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PubMedDate not supplied

Do the expression of CD44, apoptosis and thymidylate synthase inhibition rate correlate with the efficacy of chemotherapy in colorectal cancer?

BACKGROUND: Tegafur-uracil(UFT;TAIHO Pharmaceutical Co.Ltd, Tokyo, Japan) is commonly used to treat digestive cancers. However, the inhibitors of metastasis in this agent have not been fully examined. To investigate a cell adhesion molecule, CD44, which may very well contribute to the pathogenesis of metastasis, we examined the association of CD44 and the thymidylate synthase inhibition rate(TSIR) with prognosis, and examined the expression of apoptosis in patients who were administrated tegafur-uracil before surgery for colorectal cancer. MATERIALS AND METHODS: This study included 66 patients who underwent curative resection of colorectal cancer. In these patients, tegafur-uracil(600 mg) was orally administered every day for 3 to 7 days before surgery, and Tegafur-uracil (400 mg) was orally administered every day for 2 years after surgery. CD44 and apoptosis were detected immunohistochemically and by the TUNNEL method, respectively. The TSIR was calculated from the total TS level, and free TS levels by modified Spears' method using fresh tumor tissue specimens. RESULTS: The TSIR of non-recurrent patients was significantly higher than that of recurrent patients(p < 0.05). The 5-year survival rate in CD44-low grade positive/negative patients (81.6%) was significantly higher than that in CD44-high grade positive patients (46.4%) (p < 0.005). The 5-year survival rate in apoptosis-high grade positive patients (89.7%) was significantly higher than that in apoptosis-low grade positive/negative patients(46.4%) (p < 0.001). With respect to the relationship between CD44 and apoptosis, the proportion of apoptosis-high grade positive patients among CD44-low grade positive/negative patients (55.3%) was significantly higher than that among CD44-high grade positive patients(28.6%) (p < 0.05). In the multivariate analysis, the CD44 expression was suggestive of an independent prognostic factor. CONCLUSION: Based on our results for TSIR, Tegafur-uracil may induce apoptosis of tumor cells in patients by the inhibition of thymidylate synthase. It was suggested that CD44 expression could be used as a possible independent predictor of survival. In addition, it was suggested that UFT, via the inhibition of CD44 expression caused the inhibition of distant metastasis.

Aged↗
PubMed1994

A novel form of congenital dyserythropoietic anemia associated with deficiency of erythroid CD44 and a unique blood group phenotype [In(a-b-), Co(a-b-)].

We have used a panel of well-characterized monoclonal antibodies (MoAbs) to examine the blood cells of a patient with a novel form of congenital dyserythropoietic anemia (CDA) characterized by intra-erythroblastic and intra-erythrocytic membranous inclusions. Twelve antibodies defining three nonoverlapping epitope groups on the extracellular domain of CD44 all failed to react with the red blood cells (RBCs) of the patient. A rabbit antibody to the cytoplasmic domain of CD44 from normal RBCs failed to react with the patient's RBC ghosts. In contrast, the patient's lymphocytes, granulocytes, and monocytes showed apparently normal CD44 expression. Bone marrow preparations stained with CD44 antibodies and visualized with 125I antimouse Ig (F(ab')2) followed by autoradiography showed positive staining of lymphocytes and myeloid cells but not of most orthotolidine-positive erythroblasts. The patient's RBCs also gave weaker than normal reactions with MoAbs of anti-LWab specificity while MoAbs to glycophorins A, B, and C, Rh polypeptides, CD47, CD55, CD58, CD59, acetylcholinesterase, and Lutheran and Kell glycoproteins all gave normal reactions. Agglutination tests with human blood grouping sera demonstrated that the RBCs of the patient have the unique phenotype In(a-b-), Co(a-b-) and that they also lack the high incidence RBC antigen AnWj. The phenotype In(a-b-) would be expected because these antigens are known to be expressed on CD44. There is also some evidence associating the AnWj antigen with CD44. However, the CO blood group locus is on chromosome 7p whereas that for CD44 is on chromosome 11p. Quantitative binding assays using 125I-labeled Fab fragments of CD44 antibodies did not show any evidence for reduced levels of CD44 on RBCs from the parents of the patient or from her unaffected sister. The parents and sister had the common Colton blood group phenotype [Co(a+b-)]. Neither deficiency of CD44 nor absence of Colton antigens are general features of CDA because erythrocytes from patients with CDA I, CDA II, CDA III, and two other unclassified CDAs had normal expression of CD44 and normal Colton blood group phenotypes. Further analysis of the defect(s) present in the patient's erythroid cells may provide useful information regarding membrane assembly and the regulation of differentiation in normal erythroid cells.

