Prognostic value of CD44 variant expression in primary breast cancer.

CD44 is a family of cell surface transmembrane glycoproteins members which differ in the extracellular part by sequences derived by alternative splicing of 10 variant exons (v1-v10). CD44 proteins containing such variant sequences have been implicated in tumor metastasis formation. Here, we have evaluated the expression of CD44 variants by immuno-histochemistry in primary breast cancer samples of 237 node-negative and 230 node-positive patients. For the analysis of samples derived from node-negative patients, the exon-specific antibodies used were DIII, vff7 and vff18 (v6), vff17 (v7/v8), fw11.24 (v9) and vff16 (v10). With the different antibodies which recognize v6 epitopes, the majority of tumors were positively stained (> or = 65% of the tumors) with varying intensities. Thirty-nine percent of the tumors were positively stained with the antibody vff16, and approximately half of the tumors with the antibodies vff17 and fw11.24. The expression of CD44 v6 epitopes in tumors from node-negative patients was associated with a favorable prognosis, both upon univariate and multivariate analysis. The expression of CD44 v7/8, v9 or v10 epitopes was not significantly related with relapse-free survival. Samples from node-positive patients were only examined with the antibodies vff7, vff17 and vff18. The staining with none of these antibodies was correlated with the length of relapse-free survival of the patients. Our data suggest that, generally, the usefulness of knowledge of CD44 variant expression is of limited value for assessing the risk of relapse in patients with primary breast cancer. However, the expression of exon v6 of CD44 may be a marker to identify patients with a relatively favorable prognosis in node-negative patients.     

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. Int. J. Cancer 74:443–445, 1997. © 1997 Wiley-Liss, Inc.     

CD44v6 is not a prognostic factor in primary breast cancer

Background: CD44 is an adhesion molecule and represents a highly variable family of isoforms. The isoform CD44v6 has been associated with metastasis formation and poor prognosis in animal models and human colon cancer. Results of studies in primary breast cancer are relatively small and contradictory.Patients and methods: The immunohistochemical expression of CD44v6 was studied in a series of 338 patients with primary breast tumours, uniformly staged and treated in a single center with a long median follow-up of 128 months. The prognostic significance of CD44v6 as well as the correlation with several clinicopathological features were analysed.Results: Two hundred nineteen of 338 (64.8%) of the breast cancers were CD44v6-positive (>5% of tumour cells with positive staining). CD44v6 expression had no value for prognosticating disease-free or overall survival at this or any other cut-off point.Conclusion: CD44v6 expression is not a prognostic factor in primary breast cancer.     

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

Expression of specific cell adhesion molecule CD44 isoforms (splice variants) has been shown to be associated with poor prognosis in human cervical cancer. We used 3 different variant exon sequence-specific murine monoclonal antibodies (MAbs) to epitopes encoded by exons v5, v6 and v7-v8 of human variant CD44 to study the expression of CD44 splice variants in 35 primary squamous-cell carcinomas of the cervix and pelvic lymph node metastases by means of immunohistochemistry. Primary tumors showed expression of CD44 splice variants CD44v5, CD44v6 and CD44v7-8 in 93%, 73% and 33% of cases, respectively. Lymph node metastases expressed CD44v5, CD44v6 and CD44v7-8 in 83%, 53% and 21% of cases, respectively. Tumors with expression of CD44v6 in pelvic lymph node metastases showed metastatic spread to 2 or more pelvic lymph nodes significantly more often compared to patients without expression of splice variant CD44v6. Patients suffering from tumors with lymph node metastases expressing splice variant CD44v6 had a poorer recurrence-free survival compared to patients without CD44v6 expression in lymph node metastases, but this trend was not statistically significant. Expression of CD44 splice variants containing epitopes encoded by exon v6 in primary tumors and pelvic lymph node metastases of cervical cancer patients is consistent with a prominent role of CD44 in the process of metastasis formation. © 1996 Wiley-Liss, Inc.     

The prognostic significance of CD44s and CD44v6 expression in stage two breast carcinoma: an immunohistochemical study.

