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PubMed1997

Changes in CD44 and ApoE immunoreactivities due to retinal pathology of man and rat.

In cases of retinal light damage, glaucoma, or senile macula degeneration, the loss of retinal neurons is thought to cause alterations of glial cells. We performed immunocytochemical studies on retinae of (i) healthy rats and human donors, (ii) rats exposed to enhanced illumination for 24 months, a procedure which leads to complete loss of photoreceptor cells, (iii) a human donor who had suffered from senile macula (photoreceptor cell) degeneration, and (iv) human donors who had suffered from glaucoma, known to be accompanied by a loss of ganglion cells and other retinal neurons. Furthermore, Müller cells were enzymatically isolated from human glaucomatous retinae. All preparations were subjected to immunocytochemistry for CD44 antigen and Apolipoprotein E (ApoE). In normal rat and human retinae, CD44 immunoreactivity was observed in the microvillous sclerad processes of Müller cells: in human retinae, perivascular (astro-)glial cell processes were also CD44 immunopositive. ApoE immunoreactivity was only found in some perivascular (astro-)glial cell processes of human retinae. Both rat and human Müller cells respond to photoreceptor cell damage by increased, and ectopic, expression of the CD44 antigen. Increased ApoE immunoreactivity was found in Müller cells from degenerative human retinae, but rarely in light-damaged rat retinae. It is concluded that degeneration-related reorganization involves enhanced expression of the glial cell adhesion molecule CD44 as well as elevated activity of the glial lipid transport molecule ApoE.

Aged↗
PubMed1997

CD44 regulates phagocytosis of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human macrophages.

Phagocytosis of apoptotic neutrophil granulocytes by macrophages at inflammatory sites is an important determinant of the process by which inflammation resolves. We demonstrate that phagocytosis of apoptotic neutrophils, but not apoptotic lymphocytes, by human monocyte-derived macrophages is augmented rapidly following ligation of CD44 by bivalent Abs in vitro. Previously defined inhibitors of apoptotic cell recognition did not affect CD44-augmented phagocytosis of apoptotic neutrophils, suggesting that unique molecular recognition pathways are involved. These observations, together with the lack of effect of CD44 Abs upon macrophage phagocytosis of zymosan or Ig-opsonized erythrocytes, imply that CD44 may regulate the differential clearance of apoptotic leukocytes during evolution of inflammatory responses. This represents a novel role for CD44 in inflammation and tissue repair.

Apoptosis↗
PubMed1997

CD44 activation and associated primary adhesion is inducible via T cell receptor stimulation.

A defining juncture in the life of a T cell is its encounter with its cognate Ag, resulting finally in effector and/or memory T cells known to express, among other characteristics, increased surface levels of CD44. The requirements for the "activation" of CD44 to bind its major ligand, hyaluronan (HA), and the in vivo role of this interaction remain unresolved. We have recently proposed that the CD44/HA interaction is involved in primary lymphocyte adhesion, leading to extravasation at inflammatory sites. We show here that activation of CD44 and ability to engage in rolling occurs directly through polyclonal as well as Ag-specific TCR-initiated signaling. Using a superantigen, it is primarily the Ag-specific activated Vbeta-bearing cells that are induced to bind HA. In addition, this CD44 activation does not appear to be the result of overt changes in glycosylation. These results connect activation of CD44 on T cells with the initiation of immune responses and suggest potential roles for the CD44/HA interaction.

Animals↗
PubMed1997

Detection of CD44 variants in fine needle aspiration biopsies of thyroid tumor by RT-PCR.

Increased expression of CD44 variants is often observed in differentiated thyroid carcinomas. To establish a method for gene diagnosis of thyroid without any additional invasions to the patients, RNA in leftover cells inside the needle used for fine needle aspiration biopsies (FNABs) was extracted to detect the expression of CD44 variants by reverse transcription-polymerase chain reaction (RT-PCR). After FNAB and preparation of sample on a slide glass for cytological examinations, RNA in leftover cells inside the needle was extracted. After reverse transcription, cDNA was amplified by PCR with specific primers for CD44. The results were compared with the cytological diagnosis. CD44 variants were detectable in all seven samples that were diagnosed as positive cytology. However, they were detected in only five of the 29 samples of negative cytology. Therefore, thyroid tumors may be more accurately diagnosed by a combination of cytological examination and detection of CD44 variants in RNA obtained by FNAB.

