Correlation and prognostic significance of MMP-2 and TFPI-2 differential expression in pancreatic carcinoma

Aberrant expression of matrix metalloproteinase (MMP)-2 and tissue factor pathway inhibitor (TFPI)-2 not only correlate with tumorigenesis, but also with tumor invasion and metastasis. This study aims to investigate the correlation and prognostic significance of MMP-2 and TFPI-2 differential expression in pancreatic carcinoma. Immunohistochemistry was used to evaluate MMP-2 and TFPI-2 expression in tumor tissues and corresponding non-tumor tissues from 122 patients with pancreatic carcinoma. The results showed that the expression of MMP-2 was significantly (P < 0.05) higher in tumor tissues (78.7%) than in adjacent non-tumor tissues (27.9%), whereas the expression of TFPI-2 was significantly (P < 0.001) lower in tumor tissues (27.9%) than in adjacent non-tumor tissues (79.5%). Spearman’s rank correlation test showed a negative correlation between MMP-2 and TFPI-2 expression (r = -0.346, P < 0.001). Kaplan-Meier survival analysis showed that high MMP-2 expression was significantly correlated with decreased disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001), while high TFPI-2 expression was significantly associated with increased DFS (P < 0.001) and OS (P < 0.001) of the patients. Multivariate analysis showed that high MMP-2 expression can act as an independent predictive factor for poor DFS (P = 0.01); and low TFPI-2 expression as an independent prognostic factor for poor DFS (P < 0.001) and OS (P < 0.001). In conclusion, our findings suggested that the differential expression of MMP-2 and TFPI-2 have a negative correlation in pancreatic carcinoma tissues; they may be considered as valuable biomarkers for prognosis of pancreatic carcinoma.     

Prognostic value of CD133 expression in stage I lung adenocarcinomas

CD133 is one of the most representative cancer stem cell markers. This study evaluated the potential prognostic value of CD133 expression in stage I lung adenocarcinomas (ADC). Tumors from 177 patients were immunohistochemically examined for CD133 expression, and their associations with disease recurrence were analyzed. Also, the potential prognostic value of combining CD133 expression with proliferating activity measured by immunohistochemical expression of Ki-67 and vessel involvement was evaluated. CD133 high expressers showed a significantly higher risk of recurrence than CD133 low expressers: 5-year disease-free survival (DFS) rate 77.2% vs. 95.1% (p=0.004), adjusted Hazard ratio (HR) 4.37, 95% Confidence Interval (CI) 1.30-14.71 (p=0.017). CD133 high expressers having strong proliferating activity and/or with vessel invasion showed a higher risk of recurrence: 5-year DFS rate 66.5% in CD133 high/Ki-67 high expressers vs. 93.2% in the other types (p<0.001), adjusted HR 8.39, 95% CI 2.65-26.54 (p<0.001): 5-year DFS rate 51.0% in CD133 high expressers with vessel invasion vs. 92.9% in the other types (p<0.001), adjusted HR 4.50, 95% CI 1.51-13.34 (p=0.007): 5-year DFS rate 53.9% in CD133 high/Ki-67 high expressers with vessel invasion vs. 91.2% in the other types (p<0.001), adjusted HR 9.32, 95% CI 3.42-25.39 (p<0.001). In conclusion, the level of CD133 expression is an independent prognostic marker and its combination with proliferating activity and/or vessel invasion could have excellent prognostic value to predict postoperative recurrence in patients with stage I lung ADC.     

CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors

High-grade oligodendroglial tumors, that is, anaplastic oligodendroglial tumors and glioblastomas with oligodendroglial component, differ significantly in terms of prognosis and response to chemotherapy. Differentiation might be difficult because the histological differences are vague and reliable markers are not established. We correlated the presence of putative cancer stem cells (CSC) in high-grade oligodendroglial tumors (WHO grades III and IV) with clinical outcome. Tumors with favorable prognosis neither contained CSC nor did they show CD133 expression. Tumor cells resembled lineage-restricted progenitor cells with limited proliferative capacity and differentiation profile. In contrast, CD133 expression and stem cell-like tumor cells characterized tumors with poor prognosis. They showed neurosphere-like growth, differentiated into cells of all neural lineages, and were tumorigenic in nude mice. In our series, CSC and expression of CD133 predicted the clinical course of disease better than the histological grading. To confirm these results, we retrospectively analyzed 36 high-grade oligodendroglial tumors. Again, CD133 expression indicated shorter survival and predicted clinical outcome more reliable than the histological assessment. Our data show that detection of CSC and expression of CD133 is predictive of prognosis in high-grade oligodendroglial tumors. The presence or absence of CD133(+) CSC might explain the crucial biological difference between WHO grade III and IV oligodendroglial tumors.     

甲状腺髓样癌中CD133和CD44的表达及意义

目的 探讨肿瘤干细胞(cancer stem cells,CSC)标志物CD133及CD44在甲状腺髓样癌(medullary thyroid cancer,MTC)组织中的表达及临床病理意义.方法 采用免疫组化SP法检测51例MTC组织中CD133和CD44的表达.结果 (1)CD133蛋白在MTC伴有包膜浸润组的阳性率(76.2％,16/21)明显高于无包膜浸润组(43.3％,13/30);CD133蛋白在MTC病灶直径≥1 cm组的阳性率(64.4％,29/45)显著高于病灶直径＜1 cm组(0,0/6),差异均有统计学意义(P均＜0.05).(2)CD44蛋白在MTC伴有包膜浸润组的阳性率(66.7％,14/21)明显高于无包膜浸润组(20％,6/30),差异有统计学意义(P＜0.01).(3) MTC中CD133和CD44蛋白的表达与患者年龄、性别、是否散发、甲状腺受累范围、淋巴结转移、远处脏器转移、TNM分期均无关(P＞0.05).(4)CD133与CD44共表达与MTC包膜浸润密切相关(P＜0.01).结论 MTC中存在CSC,其与肿瘤的浸润生长及恶性增殖相关,可考虑将CD133及CD44作为MTC临床评价肿瘤生物学行为的指标.二者可能存在互相调节的机制,共表达在MTC的恶性进展中发挥作用.     

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。     

Prognostic value of cancer stem cell marker CD133 expression in non-small cell lung cancer: a systematic review

Objective: To investigate the correlation between CD133-positive non-small cell lung cancer (NSCLC) and clinicopathological features and its impact on survival. Methods: A search in the Pubmed, Embase and Wanfang databases (up to July 15, 2013) was performed. Only articles in which CD133 antigen was detected in situ localization by immunohistochemical staining were included. This meta-analysis was done using RevMan 5.2 software. Outcomes included overall survival and various clinicopathological features. Results: A total of 1004 NSCLC patients from 11 studies were included. Meta-analysis showed that CD133 expression patients had a significant worse 5-year overall survival compared to the low expression ones (RR = 3.19, 95% CI: 2.05-4.98, P<0.0001 fixed random). With respect to clinicopathological features, CD133 expression by IHC method was closely correlated with tumor T stage (OR = 0.91, 95% CI: 0.59-1.39, P = 0.67 fixed-effect) and tumor grade (OR = 1.20, 95% CI: 0.80-1.79, P = 0.37 fixed-effect). Conclusion: CD133-positive NSCLC patients had worse prognosis, and was associated with common clinicopathological poor prognostic factors.     