Anemia, Dyserythropoietic, Congenital↗
PubMed1994

Different splice variants of CD44 are expressed in gastrinomas but not in other subtypes of endocrine pancreatic tumors.

Endocrine pancreatic tumors are neuroendocrine neoplasms with malignant potential and give rise to varied clinical syndromes due to excessive secretion of multiple hormones. In this study 22 endocrine pancreatic tumors and 11 carcinoid tumors were examined for the expression of CD44 using a monoclonal antibody. CD44 gene activity of 11 endocrine pancreatic tumor tissues and five carcinoid tumor tissues was also studied by amplifying messenger RNA with the polymerase chain reaction followed by electrophoresis and blot hybridization. Strong immunoreactivity was detected on all gastrinomas examined (P < 0.001), and in two non-functioning endocrine pancreatic tumors. Such immunoreactivity was not observed in other subtypes of endocrine pancreatic tumors. In the normal human pancreas, the acinar portion and ductal epithelial cells stained strongly positive but pancreatic islet cells did not show any significant immunostaining. Furthermore, in endocrine pancreatic tumors with metastatic disease, CD44-positive tumors had a tendency to metastasize to lymph nodes (P = 0.005), as compared with CD44-negative tumors which were locally invasive or metastasized to the liver. Although, in this limited material and short follow-up, we were not able to show any statistical significance, patients with CD44-negative endocrine pancreatic tumors had prolonged survival time compared with patients with CD44-positive tumors (73% versus 59% at 5 years; P = 0.7). Of 10 carcinoid tumors examined, all three foregut carcinoids and one midgut carcinoid stained strongly positive, whereas all other midgut carcinoids were negative. Analysis of CD44 splice variants showed that in all five gastrinomas there was overproduction of alternatively spliced larger molecular variants as compared with other types of endocrine pancreatic tumors and carcinoid tumors. The band pattern from one case of carcinoid tumor with a fulminant clinical course was similar to that of gastrinomas, whereas other carcinoid tumors expressed the epithelial form of CD44. The earlier identified splice variants which confer metastatic behavior on a pancreatic tumor cell line were not expressed in neuroendocrine tumors. Our data indicate that CD44 expression in endocrine pancreatic tumors correlates with the ability to give rise to lymph node metastases and may play a vital role in determining the fate of metastasizing cells. Moreover, because gastrin is not detectable in the normal human pancreas, the pancreatic ductal cell positivity for CD44 strengthened the ductal origin concept of gastrinomas. The band pattern of CD44 splice variants suggests that the previously described splice variants conferring metastatic behavior do not accompany metastatic activity of neuroendocrine tumors.

Adult↗
PubMed1994

CD44 is a cytotoxic triggering molecule in human peripheral blood NK cells.

Previous studies have shown that target cells that bind to CD44 adhesion molecules on cloned cytotoxic T cells are lysed by the CTL. To determine whether CD44 is also a cytotoxic trigger molecule in human PBL, we tested a bispecific Ab consisting of anti-CD44 Fab cross-linked to a Fab against a target cell Ag, in cytotoxicity assays using PBL as effectors. We found that PBL mediated lysis in the presence of the anti-CD44 bispecific Ab provided that the effector cells were stimulated with either IL-2 or IL-12. Cell fractionation experiments showed that CD44-directed cytolysis was mediated exclusively by CD56+ low buoyant density cells, mainly by NK (CD16+) cells, but also to a lesser extent by CD56+ T cells. CD44-directed cytolysis appeared in these subsets 24 to 48 h after addition of IL-2 and paralleled the acquisition of Ab-independent (LAK) activity; in contrast, these cells mediated Ab-dependent cellular cytotoxicity and CD3 redirected lysis before stimulation with IL-2. Unstimulated CD56+ cells uniformly expressed high levels of CD44 that increased modestly after incubation with IL-2. No changes in isoform expression in the extracellular domain of CD44 could be detected upon activation with the use of isoform-specific mAbs. Thus, lymphokine stimulation caused CD44 to become a cytotoxic trigger in subsets of PBL that mediated other forms of cytotoxicity and expressed CD44 before activation, suggesting that activation of these cells was accompanied by a coupling of CD44 to their lytic machinery.