Adult↗
PubMed1997

The prognostic value of CD44 isoforms in prostate cancer patients treated by radical prostatectomy.

CD44 forms a group of transmembranous glycoproteins formed by alternative splicing of a single mRNA. The expression of v6 exon-containing variants correlates with metastasis and poor prognosis in a number of malignancies. The distribution and prognostic value of CD44s, CD44v5, and CD44v6 were studied immunohistochemically in the radical prostatectomy specimens of 97 patients with prostate cancer and in 12 lymph node metastases. The mean follow-up period was 84 months. The percentage of CD44-immunoreactive cells was scored semiquantitatively. CD44 mRNA expression was studied in nine prostate cancer and eight benign prostatic hyperplasia (BPH) samples by reverse transcriptase-PCR. Benign prostatic glands almost always expressed CD44s, CD44v6, and, at a lower intensity, CD44v5. CD44 scores decreased from low- to high-grade prostatic intraepithelial neoplasia. CD44s, CD44v5, and CD44v6 were expressed in 86, 23, and 69% of the adenocarcinomas, respectively. Gleason sum score (GSS) and pT stage were correlated inversely with CD44s and CD44v6 scores. CD44 was not found in the lymph node metastatic tumor cells. At the mRNA level, 89% of the tumors and all BPH samples expressed CD44s. CD44v6-v10 mRNA was present in 44 and 75% of the tumors and BPH samples, respectively. Loss of CD44s and CD44v6 predicted an adverse prognosis at univariate analysis. The independent prognosticators identified by multivariate analysis were: GSS, pT stage, and CD44s for clinical progression; GSS and CD44s for prostate-specific antigen progression; and GSS for tumor-specific survival. Loss of CD44s expression in prostate adenocarcinoma predicts a poor prognosis, independent of stage and grade.

Disease Progression↗
PubMed1996

Expression of CD44 variant isoforms in malignant melanoma.

In a variety of human tumors, expression of splice variants of the adhesion molecule CD44 (CD44v) has been described as correlating with tumor progression. Here, we report on the expression of CD44v in melanocytes, nevi, primary melanomas, and cutaneous and lymph node metastases. Thirteen nevi, 65 primary melanomas of varying thickness, 39 cutaneous and 15 lymph node metastases, and melanocytes and a panel of melanoma lines were tested for surface expression of the standard form of CD44 and the variant exons v5, v6, v7, v7-v8, and v10 by immunohistology or fluorescence-activated cell sorting. Melanocytes did not express any variant isoform of CD44. However, nevi, as well as primary melanoma and melanoma metastases, stained to a varying degree with anti-CD44v5, anti-CD44v7-v8, and anti-CD44v10. Exons v6 and v7 were not detected on any of these tissue specimens. Compared with nevi, expression of exon v10 was up-regulated in thick primary tumors and skin metastases. Lymph node metastases displayed elevated levels of exon v5. Expression of CD44v in melanoma lines (n = 20) differed, inasmuch as many lines did not express variant isoforms; in particular, exon v10. Interestingly, however, the few CD44v5-positive melanoma lines metastasized in the nu/nu mouse. Because benign as well as malignant growth of melanocytes was accompanied by expression of CD44 variant isoforms, a linkage between expression of CD44 variant isoforms and malignant transformation or tumor progression was excluded. Considering the function of distinct isoforms, one might speculate that expression of exon CD44v5, which was up-regulated in lymph node metastases compared with nevi and primary melanoma, provided a growth stimulus. Exon v10 is present at high density in epidermal cells. The de novo expression of this exon in nevi and the increased expression in thick melanoma and skin metastases would be in line with the assumption of an anchoring advantage in the surrounding epidermal tissue.

Animals↗
PubMed1998

Expression of adhesion molecule CD44 in metastatic brain tumors.