5氟尿嘧啶上调干细胞标记物CD133在结肠癌细胞中的表达

目的: 研究通过5氟尿嘧啶(5-FU)对结肠癌干细胞标记物CD133表达的影响,探讨5-FU对结肠癌干细胞的影响。方法: 用流式细胞仪检测CD133在结肠癌细胞株表面的表达, 磁珠细胞分离的方法分离结肠癌细胞株DLD1中CD133阳性和阴性的细胞群,细胞克隆形成实验检测2群细胞的自我更新能力,新型四唑氮盐方法(MTS)检测2群细胞对5-FU敏感性的差异,qPCR方法检测5-FU处理结肠癌细胞后CD133mRNA水平的变化。结果: 结肠癌细胞株DLD1、HT29、SW480、HCT116、Lovo、RKO细胞表面CD133的表达率分别为30.20%、82.00%、0.34%、91.80%、85.30%、0.28%。DLD1细胞中以CD133为标记有2群明显的细胞,MACS方法分离后阳性细胞群中CD133为87.21%±5.33%, 而阴性细胞群中阴性细胞的比例为84.30%±4.65%;CD133阳性的细胞与未分离及CD133阴性细胞相比,克隆形成能力强(46.33%±4.44% vs 31.00%±2.00%,P<0.05),对5-FU的敏感性下降20%,P<0.01。在DLD1和HT29细胞中,5-FU 1 mg/L上调CD133mRNA水平的表达,从1升为1.684±0.012(P<0.01)、HT29细胞从30.702±0.284升为49.379±0.460(P<0.01)。结论: 与CD133阴性细胞相比CD133阳性细胞克隆形成能力强,对5-FU的敏感性下降;5-FU上调干细胞标记物CD133mRNA水平的表达,CD133阳性的结肠癌干细胞在5-FU的治疗过程中被富集。     

人CD133基因转染细胞株的建立及其生物学功能的初步研究

目的:构建人干细胞标记分子CD133-2转基因细胞并探讨CD133-2分子的生物学功能。方法:利用分段克隆和重叠PCR方法从人胎肝cDNA文库中克隆出人CD133-2全长基因,经双酶切后装入真核表达载体p IRES2-EGFP中,用脂质体法转染L929细胞,加入G418选择性培养基进行筛选。经RT-PCR、Western blot、流式细胞术(FCM)等方法鉴定转基因细胞;MTT法分析转基因细胞对T细胞的体外增殖作用;流式细胞仪分析T细胞表面活化分子标记CD4CD25、CD8CD25的表达。结果:成功克隆和构建了能稳定表达人CD133-2分子的转基因细胞CD133-2/L929,该转基因细胞与T细胞共培养可抑制其体外增殖,下调T细胞表面分子CD4CD25和CD8CD25的表达。结论:稳定表达CD133-2蛋白的转基因细胞株的建立为该基因功能的后续研究奠定了物质基础。     

Overexpression of PROM1 (CD133) confers poor prognosis in non-small cell lung cancer

The surface marker PROM1 is considered one of the most important marker of tumor-initiating cells, and its high expression is believed to be an adverse prognostic factor in gliomas, medulloblastoma and in other malignancies. The aims of our research were to explore the expression profile of the PROM1 in non-small cell lung cancer (NSCLC) and to assess its possible role as a prognostic factor. The protein expression profiles were determined via immunohistochemical staining assay. The clinical prognostic values of protein expression were investigated with univariate and multivariate survival analysis. The quantitative variable PROM1 expression was dichotomized according to the best cutoff value obtained by the receiver operating characteristics (ROC) analysis. The protein level of PROM1 of NSCLC was higher compared with normal tissues, and the survival analysis demonstrated the positive membrane expression and combination of membrane/cytoplasm groups of PROM1 had worse prognosis than those negative expression groups. Also, multivariate Cox regression analysis showed membrane expression of PROM1 and lymph node invasion were the independent prognostic factors. The expression of PROM1 was significantly higher than normal tissue, and high levels of PROM1 membrane expression and combination of membrane/cytoplasm expression were associated with adverse prognosis.     

