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1.
The expression of the standard CD44 (CD44s) and its v6 isoform (CD44v6) was analysed immunohistochemically in 173 cases of transitional cell bladder cancer. The results of immunohistochemical analyses were related to established prognostic factors and clinical follow-up data. The expression intensity of CD44s in non-basal tumour cells was significantly related to TN classification, S-phase fraction (SPF), mitotic index, grade, density of tumour infiltrating lymphocytes. The expression intensity of CD44v6 in non-basal tumour cells was inversely related to DNA ploidy, SPF, and mitotic index. The expression intensity of CD44v6 in basal tumour cells was also inversely related to T-category, grade, papillary status, DNA ploidy, SPF, and mitotic index. Strong expression of CD44s in non-basal tumour cells was related to unfavourable outcome in univariate analysis (p=0·008), whereas the strong expression of CD44v6 in both non-basal cells (p=0·005) and basal cells (p=0·0008) was related to high survival probability. In multivariate survival analysis, the expression intensity of CD44v6 was independently related to favourable outcome in muscle invasive tumours, while in superficial tumours, CD44s was an independent prognostic factor. The results suggest that the expression of CD44s and CD44v6 is associated with malignant features and prognosis in bladder cancer. Copyright © 1998 John Wiley & Sons, Ltd.  相似文献   

2.
The potential human metastasis molecule CD44 and its isoforms V5 and V6 are overexpressed in human gastric carcinoma. Among the numerous extracellular matrix components, hyaluronate, a CD44 ligand, is of increasing interest in relation to its role in cancer cell development and invasion. By using the dynabead separation method, the SC-M1 cell line was separated into V5 and V6 isoform-positive and -negative populations. The V5 and V6 isoform-negative populations exhibited significantly higher hyaluronate binding activity than the corresponding positive cells. The hyaluronate binding activity of V5 and V6-positive cells could be restored by pretreatment with anti-CD44 V5 and V6 monoclonal antibodies (MAbs). In addition, transfection of an expression vector containing CD44 V5 and V6 into V5 and V6-negative cells decreased their hyaluronate binding activity to the levels of CD44 V5 and V6-positive cells. Cells transfected with V5 and V6 recovered their hyaluronate binding activity after pretreatment with MAbs against V5 and V6. These data suggest that cell adhesion involving hyaluronate can be regulated by multiple mechanisms, one of which involves alternative splicing of CD44 isoforms. © 1998 John Wiley & Sons, Ltd.  相似文献   

3.
AIMS: To examine the expression of CD 44 s, CD 44 v 3 and CD 44 v 6 in breast lesions, and to correlate it with the expression of hyaluronan (HA). Methods and results: CD 44 expression was studied in 75 breast tissue samples, consisting of benign, premalignant and malignant breast lesions, using immunohistochemistry. CD 44 s, but not CD 44 v 3 or CD 44 v 6, was found in the stromal cells, and it was similar in benign and malignant tumours. In benign lesions CD 4 v 6 was detected in 20-30% of the ductal epithelial cells, while C 44 v 3 and CD 44 s were not expressed. CD 44 s, CD 44 v 3 and CD 44 v 6 were all up-regulated in the in situ carcinomas and invasive carcinomas. The level of CD 44 expression in carcinoma cells did not correlate with the type or differentiation of the tumours. CD 44 and HA expression levels were not closely linked in the benign or malignant breast lesions, because HA was overexpressed later in breast cancer progression than CD 44. However, in breast carcinomas CD 44 and HA positivity was often found in the same areas of the sections, and the dual staining confirmed actual colocalization of CD 44 s and HA in the same cells. Conclusions: CD 44 s, CD 44 v 3 and CD 44 v 6 are up-regulated earlier than HA in breast carcinoma progression, and in later stages they often colocalize with cell surface HA.  相似文献   

