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.     

Reduced expression of CD44 v3 and v6 is related to invasion in lung adenocarcinoma

We have previously reported that the histological pattern of invasion is correlated with the prognosis of surgically treated patients of lung adenocarcinoma. On the other hand, several clinicopathologic studies have shown that CD44 variant isoforms are associated with invasion and metastasis in human malignant tumors. The expression of CD44 variant isoforms v3 and v6 was analyzed in 93 Japanese lung adenocarcinoma patients by immunostaining to study the relationship between their expression and the invasion in lung adenocarcinoma. The specimens were histologically categorized into three groups. Both the invasive lesion and the noninvasive lesion were observed in 49 out of 93 cases (group I). Twenty cases were noninvasive carcinoma growing mainly in a lepidic pattern (group II). Twenty-three cases were invasive carcinoma which showed no frankly noninvasive lesion growing in a lepidic pattern (group III). The significant reduced expression of CD44 v3 and v6 was observed in the invasive lesion compared with the noninvasive lesion in adenocarcinoma of group I (P < 0.05). Although reduced expression of CD44 v3 and v6 was observed in the invasive carcinoma of group III compared with the noninvasive carcinoma of group II, it was not significant (P = 0.0693 for v3, P = 0.0827 for v6). The pattern of expression of CD44 v3 was significantly concordant with that of CD44 v6 (P < 0.0001). Our results suggest that reduced expression of CD44 v3 and v6 is associated with the invasion in the lung adenocarcinoma.     

CD44v6与可溶性CD44v6在胃癌中的表达及与预后的关系

目的 探讨CD44v6与可溶性CD44v6(sCD44v6)在胃癌中的表达及与胃癌生物学行为和预后的关系.方法 应用免疫组化S-P法检测103例胃癌组织和10例正常胃黏膜标本的CD44v6表达,并对患者进行术后随访,随访期为3～91个月;应用酶联免疫吸附(ELISA)法检测86例胃癌、30例胃溃疡患者和30例健康人外周血血清中sCD44v6的浓度,并对患者进行术后随访,随访期为1～91个月.结果 (1)CD44v6在正常胃黏膜中不表达,而在胃癌中的表达率为60.2%;CD44v6的表达与淋巴结转移、TNM分期、脉管是否存在癌栓以及Borrmann分型有关(P＜0.05),而与胃癌浸润深度、是否远处转移、分化程度以及患者的生存率无关(P＞0.05);9例伴有肝转移的胃癌患者中,有7例CD44v6为强阳性表达.(2)胃癌患者外周血血清中sCD44v6的浓度明显高于胃溃疡组和健康对照组(P＜0.01);胃癌根治术后患者血液中sCD44v6的浓度比术前明显下降(P＜0.01),而姑息术后患者的浓度变化却不明显(P＞0.05);sCD44v6的浓度与胃癌浸润深度、淋巴结转移、是否远处转移、脉管是否存在癌栓、Borrmann分型以及分化程度无关;sCD44v6浓度较高组的生存率较sCD44v6浓度较低组高,且差异有统计学意义(P=0.0281),但经Cox回归分析显示,sCD44v6的浓度与生存期有关(P=0.415),而手术方式却与生存期有关(P=0.000).(3)胃癌组织中CD44v6的表达与外周血血清中sCD44v6的表达无明显平行关系(P＞0.05).结论 CD44v6的表达对评估胃癌生物学行为有参考价值,但是否与预后有关仍需探讨;sCD44v6的表达对胃癌辅助诊断、手术彻底性判定及生物学行为评估有一定的意义;CD44v6与sCD44v6的表达无明显平行关系.     

CD44v6在胃癌中的表达

[目的]研究胃癌CD44v6的表达及意义。[方法]应用免疫组织化学ABC法 ,研究85例胃癌手术标本中CD44v6的表达。[结果]胃癌原发灶中CD44v6表达阳性率为61 2%(52/85)。CD44v6表达阳性率在进展期胃癌(66 7%)、累及浆膜层胃癌(72 2%)、淋巴结阳性胃癌(73 2%)均高于早期胃癌(30 8%)、未累及浆膜层胃癌(41 9%)、淋巴结阴性胃癌(37 9%)(P<0 05或P<0 01)。[结论]CD44v6可能参与胃癌的浸润和淋巴结转移过程。检测胃癌CD44v6的表达 ,有助于对胃癌生物学行为的了解及对患者预后的判断     