CD133: molecule of the moment

CD133 (prominin-1) was the first in a class of novel pentaspan membrane proteins to be identified in both humans and mice, and was originally classified as a marker of primitive haematopoietic and neural stem cells. Due to the highly restricted expression of CD133 family molecules on plasma membrane protrusions of epithelial and other cell types, in association with membrane cholesterol, a role in the organization of plasma membrane topology has also recently been assigned to this family. Studies have now confirmed the utility of CD133 as a marker of haematopoietic stem cells for human allogeneic transplantation. In addition, CD133 represents a marker of tumour-initiating cells in a number of human cancers, and therefore it may be possible to develop future therapies towards targeting cancer stem cells via this marker. The development of such therapies will be aided by a clearer understanding of the molecular mechanisms and signalling pathways that regulate the behaviour of CD133-expressing cells, and new data outlining the role of Wnt, Notch, and bone morphogenetic protein (BMP) signalling in CD133(+) cancer stem cell regulation are discussed within.     

Interleukin-8 is a prognostic indicator in human hilar cholangiocarcinoma

Interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9) and neovascularization have been implicated to be associated with biological processes, especially cancer progression. However, few studies have investigated the role of IL-8 in human hilar cholangiocarcinoma. In this study we detected the expression of IL-8 combined with MMP-9 and microvessel density (MVD) in hilar cholangiocarcinoma to evaluate their clinicopathological significance and prognostic value. A total of 62 patients with hilar cholangiocarcinoma who underwent curative surgery were enrolled in this study. The expression of IL-8, MMP-9 and MVD were examined immunohistochemically. The correlation of IL-8 with MMP-9 expression, MVD, clinicopathological features and survival time of patients were then analyzed. Expression of IL-8 was observed in 56.5% tumors, which was related to advanced TNM stage (P = 0.026) and tumor recurrence (P = 0.018). IL-8 had a positive correlation with MMP-9 expression and MVD. Furthermore, patients with high IL-8 expression had a significantly shorter overall survival than those with low IL-8 expression (P = 0.01). Multivariate analysis confirmed IL-8 as an independent prognostic factor (P = 0.005). In conclusion, IL-8 expression significantly correlated with MMP-9 expression and MVD, and IL-8 was a valuable prognostic factor for human hilar cholangiocarcinoma.     

Long-term prognostic significance of neoangiogenesis in breast carcinomas: comparison of Tie-2/Tek, CD105, and CD31 immunocytochemical expression

The immunocytochemical detection of Tie-2/Tek, CD105, and CD31 was assessed in a large series (n = 905) of breast carcinomas on frozen sections. Results were correlated with patients' long-term outcome (median, 11.7 years) to define the respective prognostic significance of these markers. Univariate (Kaplan-Meier) analysis demonstrated that higher expression of CD31 (P = 0.032), CD105 (P = 0.001), and Tie-2/Tek (P = 0.025) correlated with poorer survival. However, only greater CD105 expression could significantly (P = 0.035) identify node-negative patients with poorer survival. Moreover, in multivariate analysis, CD105 and Tie-2/Tek, but not CD31, expression proved to be independent significant prognostic indicators. Marked expression of CD31 (P = 0.024), CD105 (P = 0.001), and Tie-2/Tek (P = 0.01) also correlated with higher risk of metastases in node-negative patients. It is concluded that CD105 immunoexpression in breast carcinomas is an independent prognostic indicator in node-negative patients, better in terms of overall survival than Tie-2/Tek and CD31. Also, Tie-2/Tek expression proved more sensitive than CD31 expression in terms of prognostic significance. Compared with CD31, CD105 and Tie-2/Tek have more clinical relevance for patient monitoring and also can serve as targets for specific therapy, such as CD105 immunotoxins or Tie-2/Tek pathway blockade, as recently suggested in experimental studies.     