4.
AIMS: To assess whether standard and variant isoforms of CD44 (CD44s, CD44v5, and CD44v6) have a differential expression profile in early versus advanced gastric adenocarcinoma of the diffuse and intestinal types and their metastases. METHODS: Immunohistochemical expression of CD44s, CD44v5, and CD44v6 was evaluated in 14 early gastric cancers (nine intestinal and five diffuse) and 37 advanced adenocarcinomas (21 intestinal and 16 diffuse) as well as in 18 cases of perigastric lymph node metastasis. Ten normal and five metaplastic gastric mucosa samples were also included in the study. RESULTS: Although no significant association was found between the degree of invasion and the CD44 expression profile, CD44v6 positivity was detected more frequently in metastases of intestinal-type carcinomas (66%) than in metastases of diffuse-type neoplasms (11%) (p < 0.05). Weak CD44s, CD44v5, and CD44v6 expression was observed focally in both normal and metaplastic gastric mucosa samples. CONCLUSIONS: These data suggest that CD44v6 expression may be involved in the production of lymph node metastases in intestinal-type gastric carcinoma but not in the diffuse-type disease, the metastatic potential of which is most likely unrelated to the CD44 family of adhesion molecules.  相似文献   

5.
CD44 is a family of cell adhesion molecules involved in a variety of cellular functions. The present study analysed the expression of two CD44 isoforms in serous effusions of patients diagnosed with ovarian carcinoma and corresponding primary and metastatic lesions. Fifty-eight effusions, 23 primary ovarian tumours, and 44 metastatic lesions were studied for protein expression of CD44s and v3-10 using immunohistochemistry. Results were correlated with clinical parameters. CD44v3-10 was seen in carcinoma cells in the majority of cases at all sites. Malignant effusions showed an up-regulation of CD44s compared to both primary tumours and metastatic solid lesions. Mesothelial cells frequently expressed CD44s, but were rarely immunoreactive for v3-10. CD44s immunoreactivity in cancer cells in effusions was significantly more often observed in patients with FIGO stage 3 than in stage 4 patients (P = 0.045). Staining results did not correlate with age, effusion site, metastatic site, tumour grade or residual tumour mass after initial surgery. Likewise, comparison of overall and disease-free survival with expression of the CD44 isoforms studied did not reveal any statistically significant associations. The up-regulation in CD44 levels in effusions, primarily in stage 3 disease, suggests that adhesion of ovarian carcinoma cells to mesothelium may be regulated at the level of CD44s expression, and provides further evidence of phenotypic alteration in the transition from primary tumour cell clones to effusions. The similar expression profile of CD44 in carcinoma cells in peritoneal and pleural effusions supports our previous observations and the hypothesis that carcinoma cells in peritoneal effusions are truly metastatic. This revised version was published online in July 2006 with corrections to the Cover Date.  相似文献   

6.
食管癌组织中多药耐药相关蛋白和CD44v6的表达   总被引:3,自引:0,他引:3  
目的 探讨多药耐药相关蛋白 (multidrugresistance associatedprotein ,MRP)和CD44v6在食管癌组织中表达的意义 ,以及两者之间的关系。方法 采用免疫组织化学S P法检测 74例食管癌组织中MRP和CD44v6的蛋白表达。结果 MRP和CD44v6在食管癌组织中的阳性表达率分别为 5 1 4 %和 83 8%,食管癌中MRP的表达与肿瘤的浸润深度和淋巴结转移呈正相关 (P <0 0 5 ) ,而与肿瘤的分化程度无关 (P >0 0 5 )。CD44v6在食管癌中的表达与肿瘤的浸润深度和淋巴结转移密切相关 (P <0 0 5 ) ,而与肿瘤的分化程度无关 (P >0 0 5 )。CD44v6在MRP阳性食管癌中的表达明显高于其在MRP阴性食管癌中的表达 (P <0 0 5 )。结论 肿瘤多药耐药可能与肿瘤转移有关 ,检测食管癌中MRP和CD44v6的表达可能反映肿瘤细胞的生物学行为。  相似文献   