AIMS: Expression of the v6 variant isoform of CD44 has been causally associated with the development of metastases. This study, using immunohistochemical techniques, examined the prognostic significance of CD44s and CD44v6 expression. METHODS: A cohort of 109 women presenting with stage 2 breast cancer, with a minimum follow-up of 5 years, were assessed. RESULTS: Eighty percent of patients demonstrated CD44v6 expression on immunohistochemical studies. CD44v6 expression in tissue sections was found to be independent of age, tumour size, grade, and lymph-node status. No significant association was demonstrated between CD44v6 expression and either disease-free or overall survival. Similar findings were observed for CD44s. CONCLUSIONS: CD44s and CD44v6 do not appear to be useful as prognostic indicators in early breast cancer. The increased expression of variant CD44 isoforms seen in breast neoplasia may merely be a marker for loss of control of alternative splicing within tumour tissue.     

The expression of variant exon v7–v8 CD44 antigen in relation to lymphatic metastasis of human breast cancer

The purpose of this prospective study was to evaluate the expression of CD44 splice variant epitopes in human breast cancer and their potential as prognostic indicators.Invasive breast cancer tissues obtained from 91 patients were examined for expression of the standard CD44 antigen and variant CD44 antigens (v5, v6, v7, v7–v8, and v8–v10) by immunohistochemical staining to investigate the relations of these antigens to clinicopathological factors and prognosis.The expression of standard CD44 antigen was detected in 54.9% of 91 patients with primary human breast cancer. The variant epitopes of CD44 examined, i.e., v5, v6, v7, v7–v8, and v8–v10, were expressed in 54.9%, 54.9%, 0%, 34.1%, and 0%, respectively. There was a significant difference in tumor size, lymph nodal status, and degree of lymphatic permeation between patients who were positive for exon v7–v8 and those negative for this variant (p < 0.01). Prognosis was also significantly worse in patients positive for CD44 v7–v8 than in those negative for this variant. However, multivariate analysis with the three prognostic indicators tumor size, lymph nodal status, and the degree of lymphatic invasion, has shown that the expression of CD44 v7–v8 antigen in breast carcinoma was not a significant independent prognostic factor and was closely dependent on lymphatic invasion and nodal status. Fourteen of 31 patients who were positive for CD44 v7–v8 experienced recurrences. The mode of recurrence was lymphatic metastasis in 10 out of these 14 patients. Breast cancer cells expressing v7–v8 CD44 antigen have an extremely high affinity for lymph nodes and lymphatic vessels, and are likely to metastasize to distant lymph nodes even at a very early stage in the progression of this disease. This suggests that not only the anatomical factors but also organ affinity plays an important role in the establishment of lymph nodal metastasis of breast cancer.     

The influence of hormones on CD44 expression in endometrial and breast carcinomas

The expression of distinct variant isoforms of the cell surface glycoprotein CD44 (CD44v) has been found to be associated with metastatic potential of rodent adenocarcinoma cells and with an altered prognosis in several types of human cancer. In hormone-dependent gynecological cancers, different CD44v expression patterns have been observed. The influence of ovarian steroid hormones and their antagonists on CD44v expression is still unclear, since there are only retrospective correlation studies so far. Therefore, we examined the CD44 mRNA expression in a standardized stimulation experiment in a number of breast and endometrial carcinoma cell lines varying in estrogen receptor (ER) status. Higher CD44 overall expression was observed in ER positive endometrial and breast carcinoma cell lines when compared to corresponding ER negative cell lines. The number and composition of alternatively spliced isoforms showed no clear correlation to the ER expression status. Three CD44v isoforms were detected in all cell lines expressing CD44v, two of which have not been reported previously in normal endometrial cells. These isoforms may have specific functions in this type of carcinoma. In the second part of the study, the influence of (anti-) hormones on CD44 expression in endometrial carcinoma cell lines was examined. CD44 overall expression showed an increase when the cells were grown in medium containing fetal calf serum (FCS) as compared to cells maintained in medium-free of FCS. CD44 expression was transiently increased by estradiol (1 h). The CD44 splice pattern of endometrial cancer cell lines RL95-2 and Hec-1-A, after treatment with (anti-) hormones showed constant and high expression rates for distinct CD44v-isoforms such as CD44E (CD44v8-v10). Only certain weakly expressed isoforms changed their expression level during the experimental period, but no direct correlation to hormone treatment was observed. In conclusion, estradiol or FCS increase CD44 overall expression, but there seems to be no direct influence of ovarian steroid hormones on the CD44v splice machinery in endometrial carcinoma cell lines.     

