Systematic assessment of the prognostic impact of membranous CD44v6 protein expression in colorectal cancer

Aims:  To assess systematically the membranous expression of CD44v6 in colorectal cancer by immunohistochemistry to determine its prognostic impact, the differential expression between primary and metastatic tumours and expression differences between the tumour centre and invasive front.
Methods and results:  Immunohistochemistry was performed for CD44v6 on two tissue microarrays. The first included 1279 colorectal tumours with full clinicopathological data. The second consisted of 50 matched primary and metastatic tumours sampled from the tumour centre and the invasive margin. A scoring system was tested by multiple observers. Receiver–operating characteristic curve analysis was used for cut-off point determination. Loss of membranous CD44v6 was associated with pT stage ( P  = 0.016; sensitivity 85.8%, specificity 20.1%), lymph node metastasis ( P  = 0.015; sensitivity 52.8%, specificity 55%), an infiltrating tumour margin ( P  < 0.001; sensitivity 71.4%, specificity 40%) and adverse prognosis ( P  = 0.011; hazard ratio 0.79, 95% confidence interval 0.7, 0.9), but was not an independent prognostic factor on multivariable analysis. Loss of expression occurred at the invasive front in both primary and metastatic lesions ( P  < 0.001).
Conclusions:  This study outlines an approach to help standardize the immunohistochemical evaluation of CD44v6 and similar markers in colorectal cancer and highlights a significant role for loss of membranous CD44v6 expression in colorectal cancer progression and prognosis.     

CD44v6和E-cadherin表达与结直肠癌浸润转移关系

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。     

结直肠癌CD44V6、E-cadherin和VEGF的表达及其意义

目的：探讨结直肠癌CD44V6、E-cadherin和VEGF的表达及其临床意义。方法：应用免疫组化S－P法检测46例结直肠癌CD44V6、E-cadherin和VEGF的表达，并分析其与结直肠癌临床病理特征的关系。同时检测了23例淋巴结转移灶CD44V6、E-cadherin和VEGF的表达。结果：结直肠癌组织中CD44V6、E-cadherin和VEGF阳性表达率分别为50．0％、56．5％、和50．0％；原发灶CCD4V6和VEGF阳性表达率低于淋巴结转移灶（60．9％和56．％），而原发灶E-cadherin阳性表达率则高于淋巴结转移灶（43．5％）。结直肠癌CDV46和VEGF阳性表达与淋巴结转移，局部浸润深度和Dukes分期等有关。E-cadherin阳性表达与结直肠癌临床病理特征无关。结论：CD44V6和VEGF是结直肠癌发生与发展重要的促进因子，其过度表达与结直肠癌浸润转移，病理分期有关，可作为预测结直肠癌预后的生物学指标之一。     

CD44v6和Bcl-2蛋白在甲状腺癌中的表达及相关性研究

目的:探讨甲状腺癌组织中CD44v6和Bcl-2蛋白的表达与肿瘤发生和转移的关系,并探讨CL44v6和Bcl-2表达的相关性。方法:应用催化信号放大系统免疫组化技术,检测50例甲状腺癌、45例甲状腺腺瘤和20例癌旁正常甲状腺组织中CD44v6和Bcl-2蛋白表达。结果:在甲状腺癌CD44v6和Bcl-2表达阳性率分别为64.0％和46.0％,均显著高于甲状腺腺瘤和癌旁正常甲状腺组织（P<0.05）,CD44v6和Bcl-2阳性率均与甲状腺癌淋巴结转移相关（P<0.05）。CD44v6和Bcl-2表达呈正相关。结论:CD44v6和Bcl-2表达对预测甲状腺癌转移和评估预后是一种重要参考指标。     