Expression of CD44 (m.w. 80-95 kD) in 48 metastatic brain tumors was examined using monoclonal antibody on paraffin sections. The CD44 expression was found in 48% of studied tumors. The most constant expression of CD44 was observed in metastases from thyroid, skin and breast cancer. The brain metastases were characterized by quite heterogenous distribution of CD44 glycoprotein--the most pronounced expression was seen in individual neoplastic cells embedded in abundant stroma and in the vicinity of preserved neural tissue. Such a topographical distribution of CD44 supports its role in interactions of cancer cells with extracellular matrix components of the tumor stroma as well as of neural tissue.

Adenocarcinoma↗
PubMed1998

High frequency expressions of CD44 standard and variant forms in non-small cell lung cancers, but not in small cell lung cancers.

BACKGROUND AND OBJECTIVES: Organ specificity has been demonstrated in the mode of CD44 expression among several cancers. METHODS: We examined the expressions of CD44 standard (CD44s) and CD44 variants (CD44v) in 14 cell lines (small cell lung cancer (SCLC): 5, non-small cell lung cancer (NSCLC): 9 and 20 surgically resected samples (SCLC: 7, NSCLC: 13) of lung cancer using reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: Although both NSCLC and SCLC expressed CD44s, the frequency and intensity of CD44s expression in NSCLC were different from those in SCLC: cell lines, 89% vs. 40%; tumor samples, 100% (diffusely stained) vs. 57% (focally stained). CD44s expression was partially or completely repressed in SCLC. However, NSCLC frequently expressed CD44v, but SCLC expressed infrequently: cell lines, 67% vs. 20%; tumor samples, 69% vs. 0%. The N-417 line, which only expressed some CD44v in SCLC, falls SCLC and NSCLC both in biomarkers and in growth patterns. CONCLUSIONS: CD44 expression was repressed in SCLC but was enhanced in NSCLC.

Adenocarcinoma↗
PubMed1998

Expression of CD44 splice variant v10 in Hodgkin's disease is associated with aggressive behaviour and high risk of relapse.

Expression of CD44 isoforms has been shown to correlate with the progression and prognosis of some malignant tumours. The aim of this study was to investigate the expression of CD44 standard (CD44s) and CD44 splice variants (CD44v) v5, v6, and v10 in lymph node specimens from patients with nodular sclerosing Hodgkin's disease (NSHD), with or without initial bone marrow involvement and with or without relapse. Specimens were studied by immunohistochemistry to determine CD44s and CD44v in Hodgkin- and Reed-Sternberg (HRS) cells. For validation of the immunohistochemical of detection of CD44v10 in paraffin-embedded samples, selected cases were analysed in parallel immunohistochemically using fresh frozen material and by reverse transcription-polymerase chain reaction (RT-PCR). There was high expression of CD44 isoforms containing the variant exon v10 selectively in HRS cells of patients with relapse within 2-3 years or with initial bone marrow involvement. In patients without relapse, however, no or only very few HRS cells were positive. These differences were statistically highly significant (p < or = 0.001), whereas evaluation of CD44s, CD44v5, and v6 expression revealed no marked differences. It is concluded that evaluation of CD44v10 expression could serve as a new prognostic marker in NSHD. These results are considered to be of sufficient importance to initiate a large multi-institutional study for confirmation; furthermore, they might suggest causal involvement of CD44v10 in the progression of NSHD.

Antigens, Neoplasm↗
PubMed1997

Low serum levels of soluble CD44 variant 6 are significantly associated with poor prognosis in patients with pancreatic carcinoma.