Neoadjuvant chemotherapy in breast cancer significantly reduces number of yielded lymph nodes by axillary dissection

Background

CD44 has been reported to be involved with tumor growth and metastasis and has also been implicated as a CSC marker in head and neck squamous cell cancer (HNSCC). However, the prognostic value of CD44 still remains controversial; hence, we investigated the correlation between CD44 and the clinicopathological features of HNSCC by meta-analysis.

Methods

A comprehensive search was performed using PubMed, ISI web of Science and China National Knowledge Infrastructure (CNKI) up to April 2013. Only studies with immunohistochemical staining of HNSCC were considered. Data on TNM classification, tumor grade, disease free survival and 3- or 5-year overall survival rate were extracted.

Results

Thirty studies with 2102 patients met the inclusion criteria for the meta-analysis. Fifteen studies used anti-pan-CD44 antibody, 9 used anti-CD44-v6 antibody, 2 used anti-CD44-v3 and 2 used anti-CD44s antibody, 1 used anti-CD44-v9, and 1 used anti-CD44-v6,-v3 and -v4-5 simultaneously. The total percentage of CD44 expression was 57.8%, with 49.3% in oral cancer patients, 66.4% in pharynx and 54.7% in larynx cancer patients expressing CD44. No significant correlation between clinical features and CD44 expression was revealed for oral cancer patients, but CD44 was shown to be associated with advanced T categories (larynx: RR?=?1.33, 95% CI 1.01-1.76; larynx & pharynx RR?=?1.21, 95% CI 1.08-1.35), worse N categories (larynx: RR?=?2.53, 95% CI 1.99-3.21; larynx & pharynx RR?=?1.95, 95% CI 1.35-2.82), higher tumor grades (larynx & pharynx RR?=?1.71, 95% CI 1.04-2.79) and 5-year OS rates (larynx: RR?=?0.62, 95% CI 0.47-0.83; larynx & pharynx RR?=?0.66, 95% CI 0.47-0.94) in patients with laryngeal and pharyngolaryngeal cancer. In stratified analysis, pan-CD44 and CD44-v6 expression were both correlated with 5-year OS rate of patients with laryngeal (CD44: RR?=?0.66, 95% CI 0.46-0.95; CD44-v6 RR?=?0.53, 95% CI 0.37-0.77) and pharyngolaryngeal cancer (CD44: RR?=?0.56, 95% CI 0.34-0.93; CD44-v6 RR?=?0.53, 95% CI 0.37-0.77).

Conclusions

Our analysis suggested that CD44 is related to worse T category, N category, tumor grade and prognosis, in pharyngeal and laryngeal cancer, but no clear association was revealed between CD44 expression and oral cancer.     

CD44v3 and v6 variant isoform expression correlates with poor prognosis in early-stage vulvar cancer.