7.
CD44v6和E-cadherin表达与结直肠癌浸润转移关系   总被引:12,自引:2,他引:12  
目的 探讨CD44v6和E cadherin(E cad)蛋白表达与结直肠癌浸润转移的相关性。方法 应用免疫组织化学技术 ,检测 90例结直肠癌组织中CD44v6和E cad蛋白表达。结果  90例结直肠癌中CD44v6和E cad蛋白阳性表达率分别为75 6 %和 46 7%。CD44v6高表达及E cad低表达与结直肠癌Dukes分期、浆膜浸润、淋巴结转移、肝脏转移均呈正相关 (P <0 0 5 )。结直肠癌中CD44v6表达与E cad表达呈负相关 (r =- 0 4 3,P <0 0 0 5 )。结论 CD44v6和E cad表达与结直肠癌浸润转移密切相关。检测CD44v6和E cad蛋白表达可作为判断结直肠癌预后的客观指标。  相似文献   

8.
目的研究食管鳞癌组织中血管内皮细胞生长因子-C(VEGF-C)与CD44v6的表达及其与淋巴结转移的关系。方法应用免疫组织化学方法对152例食管鳞癌组织进行VEGF-C与CD44v6蛋白检测结果VEGF-C与CD44v6蛋白在食管鳞癌的阳性表达为55.3%和71.7%,VEGF-C与CD44v6的表达与食管癌有无转移有显著差异(P<0.05)。结论VEGF-C与CD44v6与食管鳞癌淋巴结转移密切相关,可作为判断食管鳞癌预后的指标。  相似文献   

9.
Expression of CD44 splice variants in human skin and epidermal tumours   总被引:4,自引:0,他引:4  
Splice variants of the adhesion molecule CD44 (CD44v) are important in the lymphatic spread of rat carcinoma cells. In several human tumours expression of CD44v correlates with tumour progression. However, little is known about the physiological functions of distinct variant exons. Here we report on the immunohistological evaluation of CD44 expression in normal human skin and epidermal tumours which do not metastasise, or do so vary rarely. Frozen tissues were stained with a panel of monoclonal antibodies, recognizing epitopes of the CD44 standard isoform, as well as of variant exons v5, v6, v7, v7–v8 and v10. Stratum basale and spinosum as well as the root shaft of hairs reacted strongly with the whole panel of anti-CD44 antibodies. Stratum corneum, acinar cells of sebaceous and eccrine sweat glands stained with anti-CD44v5, anti-CD44v6 and anti-CD44v7, but not with anti-CD44v10, the latter recognizing the epithelial isoform (CD44v8–v10) of CD44. Ductal cells of glands and apocrine glands did not express CD44v. Compared with its expression in normal human skin, CD44v expression was reduced in basal cell carcinoma and squamous cell carcinoma of the skin. This was particularly true of CD44v10. The expression of CD44v in normal skin and dermal appendages indicates that not all combinations of variant exons are involved in tumour progression. Since the epithelial isoform is particularly downregulated in basal cell carcinoma and squamous cell carcinoma of the skin, it is unlikely that exons v8–v10 play a role in tumour progression. Rather, they may be of functional importance in maintenance of the epidermal structure.  相似文献   

10.
CD44 is a member of cell surface glycoproteins which are involved in cell-matrix adhesion and tumor metastasis. Certain types of tumors express complex CD44 isoforms generated by alternative splicing of 2v-10v exons, and their expression appears to promote metastasis of tumor cells. Using a nested RT-PCR, we analyzed expression of CD44 variants in 26 stomach carcinoma, 21 matched normal tissues, and 2 carcinoma cell lines. We observed frequent and complex patterns of CD44 variant expression in tumor tissues. While exons 6v and 7v expression was detected in most normal and tumor tissues, exon 9v was most rarely detected. Exon 5v showed a significantly frequent expression in carcinoma, suggesting that its expression might contribute to the malignant progression. While exon 9v was frequently observed in diffuse-type tumors, the other 8 variant exons including 6v showed more frequent expression in intestinal-type tumors. Exons 9v and 10v were predominantly expressed in advanced tumor tissues and exon 8v was expressed more frequently in tumors of lymph node metastasis. We believe that series with a longer follow-up now need to be tested to clarify the association between CD44 splice variant expression and distant metastasis or long-term prognosis.  相似文献   