BACKGROUND: Variant CD44 splice products, especially CD44 variant 6 (CD44v6), are expressed on activated lymphocytes and tumor cells. The soluble forms of CD44 standard (CD44s) and CD44v6 are present in the serum of normal individuals. The aim of the current study was to evaluate the concentrations and the prognostic potential of soluble CD44s and CD44v6 in patients with pancreatic carcinoma. METHODS: The serum CD44s and CD44v6 levels were determined quantitatively by enzyme-linked immunosorbent assay. The molecular mass of CD44v6 isoforms was determined by immunoprecipitation and Western blot analysis. CD44 mRNAs were analyzed by reverse transcriptase polymerase chain reaction followed by exon specific analysis. RESULTS: Both serum CD44s and serum CD44v6 were significantly reduced in patients with pancreatic carcinoma (n = 93, P < 0.001 and P < 0.00005). The median survival in the group with CD44v6 serum concentrations below 100 ng/mL was significantly decreased compared with that in the group with serum concentrations higher than 100 ng/mL (6.7 vs. 15.1 months, P < 0.0005). The isoforms containing soluble CD44v6 (sCD44v6) that were detected in the sera of pancreatic carcinoma patients showed molecular masses comparable to the sCD44v6 isoforms detected in the supernatant of lymphocytes activated by phorbol myestral acetate, whereas the sCD44v6 isoforms detected in the supernatant of pancreatic carcinoma cell lines exhibited higher molecular masses. CONCLUSIONS: These results suggest that serum CD44v6 is significantly reduced in pancreatic carcinoma patients and could serve as a good prognostic marker for patients with this disease.

Adenocarcinoma↗
PubMed1997

Soluble CD44 splice variants in metastasizing human breast cancer.

The local expression of CD44 splice variants in human breast cancer tissue has been previously shown to be associated with metastasis. We show here that elevated systemic serum levels of CD44 splice variants occur in breast cancer and may represent a new tool for staging and differential diagnosis. Sera of node-negative and node-positive breast cancer patients in comparison with healthy control subjects were analyzed for serum CD44 (sCD44) and 2 different splice variants (v5 and v6). Node-positive breast cancer patients showed significantly (p < 0.01) elevated levels of sCD44-v5 and -v6 splice variants in comparison to node-negative patients and healthy controls. None of the node-negative breast cancer patients or healthy controls showed elevated levels of both sCD44-v5 and -v6. Interestingly, no differences were seen for serum levels of non-spliced sCD44-standard between the 3 groups. Soluble forms of CD44 variants may promote migration of tumor cells. This may occur through interference with tumor cell adhesion or by modulation of immune defense mechanisms.

Alternative Splicing↗
PubMed1997

Expression of CD44 variants in gastric carcinoma with or without Epstein-Barr virus.

The significance of CD44 variants in gastric carcinoma has not been fully investigated in terms of the pathological features of the carcinoma, including its association with Epstein-Barr virus (EBV). In this study, a total of 104 primary gastric carcinoma tissues (EBV-associated gastric carcinomas, EBVaGC, and EBV-negative carcinomas) were evaluated by immunohistochemistry. When the immunoreactivity of formalin-fixed, paraffin-embedded sections was graded on a scale of 0-3, the frequencies of grades 0-1, 2 and 3 were, respectively, 77%, 16% and 7% using monoclonal antibody (MAb) 3G5, which recognizes V3-5, and 70%, 14% and 15% with MAb 2F10, which recognizes V6. The expression of CD44 variants is independently correlated with lymph node metastasis and EBV-association in gastric carcinoma. Significant correlations were observed between V3-5 expression and lymph vessel invasion or lymph node metastasis, and between V6 expression and lymph node metastasis. The expression of both variants was significantly correlated with EBV-association. EBV-association and lymph node metastasis contributed independently to CD44 variant expression by multivariate analysis. Thus, the mechanism and significance of CD44 variant-expression are different in gastric carcinomas with or without EBV. EBVaGC is a distinct type of gastric carcinoma which should be considered separately from EBV-negative carcinoma.

Adolescent↗
PubMed1996

Selective expression of CD44 cell-adhesion molecule in thyroid papillary carcinoma fine-needle aspirates.

Recent descriptions of numerous pitfalls in the cytologic diagnosis of thyroid papillary carcinoma on fine-needle aspiration biopsy specimens have prompted studies of new ancillary diagnostic methods. We evaluated the potential use of immunocytochemical staining of thyroid fine-needle aspiration biopsy specimens for CD44, a glycosylated cartilage link protein associated with extracellular matrix adhesion and lymphocyte homing. Fourteen of 16 (88%) classic, surgically confirmed, thyroid aspiration biopsies stained intensely positive for this marker, whereas 0 of 30 (0%) similarly-processed benign aspirates from colloid nodules showed immunoreactivity for CD44 antigen. From this study, we conclude that most papillary carcinomas of the thyroid express the celladhesion molecule CD44, which may be of clinical value in confirming the diagnosis on borderline fine-needle aspiration specimens. Further study of CD44 expression may prove of significant interest in explaining the unusual mode of spread and clinical course of this disease.