Expression of alternatively spliced CD44 isoforms has been reported to correlate with poor prognosis in human squamous cell cancers, i.e. squamous cell cancer of the lung and cervix. The aim of this study was to evaluate whether CD44 isoform expression is a prognostic factor in early-stage squamous cell cancer of the vulva. Seventy cases of squamous cell carcinoma of the vulva International Federation of Gynaecology and Obstetrics (FIGO) stage I were examined immunohistochemically for expression of CD44 isoforms. We used four different variant exon sequence-specific murine monoclonal antibodies to epitopes encoded by exons v3, v5, v6 and v7-8 of human variant CD44. The correlation of CD44 expression with histological grade and disease-free and overall survival was investigated. CD44 isoforms CD44v3, CD44v5, CD44v6 and CD44v7-8 were detected in 28% (20/70), 47% (33/70), 33% (23/70) and 17% (12/70) of the tumour samples respectively. Patients suffering from tumours expressing CD44v6 had a poorer relapse-free (log-rank test, P = 0.02) and overall survival (log-rank test, P = 0.03). Likewise, patients suffering from tumours expressing CD44v3 had a poorer relapse-free (log-rank test, P = 0.04) and overall survival (log-rank test, P = 0.01). Expression of CD44v5 and CD44v7-8 did not compromise the patients'' outcome. Histological grade did not correlate with CD44 isoform expression. Immunohistochemically detected expression of CD44 isoforms containing variant exon v6 or v3 is correlated with a poor relapse-free and overall survival in FIGO stage I vulvar cancer patients.     

VEGF-C,VEGF-D在乳腺癌中的表达及其与淋巴结转移及预后的关系

目的探讨VEGF-C和VEGF-D在乳腺癌组织中的表达以及与淋巴结转移、预后的相关性。方法采用SP免疫组化法检测78例乳腺癌癌组织和30例癌旁组织中VEGF-C,VEGF-D的表达水平,并完成所有患者的5年的随访资料。结果 78例乳腺癌癌组织中VEGF-C/D表达与癌旁组织相比差异有统计学意义(P<0.05);乳腺癌中VEGF-C表达与VEGF-D表达无相关性。VEGF-C,VEGF-D的表达水平与乳腺癌脉管内侵犯、淋巴结转移密切相关(P<0.05),但与年龄、肿瘤大小、TNM临床分期、ER、PR及Her-2的表达无关(P>0.05)。VEGF-C和VEGF-D的表达水平与乳腺癌的总生存期及无病生存期密切相关(P<0.05)。结论 VEGF-C,VEGF-D在乳腺癌组织中呈高表达;VEGF-C/D的表达水平与乳腺癌淋巴结转移能力和预后密切相关。     

Cytosol concentrations of CD44 isoforms in breast cancer tissue

The role of the adhesion molecule CD44 in the natural history of breast cancer is controversial. We investigated the CD44 isoform CD44v5 and CD44v6 concentrations in the cytosol of 90 breast cancer specimens, 9 fibroadenomas and 22 normal breast tissue specimens by means of ELISA. CD44v5 and CD44v6 cytosol concentrations were statistically significantly higher in breast cancer compared with fibroadenoma and normal breast tissue (Mann-Whitney U-test, p = 0.009 and p < 0.001, respectively). When CD44 isoforms were correlated with lymph node involvement, histological grading, histological type, tumor stage and age at diagnosis, we found no statistically significant correlation with any of the investigated clinico-pathological parameters. In univariate and multivariate analyses, CD44v5 and CD44v6 were of no prognostic relevance regarding disease-free survival in breast cancer patients (log-rank test, p = 0.16 and p = 0.08, respectively). Our results indicate that CD44 isoforms are increased in samples from tumors relative to normal tissue. Our data show that CD44v5 and CD44v6 isoform expression, although up-regulated by malignant transformation, is not required to acquire a metastatic phenotype in breast cancer. Furthermore, our data support the assumption that cytosolic CD44 isoforms are of no prognostic relevance for disease-free survival of breast cancer patients. Int. J. Cancer (Pred. Oncol.) 79:541–545, 1998.© 1998 Wiley-Liss, Inc.     