Animals↗
PubMed1993

Antibodies to CD44 trigger effector functions of human T cell clones.

mAb against the lymphocyte homing receptor CD44/Hermes up-regulate the proliferation of human T PBL induced by anti-CD3 or anti-CD2 mAb. Moreover, certain anti-CD44 mAb can activate human resting T cells and mouse cytotoxic T cells in the absence of anti-CD3 or anti-CD2 mAb. Here, we show that anti-CD44 mAb trigger proliferation of human CD3+/CD4+ T cell clones in a fashion similar to that observed with mAb to CD3. Such an effect is IL-2-dependent, as shown by IL-2 production induced by anti-CD44 mAb and by complete inhibition of cell proliferation in the presence of anti-IL-2 antibodies or cyclosporin A. Moreover, anti-CD44 mAb trigger human cytolytic T cell clones to lyse Fc gamma-R+ P815 cells in the absence of additional stimuli. The magnitude of the cytolytic response induced by anti-CD44 mAb is comparable to that observed in the presence of anti-CD3 mAb for both CD4+ and CD8+ TCR-alpha/beta+ clones, and for V delta 1 or V delta 2 TCR-gamma/delta+ clones. By contrast, in CD3-/CD16+ NK cell clones, no cytolytic responses to anti-CD44 mAb could be observed. Granule trypsin-like esterase enzyme (granzyme) release by cytolytic T cell clones is induced by plastic-immobilized anti-CD44 mAb. Anti-CD44 mAb-triggered proliferation ([3H]thymidine incorporation) and cytotoxicity are blocked by the protein tyrosine kinase inhibitor, genestein. In addition, ligation of the CD44 molecule induces tyrosine phosphorylation of proteins identical, by molecular mass, to those phosphorylated after anti-CD3 mAb stimulation. Notably, anti-CD44 mAb does not induce tyrosine phosphorylation of a 21-kDa protein (the phosphorylated zeta-chain of the TCR molecular complex) typically observed upon anti-CD3 mAb stimulation. In conclusion, this study shows that the ligated CD44 molecule provides the necessary stimuli for a variety of T cell-mediated functions triggered via protein tyrosine kinase-dependent signal transduction pathways at least in part similar to those that follow stimulation of the CD3/TCR complex.

CD4-Positive T-Lymphocytes↗
PubMed1993

HIV-induced loss of CD44 expression in monocytic cell lines.

We have found that HIV-1 infection of monocytic cell lines results in a new adhesion phenotype. Whereas uninfected cells grow as single cell suspensions, HIV-infected cells grow as large aggregates. When the expression of adhesion molecules was investigated, CD44 was almost completely depleted from the surface of HIV-infected cells. Immunoprecipitation with mAb confirmed the loss of CD44 from the surface of infected cells. In addition, loss of surface CD44 was not due to formation of internal complexes or release into the culture supernatant. Soluble CD44 was not detected in culture supernatant from HIV-infected cells. Northern blot analysis showed an altered RNA pattern in HIV-infected cells. The high molecular mass CD44 RNA (7.0 kb) was lost from infected cells, and the low molecular mass CD44 RNA (1.2 kb) remained. We have previously shown that anti-CD44 mAb induces homotypic adhesion in CD44+ cell lines. In this report, we show that homotypic adhesion of the HIV-infected cells occurs through a different mechanism than anti-CD44 mAb-induced aggregation. The homotypic adhesion in infected cells was CD18-mediated, but anti-CD44 mAb-induced homotypic adhesion in uninfected cells was CD18-independent. The change in adhesion phenotype and the loss of CD44 from the surface of HIV-1-infected monocytic cells are discussed in terms of their potential implications in cell-to-cell transmission of HIV.