非小细胞肺癌中CD44v6的表达

目的　探讨CD4 4v6表达与非小细胞肺癌临床病理特征之间的关系。方法　采用免疫组化S P法检测 132例非小细胞肺癌、6 6例淋巴结转移癌和 115例正常肺组织CD4 4v6表达的情况。结果　非小细胞肺癌CD4 4v6阳性表达率为4 8 4 8% ,高于正常肺组织 17 39%的阳性表达率。CD4 4v6阳性表达与淋巴结转移状况、TNM分期、肿瘤大小和组织学类型有相关性。非小细胞肺癌淋巴结转移组、TNMⅢ期患者、直径 >3cm的肿瘤和鳞癌CD4 4v6阳性表达率分别高于无淋巴结转移组、TNMⅠ期和Ⅱ期患者、直径≤ 3cm的肿瘤和腺癌。淋巴结转移癌CD4 4v6阳性表达率高于肺原发癌。CD4 4v6阳性表达与患者的性别、年龄和组织学分级无相关性。结论　CD4 4v6阳性表达预示非小细胞肺癌具有较强的侵袭和转移能力 ,可作为一项预测非小细胞肺癌转移潜能生物学指标。     

Evaluation of osteopontin and CD44v6 expression in odontogenic cystic lesions by immunohistochemistry

Odontogenic cysts are common lesions with different biological behavior. Odontogenic keratocysts (OKCs) and calcifying odontogenic cysts (COCs) with ameloblastoma-like epithelium are more aggressive than dentigerous cysts (DCs) and radicular cysts (RCs). Therefore, they were included in the list of odontogenic tumors by WHO. Osteopontin (OPN) is a calcium-binding glycoprotein present in many normal tissues. It plays a role in the migration and invasion of transformed epithelial cells. Binding of OPN to its receptor CD44v6 can enhance cell motility and migration. The purpose of this study was to compare the expression of these markers between odontogenic cysts of varying biological behavior. We examined OPN and CD44v6 expression in tissue sections of 14OKCs, 14COCs, 14RCs and 14DCs by immunohistochemistry. OPN and CD44v6 immunostaining was observed in all lining epithelial cells of the studied lesions with different degrees. The highest level of OPN and CD44v6 expression was found in OKCs, followed by COCs, RCs and DCs. Comparison of both markers among four groups revealed significant differences (P<0.001). Our findings suggest that higher level of OPN and CD44v6 expression in epithelial cells of some lesions such as OKC and COC can explain the local aggressive behavior of them.     

Expression and prognostic value of the CD44 splicing variants v5 and v6 in gastric cancer

In the present study, the expression and prognostic role of the CD44 splicing variants v5 and v6 were immunohistochemically investigated in 418 curatively resected gastric carcinomas. CD44v5 was expressed in 65·3 per cent (n=273) and CD44v6 in 77·0 per cent (n=322) of the tumours. Whereas the expression of CD44v5 was correlated with advanced pT categories, with lymph node involvement, and with the presence of blood and lymphatic vessel invasion, such a correlation could not be found for the variant v6. As shown by univariate analysis, patients with CD44v5-positive tumours had a significantly shorter overall survival than patients with CD44v5-negative tumours (P=0·049). In contrast, expression of CD44v6 had no impact on prognosis (P=0·574). In a multivariate analysis including the prognostic parameters pT category and pN category, as well as blood and lymphatic vessel invasion, the prognostic impact of CD44v5 expression could not, however, be maintained. Although in the present study the expression of CD44v5 was correlated with a more aggressive tumour type, these data suggest that neither CD44v5 nor CD44v6 can predict survival in patients with gastric cancer, nor is their expression a suitable tool for identifying subgroups of patients who may be at higher risk. © 1997 John Wiley & Sons, Ltd.     

CD44和CD44v6基因在胃腺癌组织中的表达及其意义

目的： 研究胃腺癌组织中ＣＤ４４ 的表达及其与淋巴结转移和预后的关系。方法： 应用免疫组化方法, 对１０５ 例胃腺癌组织中ＣＤ４４ 的表达进行了观察, 并对其中６２ 例患者做了随访。结果： ＣＤ４４ 和ＣＤ４４ｖ６ 基因的表达率分别为５４－３ ％ 和４８－６ ％ 。ＣＤ４４ｖ６ 在胃腺癌组织中的表达与癌细胞的分化、浸润深度, 以及临床分期和预后有关（Ｐ＜ ０－０５）, 而ＣＤ４４ 的表达则与上述临床病理指标无关。另外, 抗ＣＤ４４ 和抗ＣＤ４４ｖ６ 抗体的阳性反应, 与癌细胞的淋巴结转移有关（ＣＤ４４ｖ６, Ｐ＜ ０－０１ ; ＣＤ４４ , Ｐ＜ ０－０５） 。结论： ＣＤ４４ 的表达可用于胃癌患者的病情监测, 其中ＣＤ４４ｖ６ 有望作为判断预后的一个指标。     