CD44v6、E-cadhesion表达与乳腺浸润性癌预后的关系

目的检测CD44v6、E-cad在乳腺浸润性癌中的表达情况,探讨它们与乳腺浸润性癌浸润和转移的关系。方法采用免疫组化SP法检测103例乳腺浸润性癌中CD44v6、E-cad的表达,结合病理指标和临床指标分析其与预后的关系。结果CD44v6蛋白表达在细胞浆和(或)细胞膜上,阳性表达率为76.7%(79/103)。E-cad蛋白表达主要见于细胞膜,阳性表达率为35.0%(36/103)。CD44v6、E-cad蛋白表达与乳腺浸润性癌组织学类型无关(P>0.05),与组织学分级及组织浸润程度有关(P<0.05)。在56例有随访记录的患者中,CD44v6、E-cad蛋白表达与患者年龄无关(P>0.05),与腋窝淋巴结转移、局部复发、远处转移均有关(P<0.05)。两者在同一癌组织中的表达呈负相关(P<0.01)。结论CD44v6、E-cad蛋白表达与腋窝淋巴结转移、局部复发、远处转移有关(P<0.05),因此CD44v6、E-cad蛋白表达可作为判断乳腺浸润性癌的浸润程度、预测预后的参考指标之一。     

CD44v6在乳腺浸润性导管癌组织中的表达及其临床意义

背景与目的:近年研究表明,CD44v6与乳腺癌的发生、侵袭和转移密切相关,但其与乳腺癌预后关系的报道结果并不一致。本研究探讨CD44v6在乳腺癌和乳腺癌旁非癌组织中的表达及其与乳腺癌临床病理因素的关系以及对乳腺癌患者预后的预测意义。方法:采用免疫组织化学SP法检测84例乳腺浸润性导管癌和20例癌旁非癌乳腺组织中CD44v6的表达。采用SPSS10.0软件统计分析CD44v6表达与各病理因素的关系,采用Cox比例风险模型分析影响预后的因素。结果:CD44v6在乳腺浸润性导管癌上皮细胞的表达(78.6%)明显高于癌旁非癌乳腺组织上皮(5.0%),差异有显著性(P<0.05);CD44v6的表达与乳腺癌的TNM分期、肿瘤大小、淋巴结转移状况密切相关;中位随访时间为60个月,CD44v6阴性组的总体生存情况优于CD44v6阳性组,有显著性差异(P<0.05),而且随着CD44v6表达的增强,总体生存曲线有逐渐下降的趋势。Cox比例风险模型多因素的预后分析结果显示,ER、TNM分期、CD44v6均是影响预后的独立因素(P<0.05)。结论:CD44v6在乳腺癌组织中的表达明显升高;CD44v6的表达与乳腺癌患者的TNM分期、肿瘤大小、淋巴结转移呈正相关;CD44v6表达升高可作为预测乳腺癌预后的独立指标之一。     

CD44v和透明质酸介导的细胞游走受体在多阶段胃癌发生中的表达特点

目的 探讨透明质酸（ＨＡ）受体ＣＤ４４和透明质酸介导的细胞游走受体（ＲＨＡＭＭ）在多阶段胃癌发生过程中的表达情况及其肿瘤学意义。方法 以非癌粘膜,各类癌前病变和胃癌标本为研究对象,采用常规和组织选择性方法提取样本ＲＮＡ和蛋白质,进而分析其ＣＤ４４和ＲＨＡＭＭ基因表达的特点,结果 含变异型外显子/５的ＣＤ４４广泛存在于各类组织中,ｖ７常见于非癌细胞,但随癌前病变的进展而趋降低,ｖ８～ｖ１０仅见于部分肠     

Predictive Value of CD44 for Prognosis in Patients with Breast Cancer

Background: Breast Cancer (BC), is one of the most common malignancies around the world. CD44 expression correlates with cell proliferation, infiltration, angiogenesis, metastasis and prognosis in breast cancer but the exact mechanism of CD44 function is still not clear. The present study evaluates the expression of CD44 in primary HER2-positive breast cancer. The results can be used to determine the disease-free and overall survival of patients with breast cancer. Methods: We studied specimens from 100 patients with HER2-positive invasive breast cancer between March 2011 and June 2019. Immunohistochemical staining for CD44 was performed in all the specimens. Their CD44 association with clinicopathologic parameters and prognosis was evaluated. Results: The high CD44 was expression in 68(68%) of the patients and Low expression in 32(32%). CD44 expression was significantly associated with stage (p=0.007). There were no significant associations between the DFS, OS and other clinicopathologic parameters except for the stage, respectively (HR= 3.67, 95% CI =1.16-11.56, P = 0.03) (HR= 0.8.56, 95% CI =2.22-32.90, P = 0.002).20% of patients had died by the end of the follow-up. There were no significant association between DFS, OS and CD44 expression, respectively. (Log-rank p=0.13). (Log-rank p=0.10). Conclusion: The results from this study suggest that CD44 is clinically associated with stage of breast cancers. From the survival analysis, there was no statistical difference in overall survival and disease free survival with respect to CD44 expression. Further studies larger sample sizes are recommended for further investigation.     