11.
目的研究肺腺癌细胞生长环境及转移性与黏附分子CD44v6和CD29的表达关系。方法将起源相同、转移性不同的两个肺腺癌细胞系AGZY和Anip分别用简便肿瘤多细胞球体(MTS)培养法培养,并设常规单层贴壁细胞培养对照。通过倒置显微镜、扫描及透射电镜观察MTS形成情况,并用免疫组化法分别对MTS及贴壁细胞上CD44v6和CD29表达进行检测。结果MTS培养成功,贴壁细胞与MTS在细胞结构及细胞连接结构上相似,两种MTS在形态及结构上差异无显著性。免疫组化结果显示,CD29在高转移性的Anip细胞及其MTS上呈阳性表达;在低转移性的AGZY细胞及其MTS上阴性表达。CD44v6在Anip和AGZY细胞及MTS上均呈阳性表达,差异无显著性。贴壁细胞与MTS上两种黏附分子表达均无差异。结论成功建立了一种简易制备MTS的方法。细胞生长方式(单层贴壁与MTS)可能不影响CD44v6和CD29的表达。CD29表达可能与肺腺痛转移性相关;CD44v6表达可能与肺腺癌转移无关。  相似文献   

12.
Alterations of CD44 glycoproteins have been shown to play an important role in progression of various malignancies, including urothelial cancer. We investigated expression patterns of CD44s and CD44v6 in transitional cell carcinoma (TCC) of the urinary bladder in relation to tumour grade, proliferative activity, and immunoreactivity for p53. The selected markers were detected immunohistochemically in 122 samples of TCC. We found a close relationship between CD44s and CD44v6 expression and tumour grade. The extension of positive staining for CD44s and CD44v6 towards the luminal surface was a predominant feature of differentiated carcinomas (grades 1 and 2), suggesting deranged maturation of cancer cells related to their neoplastic transformation. Heterogeneous expression of CD44s and CD44v6 predominated in poorly differentiated tumours (G3-4). However, areas of squamous differentiation within the high-grade tumours displayed strong immunoreactivity for both CD44s and CD44v6. The proliferative activity and p53 overexpression increased with the dedifferentiation of the tumour. The results of this study are discussed in relation to the significance of CD44 expression in TCC and to the explanation for controversial results reported in previous studies on the relationship between CD44 expression and the biological behaviour of urothelial cells.  相似文献   

13.
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.  相似文献   

14.
15.
Cell-cell and cell-matrix interactions, which are mediated by cell adhesion molecules, play a fundamental role during many cellular processes including growth, differentiation, cell migration and cancer metastasis. One molecule playing a major role in these processes is the CD44 surface receptor, which is expressed in a wide range of cells including many cells of the hemopoietic system, where it mediates the interaction with its major ligand, hyaluronate. However, little is known about CD44 and hyaluronate in bone marrow and this was investigated immunohistochemically in trephine biopsies and in cultivated human bone marrow stromal cells. In biopsy specimens, patches of hyaluronate deposition were detected in the extracellular matrix (ECM). However, most of the areas of the ECM were devoid of hyaluronate. Single mast cells and lymphocytes scattered throughout the marrow were CD44 immunopositive. Marrow-derived stromal cells (MDSC) expanded in cell culture were immunopositive for CD44, hyaluronate synthase, and hyaluronate. Hence, a marked difference between CD44 immunolocalisation and hyaluronate deposition can be observed between in situ and under cell culture conditions. Since in normal marrow in situ the number of CD44 immunopositive cells was low, interactions of CD44 and hyaluronate would appear to not to play a major role in cell adhesion in the normal bone marrow.  相似文献   