CD44V6表达与胰腺癌增殖,转移及预后关系的研究

目的：探讨ＣＤ４４Ｖ６表达与胰腺癌增殖活性、淋巴结转移以及预后的关系。方法：应用免疫组ＬＳＡＢ法检测４７例胰腺癌组织中ＣＤ４４Ｖ６和ＰＣＮＡ的表达。结果：予性率为５７．４％（２７／４７）,与胰吕组织学类型及分级无关,伴淋巴结转移者ＣＤ４４Ｖ６阳性率（８１．０％,１７／２１）,明显高于无淋巴结转移者（３８．５％,１０／２６）,两者间有极显著性差性差异（Ｘ＾２＝８．５８,Ｐ〈０．０１）,ＣＤ４４Ｖ６阴     

CD44v6蛋白在乳腺癌中的表达及其预后意义

目的；研究CD44v6蛋白在乳腺癌中的表达，并探讨其能否成为乳腺癌的预后影响因素。方法：应用EnVision^TM免疫组化法，回顾性分析100例女性浸润性导管癌石蜡组织CD44v6的表达。结果：CD44v6在乳腺癌中表达的阳性率为66％。CD44v6的表达与患者淋巴结转移状况、临床分期密切相关。Kaplan-Meier生存曲线，Logrank检验结果显示，CD44v6低表达患者的五年、十年生存率分别为82．76％，78．37％。而CD44v6高表达的患者的五年、十年生存率分别为64．1％、49．88％，两者之间存在显著性差异（P＝0．0055）。结论：CD44v6蛋白与乳腺癌淋巴结转移相关，可能作为有意义的预后指标指导临床。     

Expression of CD44v6 is an independent prognostic factor for poor survival in patients with esophageal squamous cell carcinoma

CD44v6 has been causally associated with the development of metastases and with poor prognosis in various human malignancies. To elucidate the clinicopathological significance of CD44v6 expression in esophageal squamous cell carcinoma (ESCC), the present study aimed to investigate the expression of CD44v6 using immunohistological techniques. Using specific antibodies against CD44v6 and CD44s, expression of the proteins was analyzed immunohistochemically in 63 primary esophageal ESCCs, which were previously resected at the Nagoya City University Hospital without pre-operative induction therapy. Using light microscopy, the positive expression of CD44v6 was divided into a low- or high-expression group. The expression of CD44v6 in ESCC was analyzed with respect to various clinicopathological characteristics. The frequency of CD44v6 expression was 90.5% (57/63). The CD44v6 high-expression group comprised 55.6% of the patients (n=35) and the low expression group included 44.4% of the patients (n=28). In this study, no significant difference was observed between any clinicopathological factor and the immunohistochemical expression of CD44v6. In patients with high levels of CD44v6 expression, survival was markedly worse (p=0.0327). Favorable outcomes were observed for the clinicopathological characteristics of 6 patients whose tissue immunohistochemical expression of CD44v6 was not detected. Moreover, multivariate analysis confirmed that expression of CD44v6 was an independent prognostic indicator (risk ratio =2.793; p=0.0301). Overexpression of CD44v6 is a useful prognostic indicator of ESCC. Therefore, CD44v6 should be investigated as a potential target for therapy.     

Expression of CD44v6 in advanced gastric cancer and its relationship to hematogenous metastasis and long-term prognosis

BACKGROUND AND OBJECTIVES: Variants of CD44 have been proposed to be important in promoting tumor progression and metastasis. We attempted to determine the expression of CD44v6 product in advanced gastric cancer and to evaluate its prognostic value. METHODS: The expression of CD44v6 was analyzed immunohistochemically in advanced gastric cancers using monoclonal antibody, 44-2V. We investigated the relationship between CD44v6 expression and prognosis in 201 gastric cancer patients. RESULTS: Ninety-five (47.3%) of 201 cancer tissues expressed CD44v6. The expression of CD44v6 protein was significantly higher in differentiated, adenocarcinoma than in diffuse type carcinoma. The CD44v6-positive cancers were more frequently associated with hematogenous metastasis. There was no significant correlation between CD44v6 immunoreactivity, and prognosis among the combined cases. Among patients with differentiated adenocarcinoma, however, the prognosis was significantly poorer in patients with CD44v6-positive tumors than in those with CD44v6-negative tumors. CONCLUSIONS: CD44v6 protein may have an important role in hematogenous metastasis, and may be a biologic marker of prognostic significance in differentiated type gastric cancers.     