Adolescent↗
PubMed1998

Expression of exon v6-containing CD44 isoforms is related to poor prognosis of acute myelocytic leukemia.

CD44 is a cell surface glycoprotein with a number of isoforms generated by alternative splicing of ten 'variant' exons in humans. Variant exon 6-containing isoforms of CD44 (CD44v6) have been implicated in the metastatic potential of rat carcinoma cell lines. Human homologues of CD44v6 are expressed in several tumour types and are involved in their progression. In the present study, we examined the expression of CD44 mRNA in 20 acute myelocytic leukemias by semiquantitative RT-PCR analysis and assessed its prognostic value. In all leukemic cells the predominant isoform was the 'standard' form of CD44 (CD44H), and intense bands were found in eight cases. CD44v6 was expressed in 11 cases, although its levels and those of other variants containing exon v7 through to v10 were much lower than those of CD44H. Isoforms containing exon v4 or v5 could not be detected. The expression of CD44v6 correlated with the death rate from leukemia (p > 0.05), but was not related to other risk factors. On the other hand, the intense expression of CD44H did not correlate with the prognosis of leukemia. CD44v6 thus appears to be a marker for the poor prognosis of acute myelocytic leukemia.

Adolescent↗
PubMed2000

Reduced CD44 standard expression is associated with tumour recurrence and unfavourable outcome in differentiated thyroid carcinoma.

CD44 was detected with an antibody recognizing all forms of CD44 (CD44 standard) and others specific for its v3 and v6 variant isoforms; their prognostic value was evaluated in 213 patients with differentiated thyroid carcinoma (DTC). The staining patterns of CD44 standard (s) and CD44v6 in tumour tissue were quite similar, 176 cases (83%) being highly positive for CD44s and 153 cases (72%) for CD44v6. Only 18 (9%) tumours showed high expression of CD44v3. Papillary carcinomas were significantly more often high expressors of CD44s and CD44v6 than follicular carcinomas (p<0.001 for both). Age older than 60 years, distant metastases, and advanced pTNM stage were related to loss of expression of CD44s (p<0.001, p=0.021, and p=0.003, respectively). Tumour recurrence and cancer-related mortality were related to the reduced level of CD44s (p=0.049 and p=0.042). CD44v3 did not associate with any of the clinicopathological factors. In univariate analysis, CD44s was the only significant prognostic factor for disease-free survival (p=0.0488). In multivariate analysis, CD44s and thyroglobulin level were significant prognostic factors for disease-free survival (p=0.040 and p<0.001, respectively). The reduced level of CD44s in DTC patients seems to be an independent prognostic factor for unfavourable disease outcome.

Adolescent↗
PubMed2001

Variant expression of CD44 in preneoplastic lesions of the lung.

BACKGROUND: Specific CD44 isoforms are cell surface adhesion molecules and have been shown to be associated with tumor progression and metastasis. In lung carcinoma, CD44 expression has been reported to be a feature of nonsmall cell lung carcinoma (NSCLC) but not small cell lung carcinoma. A specific variant, CD44v6, was shown to be expressed only in a subset of NSCLC, namely the squamous cell and bronchoalveolar carcinomas, suggesting that CD44 may play a role in lung carcinoma differentiation. METHODS: To determine whether differential CD44 expression is an early event in the pathogenesis of lung carcinoma, the authors investigated the pattern of expression of the standard (CD44s) and variant (CD44v6) isoforms by immunohistochemistry in normal lung, nonneoplastic specimens, and bronchial biopsies of preneoplastic lesions. RESULTS: In normal bronchial epithelium and all nonneoplastic cases, CD44s expression was limited to the basement membrane and adjacent lower strata of the epithelium, whereas CD44v6 was expressed within the basement membrane only. However, aberrant expression of both CD44s and CD44v6 was observed in all preneoplastic lesions examined. In cases of dysplasia, squamous metaplasia, goblet cell hyperplasia, and basal cell hyperplasia, all epithelial strata showed immunoreactivity for both isoforms, in contrast to normal epithelium, in which immunoreactivity was noted to be restricted to the basal layer cells. In contrast, CD44s and CD44v6 expression was completely absent in nearly all cases of adenomatosis. CONCLUSIONS: Altered CD44s and/or CD44v6 expression appears to be a feature of all preneoplastic lesions in the lung, the precise nature of which varies according to histologic tumor type. Therefore, the authors conclude that CD44s and CD44v6 may lend themselves to be markers of preneoplastic changes in the lung.