Antigens, Surface↗
PubMed1993

CD44 is not directly involved in the binding of lymphocytes to cultured high endothelial cells from peripheral lymph nodes.

The Ager assay was adapted to a porcine lymphocyte-rat high endothelial cell (HEC) system. Using this in vitro assay, the role of porcine CD44 in lymphocyte binding to HEC was examined. The results show that the presence of soluble CD44 molecules did not inhibit the binding of porcine lymphocytes to the cultured rat HEC. Treatment of lymphocytes with anti-CD44 monoclonal antibodies (mAb), or with papain, which removes a 45,000 MW peptide from the intact CD44 molecule, did not inhibit the binding. Binding to the rat HEC did not induce modulation of CD44 molecules on the cell surface. Furthermore, modulation of the CD44 molecule by biotinylated anti-CD44 antibody followed by streptavidin-phycoerythrin, which had caused the molecule to cap on the cell surface, did not prevent the cells binding to the HEC. Similarly, cells denuded of CD44 by anti-CD44 antibody retained the capacity to bind to HEC. Moreover, the binding cells were mainly those which had been stripped of CD44 by the antigenic modulation. It is concluded that CD44 is not directly involved in the binding of lymphocytes to the cultured HEC from peripheral lymph nodes (PLN).

Animals↗
PubMedDate not supplied

Expression of CD44 standard and variant isoforms v5, v6 and v7 in human ovarian cancer cell lines.

The expression of standard CD44 protein (CD44std) and its splice variants v5, v6 and v7 was investigated in 43 human ovarian carcinoma cell lines by flow cytometry and immunocytochemistry using monoclonal antibodies raised against extracellular epitopes. Twenty six (60%) cell lines expressed CD44 std. Variant isoforms of CD44 were expressed in 12 of the 26 CD44 positive cell lines. All 12 cell lines expressed CD44 v5. In addition 6 cell lines expressed CD44 v6 and one of these expressed CD44 v7 simultaneously. No significant differences of CD44 expression were found between cell lines derived from solid tumors or ascites. In ovarian cancer cells splicing of CD44 v5 appears to be a prerequisite for expression of downstream variable exons. New acquisition of variable CD44 exons may be implicated in the tumorigenesis of ovarian cancer. The CD44 gene provides a biological model to study the role of alternative splicing in gynecologic malignancy.

Antigens, CD↗
PubMed1997

Elevated serum CD44 level is associated with unfavorable outcome in non-Hodgkin's lymphoma.

CD44 molecule is a cell surface glycoprotein involved in many cell-cell and cell-matrix interactions. Circulating serum CD44 (s-CD44) levels have been found to change in parallel with response to therapy, but little is known about the predictive or prognostic significance of s-CD44. In the present study, we measured s-CD44 levels in sera taken before treatment from 194 patients with non-Hodgkin's lymphoma using a chemiluminescence-enzyme immunoassay method. All except 1 patient were regularly followed-up after therapy at least for 60 months (range, 33 to 143 months). The median pretreatment s-CD44 level was 440 ng/mL (range, 13 to 1,220 ng/mL). Only 32% of the 92 patients with an International Prognostic Index (IPI) score of 0 or 1 had an s-CD44 concentration higher than the median as compared with 67% of the patients with an IPI score >/=2 (P < .0001). Patients with lower than the median s-CD44 achieved more often a complete remission to therapy (P = .0002) and had better survival (P = .007) than those with higher s-CD44 levels. However, in a multivariate analysis, only the IPI score had independent prognostic value (P < .001). The findings were similar if only the patients with diffuse large-cell lymphoma (n = 51) were included in the analysis, but among patients with low-grade lymphoma, the median s-CD44 level was not significantly associated with the IPI or survival. In conclusion, a high s-CD44 level at diagnosis is associated with a high IPI score, poor response to treatment, and unfavorable outcome in non-Hodgkin's lymphoma.