CD44 variant expression and estrogen receptor status in breast cancer

To understand the relationship between CD44 gene expressionand an established variable associated with aggressive behaviourin human breast cancer, we have studied apanel of 6 breast cell lines and 40breast tumors selected primarily on the basis ofestrogen receptor (ER) status. CD44s (standard form) mRNAwas assessed by semi-quantitative RT-PCR, and CD44 variantsincorporating exon v7 or v10 were studied byRT-PCR and Southern blot. While CD44 expression wasnot influenced by estrogen in ER+ve MCF-7 cells,CD44s expression was slightly higher (up to 2fold) in ER–ve cells but there was amarked decrease in the range of CD44 variantsincorporating exons v7 or v10. In microdissected tumors,the levels of CD44s showed no correlation withER status but the pattern of expression oflarger forms of CD44 incorporating variant exons v7and v10 was significantly different (p=0.005and p=0.015, respectively) between ER+ve andER–ve tumors, reflecting the pattern seen in thecell lines. These findings suggest that the profileof CD44 expression in breast cancer may reflectcellular differentiation as indicated by the ER phenotype.The influence of these differences in CD44 expressionon the increased metastatic potential of ER negativebreast cancer remains to be determined.     

CD44V6在非小细胞肺癌组织中的表达及其意义

 目的　探讨CD44v6在非小细胞肺癌（NSCLC）组织中的表达及其对预后判定的意义。方法　应用免疫组织化学方法对1995年12月至2002年9月62例手术NSCLC组织标本进行CD44v6的检测。结果　62例NSCLC中CD44v6阳性表达38例，阳性率为61.3 ％，CD44v6阳性表达率与淋巴结转移及 3年生存率有密切关系，不同肿瘤分化程度、病理分型及TNM分期间差异无统计学意义。结论　NSCLC患者CD44v6阳性表达与肿瘤淋巴结转移及患者生存率关系密切，可以作为临床评估肿瘤转移及判断预后的指标。     

血管内皮生长因子-C mRNA和微血管密度与乳腺癌预后相关性关系的探讨

目的:探讨乳腺癌组织内血管内皮生长因子-C mRNA(VEGF-C mRNA)的表达及微血管密度(MVD),分析MVD和VEGF-CmRNA表达与乳腺癌患者预后的意义.方法:采用原位杂交技术观察92例乳腺浸润性导管癌(IDC)组织中VEGF-C mRNA的表达;CD105(细胞膜糖蛋白)标记乳腺癌组织中微血管并观察MVD.结果:不同组织学分级乳腺IDC组织中VEGF-C mRNA表达差异有统计学意义,P<0.05;在淋巴结转移组VEGF-CmRNA表达明显高于淋巴结未转移组,P<0.01;VEGF-C mRNA表达阳性组MVD明显高于VEGF-C mRNA表达阴性组,P<0.001;淋巴结转移组乳腺癌组织中MVD高于淋巴结未转移组,差异有统计学意义(P<0.001),VEGF-C mRNA表达阳性组(高MVD组)较VEGF-C mRNA表达阴性组(低MVD组)5年生存率低,差异有统计学意义,P<0.05.结论:VEGF-C mRNA表达与乳腺癌淋巴结转移及MVD密切相关,检测乳腺癌组织中VEGF-C mRNA表达及观察MVD可能预测乳腺癌预后.