Membranous CD44v6 is upregulated as an early event in colorectal cancer: Downregulation is associated with circulating tumor cells and poor prognosis

Previous studies have reported that CD44 variant 6 (CD44v6) and metastasis-associated protein 1 (MTA1) are contributing factors to cancer progression. The present study aimed to evaluate the expression profiles for associations with patients'' demographic data, clinicopathological characteristics, the presence of partial epithelial-to-mesenchymal transition (pEMT), metastatic potential based on the presence of CK20⁺ CEA⁺ CXCR4⁺ circulating tumor cells (CTCs) and prognosis (median follow-up, 45 months). Thus, frozen tissue samples from 31 patients with stage I–III colorectal cancer (CRC), 15 benign colorectal polyps and seven normal colorectal tissues were analyzed to detect membranous (m)CD44v6 and MTA1 expression via flow cytometry. The results demonstrated that the mCD44v6 and MTA1 expression profiles were significantly correlated (r_s=+0.786, P<0.001). Notably, MTA1 expression was not associated with any of the clinicopathological characteristics assessed. The percentage of mCD44v6-positive cells within tumors was higher in the right-sided cancer lesions (P=0.014), suggesting that proximal and distal CRCs are distinct clinicopathological entities. Furthermore, downregulated mCD44v6 expression was significantly associated with the presence of CTCs (P=0.017). This association was stronger for pEMT (co-expression of N- and E-cadherin mRNAs) primary lesions (P=0.009). In addition, patients with CRC with low levels of mCD44v6 had unfavorable survival outcomes (P=0.037). Taken together, these results suggest that targeted analysis of membranous CD44v6 as opposed to membranous-cytoplasmic expression is important in determining the prognosis of patients with CRC. Furthermore, downregulated mCD44v6 expression in malignancies presenting CTCs reinforces the importance of tumor-stroma reciprocal influence during the metastatic process and encourages the assessment of relevant therapeutic strategies.     

Galectin-3 and CD44v6 isoforms in the preoperative evaluation of thyroid nodules.

PURPOSE: Thyroid cancer is the most frequently occurring endocrine malignancy; however, preoperative diagnosis of some lesions, in particular those with follicular histology, is difficult, and a consistent number of not otherwise-specified "follicular nodules" are surgically resected more for diagnosis than therapeutic purposes. In this study, we investigated whether the lectin-related molecules CD44v6 and galectin-3, the expression of which is altered during deregulated cell growth and malignant transformation, could be potential markers for improving the diagnostic accuracy of conventional cytology. MATERIALS AND METHODS: A comparative immuno-chemical and molecular analysis was performed on 157 thyroid specimens representative of normal, benign, and malignant tissues, and on 36 cytologic samples obtained preoperatively by fine-needle aspiration biopsy from nonselected patients with palpable thyroid nodules. RESULTS: Normal thyrocytes did not express galectin-3 nor CD44v6. Although the expression of CD44v6 isnegligible in thyroiditis, these molecules are variably detected in benign and malignant proliferative lesions. Interestingly, galectin-3 is never expressed in benign lesions, but it is invariably detected in cancers. A comparative evaluation of CD44v6 and galectin-3 expression in thyroid malignancies demonstrated that these molecules are coexpressed at the messenger RNA and protein level in almost all lesions. CONCLUSION: Our findings suggest that CD44v6 and galectin-3 could be potential markers to preoperatively identify malignant transformed thyrocytes. Immunodetection of these molecules on cytologic specimens obtained by fine-needle aspiration biopsy is an accurate and improved method for selecting, on a molecular basis, those nodular lesions of the thyroid gland that need to be surgically resected.     

Expression of variant CD44 containing variant exon v8-10 in gallbladder cancer

We studied the Cd44v8-10 expression in gallbladder cancer immunohistochemically. Eighteen of 37 gallbladder cancer tissues expressed CD44v8-10. There were significant correlations between CD44v8-10 immunoreactivity and perineural invasion, venous invasion, and lymph node metastasis. Patients with CD44v8-10-positive tumors showed poor prognoses, whereas those with CD44v8-10-negative tumors had favorable prognoses. A multivariate analysis using the Cox regression model showed the immunoreactivity of CD44v8-10 to be an independent prognostic indicator of gallbladder cancer. The results suggest that CD44v8-10 expression may be a biologic marker of prognostic significance in gallbladder cancer.     