Adolescent↗
PubMed1998

Expression of antisense CD44 variant 6 inhibits colorectal tumor metastasis and tumor growth in a wound environment.

Up-regulation of CD44 variant isoforms has been linked to the progression of epithelial tumors and the metastatic phenotype. Here we report a functional role for CD44 variant isoforms in colorectal cancer metastasis. An antisense mRNA approach was used to down-regulate CD44 variant isoforms containing CD44 variant 6 (v6) in the metastatic colorectal tumor cell line HT29. Cell lines stably expressing antisense CD44 exon 10 (v6) showed reduced expression of alternatively spliced CD44 variant isoforms but no significant change in expression of CD44 core protein, as judged by immunohistochemical analysis using CD44 domain-specific monoclonal antibodies. Expression of antisense exon 10 (v6) had no effect on HT29 tumor cell proliferation in vitro or the ability of the cells to bind immobilized hyaluronan, but it resulted in a reduced capacity to form liver metastases in nude mice following intrasplenic injection. Metastases were not detected in nude mice inoculated with antisense CD44 exon 10 (v6)-expressing cell lines after 4 months, against a background of a 30% metastasis rate in the control HT29 parental and vector alone transfected lines. Furthermore, whereas 82% of mice intrasplenically injected with control HT29 parental and vector alone cell lines developed tumors in incisional wound sites, none of the mice injected with antisense exon 10 expressing HT29 cells developed similar tumors. This is the first demonstration that antisense RNA can be used to selectively inhibit expression of specific domains of a molecule generated through alternative mRNA splicing while allowing expression of core domains to remain unaffected. Furthermore, these results provide direct evidence for a functional role of CD44 variant isoforms in the metastasis of human colorectal tumor cells and may suggest a critical role for CD44 variants in promoting cell growth specifically in the cytokine/growth factor-enriched environment of a wound site.

Adenocarcinoma↗
PubMed2006

Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer.

OBJECTIVES: To investigate whether hyaluronan (HA) and CD44 (hereinafter HA-CD44) promotes head and neck squamous cell carcinoma (HNSCC) chemotherapy resistance and whether HA-CD44 promotes epidermal growth factor receptor (EGFR)-mediated oncogenic signaling to alter chemotherapy sensitivity in HNSCC. Hyaluronan, a glycosaminoglycan component of the extracellular matrix, is a ligand for the transmembrane receptor CD44, which acts through multiple signaling pathways to influence cellular behavior. We recently determined that HA-CD44 promotes phospholipase C-mediated calcium signaling and cisplatin resistance in HNSCC. DESIGN: Cell line study. MAIN OUTCOME MEASURES: Tumor cell growth with various chemotherapeutic drugs (methotrexate, doxorubicin hydrochloride, adriamycin, and cisplatin) was measured in the presence or absence of HA and other inhibitors of the EGFR-mediated signaling pathway. Immunoblotting was used to study EGFR signaling. Migration assays provided one measure of tumor progression. RESULTS: The addition of HA, but not HA plus anti-CD44 antibody, resulted in a 2-fold reduced ability of methotrexate and an 8-fold reduced ability of adriamycin to cause HNSCC cell death. Immunoblotting studies demonstrated that HA can promote an association between CD44 and EGFR as well as CD44-dependent activation of EGFR-mediated signaling. Migration assays demonstrated that HA-CD44 can promote tumor migration with EGFR signaling. The presence of AG1478, an EGFR inhibitor, and U0126, an extracellular signal-regulated kinase inhibitor, inhibited HA-mediated tumor growth, migration, and chemotherapy resistance. CONCLUSIONS: Our results indicate that HA promotes CD44/EGFR interaction, EGFR-mediated oncogenic signaling, and chemotherapy resistance in HNSCC. Perturbation of HA-CD44-mediated signaling may be a promising and novel strategy to treat HNSCC.

Antineoplastic Agents↗
PubMed1998

Clinical significance of circulating CD44 in non-Hodgkin's lymphoma.