Expression of the stem cell markers CD133 and nestin in pancreatic ductal adenocarcinoma and clinical relevance

Background: To evaluate the prognostic implication of cancer stem cell markers in pancreac ductal adenocarcinoma (PDAC), the expression of CD133 and nestin were investigated in a series of PDAC patients in relation to the survival rate. Methods: This series included 42 cases of PDAC patients and evaluated the stem cell markers CD133 and nestin expression detected by immunohistochemistry. The presence of immunopositive tumor cells considering intensity and area was evaluated and interpreted in comparison to the patients’ clinicopathological and survival data. Results: Twenty eight cases (66.7%) showed high CD133 expression. The CD133 expression was mainly identified in the apical border of the tumor cell, but aberrant expression in the cytoplasmic or perinuclear location was also noted. High nestin expression in tumor cells were found in only 2 cases, but high nestin expression along perinuerial or stromal region was found in 15 cases (35.7%). There was no correlation between CD133, nestin expression and gemcitabine resistance. Statistically significant difference was found in patient survival in N stage (p=0.007), and CD133 expression (p= 0.014) in univariate analysis. Nestin expression wan not statistically significant, but it was helpful to identify the perineurial invasion. In Cox-regression hazard model stratified by age and sex for multivariable analysis, AJCC stage and CD133 were independent prognostic factors for overall survival. Conclusions: CD133 expression is upregulated in PDAC that is related to poor prognosis, and treatment targeted the CD133 positive cancer/cancer stem cells might be a promising therapeutic strategy for this patients.     

High expression of matrix metalloproteinase-9 indicates poor prognosis in human hilar cholangiocarcinoma

High expression of matrix metalloproteinase-9 (MMP-9) was found to be correlated with tumor progression and poor prognosis in a variety of carcinomas. However, few studies have investigated the role of MMP-9 in human hilar cholangiocarcinoma. In this study, a total of 58 patients with hilar cholangiocarcinoma who underwent curative resection were included in this study. The expression of MMP-9 was analyzed by immunohistochemistry using the streptavidin peroxidase complex method. The correlation of MMP-9 overexpression with clinicopathological features and survival time of patients was investigated. The results showed that MMP-9 overexpression was prominent in cancer cells and mainly localized in the cytoplasm. MMP-9 overexpression was observed in 46.5% tumors, which showed no correlation with clinicopathological parameters. Patients with high MMP-9 expression had a significantly poorer overall survival rate than those with negative or low MMP-9 expression (P = 0.038). Multivariate analysis confirmed that MMP-9 overexpression was an independent prognostic factor (P = 0.007). In conclusion, overexpression of MMP-9 is a valuable independent prognostic indicator in hilar cholangiocarcinoma.     

CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway

Sartelet H, Imbriglio T, Nyalendo C, Haddad E, Annabi B, Duval M, Fetni R, Victor K, Alexendrov L, Sinnett D, Fabre M & Vassal G
(2012) Histopathology  60, 1144–1155 CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway Aims: Neuroblastoma is a frequent childhood cancer with a heterogeneous prognosis. CD133 expression is an independent prognostic marker for a low survival rate in several cancers. The aim of this study was to determine the prognostic value of CD133 expression in a large cohort of neuroblastoma cases, to define the chemoresistance of neuroblastoma cells expressing CD133, and to determine whether this chemoresistance is regulated by activation of the AKT pathway. Methods and results: Two hundred and eighty samples of neuroblastoma were screened for CD133 expression. The sensitivity of purified CD133+ neuroblastoma cells isolated from two human cell lines to doxorubicin, vincristine and cisplatin, as single agents or in combination with LY294002, an AKT inhibitor, was evaluated in vitro. CD133 expression was found in 100 of 280 tumours. There was a significant association between CD133 expression and the following poor prognosis covariates: age, International Neuroblastoma Staging System stage, MYCN amplification, and phospho‐AKT (pAKT) expression. Patients with CD133? tumours had significantly better 3‐year event‐free and overall survival than patients with CD133+ tumours. In a multivariate model, CD133 expression was independently associated with decreased overall survival. CD133^high neuroblastoma cells were significantly resistant to chemotherapy as compared with CD133^low cells. Treatment of unsorted neuroblastoma cells with the three anticancer drugs significantly enriched the CD133+ subpopulation. CD133^high cells expressed significantly higher levels of pAKT than CD133^low cells. LY294002 treatment abolished the preferential survival of CD133^high cells. Conclusions: CD133 is associated with in‐vitro resistance to chemotherapy involving activation of the AKT pathway.