乳腺癌中OPN、CD44v6及CD10的表达及其临床意义

目的探讨骨桥蛋白(osteopontin,OPN)、CD44v6、CD10在乳腺癌及腺病中的表达,分析三者与乳腺癌临床病理特征及预后的相关性。方法采用免疫组化En Vision两步法检测OPN、CD44v6、CD10在浸润性癌非特指型(153例)、导管原位癌(40例)、腺病(28例)中的表达;采用χ2检验分析三者与乳腺癌临床病理特征的关系,多因素分析采用Cox回归模型,预后分析采用Kaplan-Meier法,组间差异比较采用Log-rank检验。结果在腺病、导管原位癌、浸润性癌非特指型中,OPN阳性率分别为7.1%、27.5%、56.2%,CD44v6阳性率分别为10.7%、40.0%、57.5%,CD10阳性率分别为3.5%、37.5%、55.6%。三者在腺病中的阳性率均低于乳腺癌,差异具有统计学意义(P=0.020、0.042、0.003)。浸润性癌非特指型组织中OPN、CD44v6和CD10的表达均与组织学分级、淋巴结转移相关,且OPN、CD44v6表达均与p TNM分期相关,CD44v6表达与PR状态相关(P均0.05);在导管原位癌中三者的表达与核分级相关,差异均有统计学意义(P均0.05);三者的表达与患者年龄、绝经状态、脉管浸润、Ki-67增殖指数、ER状态、HER-2状态均无关(P均0.05)。OPN、CD44v6和CD10在乳腺癌中的表达两两间均呈正相关(P均0.001)。多因素分析提示淋巴结转移、CD10阳性是浸润性癌非特指型患者的预后影响因素。生存分析显示在浸润性癌非特指型中,三者均阴性组患者的无病生存率(disease-free survival,DFS)、总生存率(overall survival,OS)均优于三者均阳性组,差异有统计学意义(P=0.010、0.007)。结论 OPN、CD44v6、CD10在乳腺癌中高表达,均与乳腺癌进展相关。联合检测OPN、CD44v6、CD10在乳腺癌中的表达,对于判断患者预后具有重要价值。     

Expression of standard CD44 in human colorectal carcinoma: Association with prognosis

The aim of the present study was to evaluate the expression of standard CD44 (CD44s) in colorectal cancer (CRC), its relationship with clinicopathological characteristics, and its potential prognostic significance. CD44s levels were measured on immunohistochemistry in tumors and surrounding normal mucosa from 74 patients with primary colorectal carcinomas. The patients were followed for a median period of 37 months. Expression of CD44s in primary tumor and surrounding normal mucosa tissues was demonstrated in 100% (74/74) and 37.9% (28/74), respectively. The expression of CD44s in tumors was significantly associated with the depth of invasion ( P  = 0.034) and lymph node involvement ( P  = 0.031). A significant difference was observed between the overall survival and level of tumor CD44s expression, especially for stage IV carcinoma ( P  = 0.038). Multivariate analysis indicated that TNM stage ( P  = 0.020) and tumor CD44s expression ( P  = 0.008) were independent predictors of overall survival in adenocarcinomas. CD44s overexpression may be an independent unfavorable prognostic factor for overall survival in advanced CRC, especially stage IV disease. Further investigation, however, is necessary to assess the biological roles of CD44 in CRC, and validate their possible value as novel therapeutic targets.     