Soluble isoforms of various adhesion molecules have recently been observed in the blood circulation, but the physiological effects of such molecules remain unsettled. Our earlier results indicate that soluble CD44 can be detected in sera of healthy individuals and that significantly higher levels of serum CD44 (s-CD44) can be found in lymphoma patients. The serum level of the standard form of CD44 parallels the clinical treatment response in patients with lymphoma. In the present study, we have investigated the clinical significance of s-CD44 in non-Hodgkin's lymphoma measured at the time of the diagnosis. S-CD44 was measured from the sera of 123 patients with non-Hodgkin's lymphoma by dot blotting high levels of s-CD44 were associated with high serum levels of lactate dehydrogenase and thymidine kinase, high histological grade of malignancy and poor overall survival. However, s-CD44 level did not have independent prognostic value in a multivariate analysis. In conclusion, a high s-CD44 level at the time of diagnosis was associated with poor survival and several other adverse prognostic factors. Our previous and present studies taken together suggest that measurement of s-CD44 is a valuable tool to monitor treatment response in lymphoma patients. However, it may not be an improved prognostic marker.

Adult↗
PubMed1999

Potential use of serum CD44 as an indicator of tumour progression in acute leukemia.

CD44 is a widely expressed cell surface glycoprotein with various functions. This molecule is shed from the cell surface and released as a soluble molecule. High serum levels of CD44 have been demonstrated in some solid tumours. In this study we measured serum CD44 in 25 patients with acute leukemia, in 12 with bacterial infections, and in 13 normal controls. The levels of serum CD44 of patients with bacterial infections were significantly higher (mean 531.3+/-60.1 ng/ml, p<0.001) than those of normal controls (299. 0+/-115.4 ng/ml). Acute leukemia patients before treatment had almost four-fold higher levels of serum CD44 than normal controls (mean 1301.9+/-1384.6 ng/ml, p<0.01). Serum CD44 levels were correlated with clinical status. After treatment the serum CD44 levels significantly decreased, but they were still higher than in normal controls. Patients in complete remission all relapsed if serum CD44 levels were higher than 500 ng/ml (normal+2 SD) after chemotherapy. The serum CD44 levels were correlated with the absolute numbers of leukemic cells in peripheral blood. The results demonstrated that serum CD44 levels correlate well with the clinical status of acute leukemia, and such evaluation may provide a reliable tumour marker of acute leukemia.

Acute Disease↗
PubMed1991

Transcripts encoding mouse CD44 (Pgp-1, Ly-24) antigen: strain variation and induction by mitogen.

The cell surface molecule CD44, thought to be a cell surface receptor for hyaluronic acid, is expressed by thymocytes and peripheral T cells. Following T cell activation with mitogens or antigens, surface expression of CD44 increases. This increase in CD44 cell surface expression has been used as a means of identifying memory T cells in vivo. In this report, using Northern analysis, we have quantitated mouse CD44 transcripts in thymocytes and a cloned T hybridoma cell line. In contrast to a recent report by Nottenburg et al. (Proc. Natl. Acad. Sci. USA 1989. 86: 8521), we show that in all instances CD44 transcripts are polyadenylated. In all cells studied, three major mRNA species of approximately 4.5, 3.5 and 1.6 kb are detected. After stimulation with phorbol 12-myristate 13-acetate (PMA), there is a de novo protein synthesis-dependent increase in the level of CD44 transcripts. The increase in CD44 transcripts precedes the increase in cell surface expression. In contrast to CD44, PMA stimulation results in a decrease in the level of Thy-1 transcripts. Thymocytes from different mouse strains vary in their level of CD44 cell surface expression and Northern analysis indicates that this mouse strain variation correlates with a corresponding difference in the level of CD44 transcripts.

Animals↗
PubMed2006

In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance.

CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ-related autoimmune disease model system. Expression of the activated, hyaluronan-binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA-affected mice as compared to control mice. LNC of AA mice displayed increased motility, proliferative activity and apoptosis resistance, which were equally well inhibited by anti-CD44 and anti-CD49d. The latter is the sequelae of the association between CD44 and CD49d that is seen in activated lymphocytes. Significantly, due to CD44-CD49d complex formation, CD44 gains access to focal adhesion kinase and CD49d gains access to CD44-associated lck and ezrin, such that downstream kinases become activated via CD44 or CD49d engagement. Thus, by their association, CD44 and CD49d mutually avail themselves of the partner's signaling pathways and the ligand binding of each one triggers signaling pathways of both. This strongly influences the lymphocytes' activation state and function.