16.
The aim of this study was to define whether or not the impaired expression of CD44, E-cadherin (E-cad), and beta-catenin (beta-cat) correlates with the clinical evolution and prognosis of oral cancer. Ninety-three primary oral squamous cell carcinomas (OSCCs) with tumour-adjacent normal and/or dysplastic mucosa, 30 associated metastases, and 12 recurrences were immunostained for CD44s, -v3, -v4, -v5, -v6, -v7, -v9, E-cad, and beta-cat. In non-neoplastic epithelium, all molecules investigated were constitutively expressed in the basal layers. In the majority of dysplasias, immunoreactivity for all adhesion molecules was increased, but there was restricted loss for CD44s, E-cad, and beta-cat in a few cases. In carcinomas, a striking accumulation of CD44s, v3, v4, v9 and a loss of E-cad/beta-cat were observed at the invasive tumour front. In metastases and recurrences, besides a loss of CD44s, v4, v7, and E-cad, a significant increase of v9 was recorded, whereas CD44v5 and v6 remained unchanged. Clinically, reduced expression of CD44v3, E-cad, and changes of CD44v9 phenotype within the primary tumours correlated significantly with poor prognosis; decreased beta-cat expression was a predictive marker for nodal metastases. These findings indicate that there is some perturbed expression of adhesion molecules during the stepwise course of oral carcinogenesis and tumour progression. Distinct phenotypic alterations project poor prognosis, while others predict metastasis. Some of these restricted molecular changes may serve as potential targets for future antibody-based tumour therapy.  相似文献   

17.
Circulating lymphocytes may home to lymph nodes (LNs) via paracortical postcapillary venules, high-endothelial venules (HEVs) that recognize circulating lymphocytes, enabling them to migrate into nodal cortical/paracortical regions. Our goal was to find any histologic, immunohistochemical, or in vitro evidence to support the hypothesis that squamous cell carcinoma (SCC) may gain access to LNs via an alternative venolymphatic pathway. Slides from 67 neck dissections with SCC were studied. Standard criteria for lymphatic-mediated metastasis were used; criteria for evidence ofvenolymphatic metastasis were tumor nests localized to the paracortical regions, directly contiguous to HEVs but not marginal sinuses. Cases in which LN architecture was obliterated by metastases were excluded. A modified Stamper-Woodruff assay, which assesses HEV binding, incubated cell lines from oral carcinomas and lung adenocarcinomas with fresh frozen LN sections. Double-blinded cell counts were performed by two observers and analyzed by Student's t test. Immunohistochemical examination was undertaken on 19 paraffin-embedded cases with the monoclonal antibody, MoAb CD44v6, to discover whether expression of this adhesion molecule correlated with metastatic pattern. Twenty-nine cases (66%) revealed evidence only for the LN route of metastasis; 4 cases (9%) were classified as venolymphatic metastasis; 11 cases (25%) showed evidence for both pathways. The Stamper-Woodruff assay confirmed that SCC cells preferentially bound to HEV within cervical LN sections more than did adenocarcinoma cells (P = .02). Strong staining to MoAb CD44v6 was seen in 18 (95%) of 19 SCCs with a membranous pattern. Occasionally, CD44v6 highlighted tumor emboli adjacent to HEVs, but no overall correlation could be made between CD44v6 expression and pattern of spread. Tumor metastasis via lymphatic channels is the predominant mode of metastatic spread, but the venolymphatic route is a plausible alternative pathway. The preferential attachment of SCC cells to HEVs supports this theory.  相似文献   