CD44v6 expression in inflammatory bowel disease is associated with activity detected by endoscopy and pathological features

AIMS: Overexpression of CD44v6 in colon crypt epithelial cells has been suggested to have diagnostic potential in differentiating ulcerative colitis from other forms of colon inflammation, including Crohn's disease. Our aim was to determine the value of CD44v6 expression in inflammatory bowel disease (IBD) and to look for possible associations between CD44v6 expression and activity of this disease. METHODS AND RESULTS: CD44v6 expression was studied using immunohistochemical techniques in 100 surgical and endoscopic colon samples of ulcerative colitis (n = 71) and Crohn's disease (n = 29), and in every case disease activity was studied by endoscopy and microscopic examination. Fifty-five of 71 (77.5%) samples of ulcerative colitis showed monoclonal antibody 2F10 stained colon epithelium, as did 16 of 29 (55.2%) samples of Crohn's disease. CD44v6 was detected in 88.2% (15 of 17) of cases of IBD with severe disease activity and in 100% of eight cases of severe ulcerative colitis. Our study showed a strong association between CD44v6 expression and the activity of IBD (P = 0.007). CONCLUSIONS: CD44v6 expression in IBD is significantly associated with activity detected by means of endoscopy and pathological features. Our data suggest that CD44v6 expression may have some usefulness in conjunction with other factors as a means of evaluating the disease activity. Moreover, CD44v6 expression was higher in ulcerative colitis than Crohn's disease (P = 0.02), although this does not confirm the utility of monoclonal antibody 2F10 in differential diagnosis between ulcerative colitis and Crohn's disease, as there was a notable percentage of positive samples of Crohn's disease.     

上皮钙黏蛋白和CD44v6蛋白在青年胃腺癌组织中的表达及其临床意义

目的:探讨上皮钙黏蛋白(E-cad)与CD44v6蛋白在青年(≤35岁)胃癌组织中的表达及其与临床病理特征之间的关系.方法:收集68例青年(≤35岁)和68例老年(≥60岁)胃腺癌组织,用免疫组织化学EnVision法检测E-cad和CD44v6的表达.结果:远离癌组织的正常胃黏膜上皮几乎全部上皮细胞膜着色,即正常表达;而胃癌组织中E-cad呈异常表达,即细胞质着色或异质性着色.青年胃癌组织E-cad异常表达率和CD44v6阳性表达率分别为70.6%和76.5%,而老年胃癌组织E-cad异常表达率和CD44v6阳性表达率分别为42.6%和51.5%,两者比较差异有统计学意义.青年胃癌淋巴结癌转移组和无淋巴转移组E-cad异常表达率分别为63.6%和32.6%,差异有统计学意义;CD44v6淋巴结癌转移组阳性表达率为80.4%;无淋巴转移组阳性表达率63.6%,差异有统计学意义.青年胃癌组织中E-cad异常表达和CD44v6蛋白表达呈正相关.结论:E-cad蛋白异常表达及CD44v6蛋白高表达预示青年胃癌具有较强的侵袭转移能力,可作为预测青年胃癌转移潜能的生物学指标.     

CD133和CD44在结直肠癌细胞中的表达及其与患者5年生存率的相关性分析

目的: 探讨不同CD133/CD44细胞亚群的成瘤能力及CD133、CD44的表达水平对根治性结直肠癌患者术后生存率的影响,明确CD133和CD44作为结直肠癌肿瘤干细胞表面标志物的意义。方法: 利用流式细胞术分选出SW480细胞系中CD133和CD44标记的不同细胞亚群,比较其在裸鼠皮下成瘤情况;并利用免疫组化的方法观察CD133和CD44在90例结直肠癌患者石蜡切片标本的表达情况,对CD133、CD44与患者临床病理资料及生存率进行分析。结果: CD133⁺CD44⁺细胞群成瘤能力明显优于其它各组。CD133和CD44均在细胞膜上表达,两者均与患者性别、年龄 、肿瘤位置、肿瘤大小、浸润深度、淋巴结转移、肝转移、肿瘤分化程度及UICC分期无关(P＞0.05)。Kaplan-Meier生存分析法显示,CD133高表达组5年生存率为45.2%,CD133低表达组5年生存率为83.8%,两者有明显差异(P＜0.01);而CD44高表达组5年生存率(75.6%)与低表达组(70.1%)无明显差异(P＞0.05);其中CD133/CD44同时高表达者5年生存率明显较差(P＜0.01)。Cox风险回归模型分析结果表明,CD133、肝转移、分化程度及淋巴结转移是影响结直肠癌患者预后的几个独立危险因素(P＜0.05)。结论: CD133可作为结直肠癌肿瘤干细胞的良好标志物。CD133是影响结直肠癌患者预后的独立危险因素,其表达水平越高,预后越差;尽管CD44与结直肠癌患者预后无明显相关性,但联合检测CD133/CD44却能更好地判断患者的预后情况。     