Alopecia Areata↗
PubMed2005

Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling.

We provided evidence previously that bikunin, a Kunitz-type protease inhibitor, can disrupt dimerization of CD44 proteins, which may result in suppression of receptor-mediated MAP kinase signaling. However, to what extent dimerization may alter ligand-induced signaling has not been documented. Given the recent recognition that some growth factor receptors can form heterodimers with CD44, the present study was undertaken to determine whether the CD44 and growth factor receptors (e.g., EGFR, FGFR, HGFR, VEGFR, TGF-betaRI, or TGF-betaRII) can form heterodimers in cancer cells and, if so, to investigate the potential functional consequences of such heterodimerization. We also examined whether bikunin can abrogate these heterodimerizations and inhibit CD44/growth factor-dependent signaling. Here, we show direct evidence for heterodimerization of CD44-FGFR and CD44-TGF-betaRI in human chondrosarcoma HCS-2/8 cells, CD44-EGFR complex in human glioma U87MG cells, and CD44-TGF-betaRI heterodimer in human ovarian cancer HRA cells. Coupling of CD44 and growth factor receptor may be selective, depending on a cell type. Bikunin does not alter the ligand binding, whereas functionally reduces heterodimerization between CD44 and growth factor receptors. The disruption of heterodimerization substantially reduces receptor-induced tyrosine phosphorylation and ERK1/2 activation. Taken together, our data suggest that bikunin-mediated suppression of heterodimerization between CD44 and growth factors may inhibit the agonist-promoted activation of the signaling pathway.

Cell Line, Tumor↗
PubMed1995

New CD44 splice variants associated with human breast cancers.

Changes in the CD44 variant (CD44v) isoforms on the cell surface have been correlated with tumor metastasis. In this study we have examined the expression of CD44 variant isoforms in human breast carcinoma samples by a variety of techniques including immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and nucleotide sequencing. Using RT-PCR, we have determined that normal human breast tissue contains primarily the CD44 epithelial (CD44E) form and very little CD44 standard (CD44s) form. However, metastatic breast carcinomas appear to overexpress both the CD44E and CD44s forms and also display multiple new species of CD44 variant isoforms. Histocytochemical staining using anti-CD44 antibody (recognizing a common determinant of the CD44 class of glycoproteins) confirms that the CD44 molecules are overexpressed and preferentially located in metastatic breast cancer tissues. Nucleotide sequencing analyses indicate that at least four new CD44 variant isoforms (i.e., displaying unique splicing via the insertion or the deletion of exons 7, 10, 11, and 14) may be closely associated with human metastatic breast cancers. These newly described CD44 variant isoforms may be useful for monitoring the progression of human breast cancer metastasis.

Base Sequence↗
PubMed2006

CD44 regulates myoblast migration and differentiation.

CD44 is a transmembrane protein that plays a role in cell-cell interactions and motility in a number of cell types. Cell-cell interactions are critical for myoblast differentiation and fusion but whether CD44 regulates myogenesis is unknown. Here, we show that CD44 plays a functional role in early myogenesis. Analyses of myofiber cross-sectional area, after local injury in mouse tibialis anterior (TA) muscles, revealed that growth was transiently delayed in the absence of CD44. A muscle-intrinsic role for CD44 is suggested as primary myoblasts from CD44(-/-) mice displayed attenuated differentiation and subsequent myotube formation at early times in a differentiation-inducing in vitro environment. Chemotaxis of CD44(-/-) myoblasts toward hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) was totally abrogated, although expression of their respective receptors did not appear to differ from wild-type. Furthermore, motility of CD44(-/-) myoblasts was decreased at early stages of differentiation as determined by time-lapse microscopy. Wild-type myoblasts contained two subpopulations of slow- and fast-migrating cells, whereas CD44(-/-) myoblasts were composed predominantly of the slower migrating subpopulation. Taken together, these data suggest that myoblast migration and differentiation are closely linked and CD44 is a key regulator.

Animals↗