胃肠道间质肿瘤CD44s和CD44v6的表达及其意义

目的:探讨CD44s和CD44v6在胃肠道间质肿瘤(GISTs)中的表达及其意义。方法:应用免疫组织化学方法检测65例胃肠道间质肿瘤中CD44s和CD44v6的表达。结果:65例GISTs中,CD44s63例阳性,阳性率达96.9%,其中阳性强度>4分者57例(87.7%),>6分者43例(66.2%)。低度、中度、高度恶性潜能组阳性强度>4分者分别为93.8%,100%,81.1%,3组之间表达水平无显著差异(P>0.05);>6分者分别为87.5%,75.0%,54.1%,3组之间表达水平有显著差异(P<0.05)。CD44v640例阳性,阳性率为61.5%,其中阳性强度>4分者19例(29.2%),阳性强度>6分者6例(9.2%)。低度、中度、高度恶性潜能组阳性强度>4分者分别为18.8%,33.3%,32.4%,3组之间表达水平无显著差异(P>0.05);>6分者分别为0%,8.3%,13.5%,3组之间表达水平无显著差异(P>0.05)。结论:CD44s表达与GISTs的恶性潜能呈负相关。CD44v6在GISTs中很少有表达,与GISTs的恶性潜能无明显相关性。免疫组化法检测CD44s可以作为预测GISTs恶性潜能的相关指标之一。     

Clinicopathologic Significance of Sox2, CD44 and CD44v6 Expression in Intrahepatic Cholangiocarcinoma

Embryonic stem cells (ESC) and cancer stem cells (CSC) have a capacity for self-renewal and differentiation into multiple cell lineages. Sox2 plays a critical role in ESC and has been shown to participate in carcinogenesis and tumor progression in many human cancers. CD44 and CD44v6 are putative CSC markers and their association with tumor progression, metastasis, and tumor relapse after treatment has been demonstrated. We evaluated the immunoexpression of Sox2, CD44, and CD44v6 in 85 cases of Intrahepatic cholangiocarcinomas (IHCC) and assessed their prognostic significance. Sox2 expression showed a significant association with lymph node metastasis (p?=?0.025), T4 stage (p?=?0.046), and worse overall survival (p?=?0.047). Greater expression of Sox2 was observed in IHCC with poor differentiation, vascular invasion, and stage IV, without statistical significance (p?>?0.05). CD44 expression showed an association with periductal infiltrative type (p?=?0.034), poor differentiation (p?=?0.012), and vascular invasion (p?=?0.009). CD44v6 expression was evident in patients with stage IV (p?=?0.019). These results demonstrated that Sox2 expression is associated with aggressive behavior and poor overall survival in IHCC.     

转移相关基因CD44v6在胃癌中的表达意义

目的：探讨转移相关基因ＣＤ４４ｖ６与胃癌某些生物学行为的关系。方法：采用免疫组化ＳＰ法对４２例进展期胃癌进行标记分析。结果：ＣＤ４４ｖ６阳性表达率肠型胃癌（７０．８３％）明显高于弥漫型胃癌（３３．３３％）（Ｐ〈０．０５）;淋巴结转移组（８２．３５％）明显高于无淋巴结转移组（３６．０％）（Ｐ〈０．０１）;ＣＤ４４ｖ６阳性率与肿瘤大小无关（Ｐ〉０．０５）;ＣＤ４４ｖ６阳性表达的不同病理分型的胃癌中淋巴     

胃癌CD44v6表达及其临床意义的研究

探讨胃癌ＣＤ４４ｖ６的表达,评价其表达对胃癌进展程度和转移的诊断意义,以及对手术预后的影响。方法收集胃癌手术标本８５例,相应的癌转移淋巴结标本４７例,应用Ｓ－Ｐ免疫组化染色技术检测ＣＤ４４ｖ６蛋白在上述组织中的表达。结论：对胃癌组织进行ＣＤ４４ｖ６蛋白的检测,有助于预测胃癌进展程度和淋巴结转移的诊断,以及评估胃癌患者的预后。