E-cadherin、β-catenin、CD44v6在乳腺癌中的表达

目的　探讨乳腺癌中E cadherin(E cad)、β catenin(β cat)、CD4 4v6蛋白表达。 方法　采用免疫组化S P法测定 4 8例乳腺癌中E cad、β cat、CD4 4v6蛋白的表达。 结果　E cad、β cat蛋白的表达强度 ,无淋巴结转移组高于有淋巴结转移组 (P <0 0 5 ) ,与肿瘤的大小、病理分级、组织学分类无关 ;在乳腺癌中随着E cad强度的增加 ,β cat阳性率亦呈上升趋势 (P <0 0 5 )。CD4 4v6蛋白的表达强度 ,有淋巴结转移组高于无淋巴结转移组 (P <0 0 5 ) ,与肿瘤的大小、病理分级、组织学分类无关。结论　E cad、β cat、CD4 4v6的表达可作为判断乳腺癌是否转移的可靠指标     

非小细胞肺癌中Ezrin和CD44v6的表达及意义

目的 探讨非小细胞肺癌中Ezrin和CD44v6的表达及其与肺癌各种临床病理参数之间的关系.方法 采用免疫组化SP法检测55例非小细胞肺癌组织中Ezrin及CD44v6的表达.结果 Ezrin的表达程度与非小细胞肺癌的TNM分期(P=0.004)和淋巴结转移(P=0.003)密切相关; CD44v6的表达程度与非小细胞肺癌的TNM分期(P=0.012)和淋巴结转移(P=0.010)密切相关;Ezrin 和CD44v6两者在非小细胞肺癌组织中的表达呈正相关(r=0.568, P=0.000).结论 Ezrin和CD44v6与肺癌淋巴结转移和临床TNM分期密切相关,联合检测Ezrin和CD44v6有助于判断肺癌的预后.     

Differential expression of CD44v6 in adenocarcinoma of the pancreas: an immunohistochemical study

Alternative splicing gives rise to numerous CD44 isoforms, some of which seem to have a role in tumour metastasis. Specifically, a variant form of CD44 with sequences encoded by exon v6 (CD44v6) confers metastatic potential when transfected into a nonmetastasizing cell line of rat pancreatic adenocarcinoma. This study has investigated standard CD44 (CD44s) and CD44v6 expression immunohistochemically in 6 samples of normal pancreatic tissue, 4 of tissue affected by chronic pancreatitis, and 24 of tissue from metastasizing and nonmetastasizing pancreatic adenocarcinomas. In addition, 18 samples from lymph node or visceral metastases were included in the study. CD44s was expressed in nonneoplastic tissue and in tissue from pancreatic adenocarcinomas. In contrast, CD44v6 was not detected in any of the normal tissue or chronic pancreatitis specimens, whereas 54% of pancreatic adenocarcinomas and 55% of metastases expressed this variant exon. Although it is not clear whether CD44 isoforms containing exon v6 play a part in malignant progression in the human exocrine pancreas, it seems plausible that the expression of multiple isoforms containing this and other variant exon confers a selective advantage on pancreatic adenocarcinoma.     

慢性乙型肝炎患者外周血淋巴细胞CD44v6的表达及意义

目的：研究慢性乙型肝炎及乙型肝炎后肝硬化患者外周血淋巴细胞（PBL）CD44v6的表达情况及意义。方法：用流式细胞术分别检测50名健康体检者、30例乙型肝炎病毒（HBV）携带者、60例慢性乙型肝炎患者及60例乙型肝炎后肝硬化患者PBLCD44v6的表达水平。结果：慢性乙型肝炎患者PBLCD44v6表达明显高于正常对照组和HBV携带组（P〈0.01）;肝炎后肝硬化组明显高于慢性乙型肝炎组（P〈0.01）;HBV携带组与正常对照组之间的差异也有统计学意义（P〈0.01）。结论：CD44v6在慢性乙型肝炎HBV致肝细胞损伤过程中可能起着重要作用。