18.
Cell adhesion to and migration through extracellular matrices (ECM) are critical events in tumor invasion and metastasis. Previous work by us had demonstrated that signaling of epidermal growth factor receptor (EGFR) confers an oncogenic phenotype on NR6 cells and that these cells when transfected with holo EGFR demonstrate greater motility and invasiveness than cells carrying a carboxy-terminal truncated EGFR. Recently, a cell surface glycoprotein, CD44, has been implicated in cell-ECM adhesion involved in tumor cell migration, signal transduction, and metastasis. We investigated whether EGF regulates cellular interactions with ECM components, and in particular, hyaluronate, by modulating CD44 expression. In vitro cell attachment assays on hyaluronate-coated plates demonstrated similar basal level of binding -33%) for murine NR6 parental cells devoid of endogenous EGFR (P) or expressing wild-type EGFR (WT), while a time-dependent increase in binding was observed in WT cells stimulated with EGF. Additionally, utilizing monoclonal antibody blocking assays, CD44, but not EGFR, was shown to be directly involved in this attachment. Both WT and P cells possessed equivalent 95 kDa bands on immunoblots, corresponding to CD44. The existence of CD44 mRNA was verified by RT-PCR using synthetic oligonucleotides in which a 1.1 kb cDNA was detected in both cell lines and confirmed by DNA sequencing. After 24-h exposure to exogenous EGF, an increase in CD44 protein and mRNA expression was found in WT cells, but not in P cells, supporting the contention that a functional EGFR signaling pathway is required for CD44 regulation. Thus, EGF stimulates cell binding to hyaluronate in vitro by regulating CD44 expression.  相似文献   

19.
Primary pulmonary adenocarcinoma was studied, looking for relationships between the expression of cell adhesion molecules (CAMs) E-cadherin, beta-catenin and CD44v6, and clinicopathological tumour parameters and patient post-operative survival. Formalin-fixed, paraffin-embedded tissue from 120 primary lung adenocarcinomas, including 23 poorly differentiated tumours, 17 of probable bronchial origin, and 29 with a prominent bronchioloalveolar pattern, together with nodal metastatic tumour from 34 of these patients was stained using monoclonal antibodies and immunohistochemistry. Sections were scored either high level (>10% cells positive) or low level (<10% positive). High level expression of CD44v6 was retained in 28.4% (34/120) of tumours, while high levels of E-cadherin (57.5%, 69/120) and beta-catenin (80. 8%, 97/120) were more frequent. For all CAMs, staining levels did not correlate with nodal status, stage or tumour type. The apical or basal staining seen in normal bronchial and alveolar epithelium was often seen in papillary, glandular, and bronchioloalveolar areas of tumour, while solid invasive tumour more often showed pericellular staining. When the staining for each CAM in 34 nodal metastases was compared with that in the corresponding primary tumour, a high degree of concordance was found, with no tendency for metastases to show less staining than the primary tumour. Expression of E-cadherin and beta-catenin in the primary tumour had no influence on post-operative survival, but patients whose tumours had low level CD44v6 expression had a poorer post-operative survival than those with high levels of CD44v6 (p=0.0014 for all patients, p=0.0012 for stage I patients only). In primary pulmonary adenocarcinoma, the levels of expression of E-cadherin, beta-catenin, and CD44v6 are not associated with lymph node metastases or tumour stage but the staining pattern is associated with tumour morphology. Low levels of CD44v6 expression predict a poor post-operative survival, independently of stage, while there is no such relationship with the expression of E-cadherin or beta-catenin.  相似文献   

20.
目的:探讨宫颈鳞癌中CD44s和CD44v6的表达及其与临床病理资料的关系。方法:应用免疫组化EnVision两步法对31例宫颈鳞标本中CD44s和CD44v6蛋白表达并进行分析。结果:肿瘤原发灶中CD44s阳性表达率为61.3%(19/31)。CD44v6阳性表达率为93.5%(29/31),CD44v6阳性率高于CD44s,CD44s阳性表达与临床分期,病理分级和分类无关(P>0.05),CD44v6阳性表达与肿瘤细胞分化程度无关,但与浸润程度及分期有关(P<0.05),结论:CD44v6基因蛋白与宫颈鳞癌的侵袭,转移相关,可作为预测肿瘤进展和预后的一种有用指标。  相似文献   

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