice variants in the normal human central nervous system.

Cluster of differentiation 44 (CD44) is a broadly distributed group of glycoproteins that are involved in many functions related to cell-cell and cell-matrix interactions. In the present study, the expression of the standard form of CD44 (CD44s) and of CD44 variants (CD44v) was explored immunohistochemically on frozen sections of various areas of the human CNS. The results demonstrate that CD44s epitopes are expressed predominantly by white matter astrocytes, whereas different CD44 variant molecules are present in neurons, on axonal membranes, on endothelium or on choroid plexus epithelium. Interestingly, neurons and axons differentially expressed CD44 variant epitopes but consistently lack immunoreactivity for CD44s epitopes. Another interesting finding was that some CD44 variant epitopes expressed by neurons were localized in the cytoplasm instead of on the cell membrane. The broad distribution of variant CD44 molecules in the human CNS suggests that CD44 may play an important role in many biological processes in the CNS.

Aged↗
PubMed2002

CD44 stimulation by fragmented hyaluronic acid induces upregulation and tyrosine phosphorylation of c-Met receptor protein in human chondrosarcoma cells.

Hepatocyte growth factor/scatter factor (HGF/SF) can induce proliferation and motility and promote invasion of tumor cells. Since HGF/SF receptor, c-Met, is expressed by tumor cells, and since stimulation of CD44, a transmembrane glycoprotein known to bind hyaluronic acid (HA) in its extracellular domain, is involved in activation of c-Met, we have studied the effects of CD44 stimulation by ligation with HA upon the expression and tyrosine phosphorylation of c-Met on human chondrosarcoma cell line HCS-2/8. The current study indicates that (a) CD44 stimulation by fragmented HA upregulates expression of c-Met proteins; (b) fragmented HA also induces tyrosine phosphorylation of c-Met protein within 30 min, an early event in this pathway as shown by the early time course of stimulation; (c) the effects of HA fragments are critically HA size-dependent. High molecular weight HA is inactive, but lower molecular weight fragments (M(r) 3.5 kDa) are active with maximal effect in the microg/ml range; (d) the standard form of CD44 (CD44s) is critical for the response because the effect on c-Met, both in terms of upregulation and phosphorylation, is inhibited by preincubation with an anti-CD44 monoclonal antibody; and (e) phosphorylation of c-Met induced by CD44 stimulation is inhibited by protein tyrosine kinase inhibitor, tyrphostin. Therefore, our study represents the first report that CD44 stimulation induced by fragmented HA enhances c-Met expression and tyrosine phosphorylation in human chondrosarcoma cells. Taken together, these studies establish a signal transduction cascade or cross-talk emanating from CD44 to c-Met.

Chondrosarcoma↗
PubMed1997

Correlation of MYCN amplification, Trk-A and CD44 expression with clinical stage in 250 patients with neuroblastoma.

In contrast to MYCN amplification, expression of either trk-A or CD44 in neuroblastoma is a favourable prognostic factor and were therefore investigated in tumours from 250 patients. One hundred and eleven localised/4s (Group 1) and 139 stage 4 (Group 2) tumours were analysed. MYCN copy number was obtained by Southern blotting or PCR amplification and was detected in 28 stage 4 tumours. Trk-A and CD44 expression was detected by immunoperoxidase staining using murine monoclonal antibodies 5C3 and L178, respectively. Expression was scored as positive (homogeneous), mixed (heterogeneous) or non-reactive (negative). Trk-A expression was found in 95% of Group 1 tumours and 49% of Group 2 tumours. CD44 expression was found in 100% of Group 1 tumours, the majority of which had a strong homogeneous expression. Lack of CD44 expression occurred in 25% of tumours, all stage 4 neuroblastoma. Of the 28 MYCN amplified tumours, 27/28 (96%) were trk-A negative, and 13/28 (46%) CD44 negative. We conclude that (1) a significant percentage of stage 4 neuroblastoma express either or both trk-A and CD44, (2) the absence of CD44 expression is highly restricted to stage 4 neuroblastoma and is associated with the lack of trk-A expression, (3) trk-A negativity among CD44-positive tumours is associated with stage 4 neuroblastoma and (4) the absence of trk-A expression is highly correlated with MYCN amplification.

Carrier Proteins↗