Glycoproteins↗
PubMed2001

Possible contribution of CD44 variant 6 and nuclear beta-catenin expression to the formation of budding tumor cells in patients with T1 colorectal carcinoma.

BACKGROUND: In an earlier study, the authors demonstrated that tumor budding was useful for predicting lymph node metastasis in patients with early invasive (T1) colorectal carcinoma. This study was undertaken to clarify the associations between tumor budding, E-cadherin-catenin complex, and CD44 variant 6 abnormalities. METHODS: In 51 T1 colorectal carcinomas, tumor budding (the number of dedifferentiation units at the invasive margin) on hematoxylin and eosin-stained slides was counted under light microscopy. Immunostaining for E-cadherin, alpha-catenin, beta-catenin, and CD44 variant 6 was performed on formalin fixed, paraffin embedded sections. The associations between locoregional failure (lymph node metastasis or local recurrence) and tumor budding and clinicopathologic parameters and immunoreactivity were examined statistically. RESULTS: In univariate analysis, tumor budding and nuclear beta-catenin expression were associated significantly with locoregional failure (P = 0.004, 0.01). Multivariate analysis showed that tumor budding alone was associated significantly with locoregional failure (P = 0.02), and the association between nuclear beta-catenin expression and locoregional failure was marginally significant (P = 0.07). Analysis of variance showed that lymphatic invasion alone was associated significantly with tumor budding (P = 0.02), and there was a significant interaction effect for tumor budding between CD44 variant 6 expression and nuclear beta-catenin expression (P = 0.01). There was a significant correlation between expression patterns of these two molecules and locoregional failure (P = 0.01). CONCLUSIONS: The current results suggest that the up-regulation of CD44 variant 6 through nuclear beta-catenin activation may contribute to the formation of tumor budding, and immunostaining of these two adhesion molecules may be useful in identifying those at high-risk for locoregional failure among patients with T1 colorectal carcinoma.

Adult↗
PubMed2000

CD44 is a potential target of amplification within the 11p13 amplicon detected in gastric cancer cell lines.

Classical cytogenetic approaches have revealed many of the chromosomal aberrations that may occur in gastric cancers (GC), although few alterations of specific genes have been identified so far. Genes that affect progression of this disease need to be identified if clinicians are to achieve optimal management of patients with GC. As the first step toward the cloning of gene(s) that may be involved in gastric carcinogenesis, we examined 25 GC cell lines for aberrations in DNA copy number to detect chromosomal gains and losses, as well as gene amplifications, by comparative genomic hybridization (CGH). Our CGH study revealed high-level amplifications in chromosomal regions that had been well defined in GC but also in sites that had not, including 3p24, 5p15, 11p11.2-14, 13q34, 15q26, Xp24, and Xq26-28. The minimal common region at 11p13, within the 11p11.2-14 amplicon, harbors the CD44 gene. Northern and Western blot analyses showed that an alternatively spliced form of CD44, with variant exons 8-10 (CD44E), was overexpressed in all cell lines bearing the 11p13 amplicon. However, cell adhesion activity was no greater in these lines than in cell lines without amplifications at the CD44 locus, suggesting that the major property of upregulated CD44 in these cases might be to transduce signals critically associated with growth and proliferation of the tumor cells.

Blotting, Northern↗