膀胱癌诊断标志物研究进展

膀胱癌发病率逐年增高且易复发,如能早期诊断,早期治疗,患者生存状况将会明显改善。目前用于临床膀胱癌检测的肿瘤标记物的研究主要集中在NMP22、Survivin、HA-HAase、BTA,UBC、TLMA、CD44V6、L-selectin、MCM5、p27、MSI、FB/FDP、VEGF、BGA、integrin、centrosome等。对于不同发展阶段或不同类型的膀胱癌,单一肿瘤标志物检测的灵敏度有不同程度的差异。它们最有价值的潜在作用是监测膀胱癌复发和筛查有膀胱刺激征和血尿的患者,并且几种肿瘤标志物的合理联合应用将成为诊断膀胱癌的有效工具。     

尿液中膀胱癌标记物研究进展

目前尿液脱落细胞学、膀胱镜检查及活检是膀胱癌诊断、随访的金标准。尿膀胱癌生物学标记物检查具有无创、简单和高敏感性等特点，可用于膀胱癌的早期诊断、监测以及预后评估，并且很有可能取代传统方法，现就此作一综述。     

胃癌组织MUC黏蛋白表达及其与胃癌分型关系的研究进展

目的:阐述黏蛋白在胃癌中表达变化的临床病理意义,探讨黏蛋白标记的胃癌分型在研究胃癌的生物学行为和发病机制方面的意义.方法:通过Pubmed文献检索系统、万方数据资源系统和维普信息资源系统,选择了43篇研究文献,内容涉及黏蛋白的研究概况,黏蛋白在胃癌中表达的变化以及黏蛋白标记的胃癌分型的最新研究进展.结果:黏蛋白MUC1、MUC5AC、MUC6在正常胃黏膜中呈强阳性表达而MUC2则不表达.在正常胃黏膜向肠上皮化生、胃癌演进过程中,MUC1、MUC5AC、MUC6表达呈下调趋势而MUC2表达上调.以黏蛋白为标记可对胃癌进行重新分型,弥补了Lauren分型的不足.结论:黏蛋白MUC质和量的变化可以反映胃上皮细胞癌变的情况.黏蛋白标记的胃癌分型有助于进一步研究胃癌的生物学行为及潜在的分子机制.     

血循环核酸作为肿瘤诊断生物标志物的研究进展

循环核酸(circulating nucleic acids,CNAs)是一种存在于动植物和人体液中的细胞外游离状态核酸,包括循环DNA、循环RNA以及新发现的微小RNA(miRNA).血液不同于其他体液,分布于全身各处,因此,血CNAs具有良好的临床应用前景.由于生理状况、疾病种类和病程的不同,CNAs在血清和血浆中存在的种类和数量也会发生变化.本文中,我们主要介绍了血CNAs的发现过程、分子结构、生物学特性、检测方法以及与肿瘤发生、发展关系等方面的研究进展.一、肿瘤患者血CNAs的发现1948年,法国科学家首次报道,在人血浆中可分离得到游离形式的核酸.由于当时人们认为,核酸需在完整细胞内传递生物遗传信息,因此,这一发现并未引起广泛关注.数十年后,植物学家Anker和Stroun发现,植物冠瘿肿瘤的转移是通过游离核酸来完成的.随后,人们证实,肿瘤患者血液中存在游离形式的DNA,血液中循环DNA不仅发生基因突变,还包括了微卫星改变、倒位、缺失和甲基化等.至此,CNAs在肿瘤诊断方面的研究有了快速发展.     

尿液中膀胱癌标记物研究进展

目前尿液脱落细胞学、膀胱镜检查及活检是膀胱癌诊断、随访的金标准.尿膀胱癌生物学标记物检查具有无创、简单和高敏感性等特点,可用于膀胱癌的早期诊断、监测以及预后评估,并且很有可能取代传统方法,现就此作一综述.     

KL-6黏蛋白/MUC1作为肿瘤标志物的研究进展

0引言侵袭和转移是治疗恶性肿瘤最大难题,许多研究从多个方面阐述肿瘤侵袭和转移的原因。从肿瘤发生学上讲,细胞表面糖链部分结构及数量的变化,尤其是唾液酸化作用在肿瘤的发展中发挥重要的作用,一些研究表明唾液酸化糖链与肿瘤细胞转移有     

黏蛋白4研究进展

黏蛋白4（MUC4）是跨膜黏蛋白家族一员，正常表达于人体的许多组织、器官和分泌物中。近年来研究发现其超乎寻常地表达于许多上皮性肿瘤中。MUC4是一种多功能蛋白，在肿瘤细胞的生长、浸润、转移中有重要作用。MUC4的特点使其可能成为一些肿瘤诊断的标记物，并为一些肿瘤的治疗提供新的途径。     

黏蛋白4研究进展

黏蛋白4(MUCA)是跨膜黏蛋白家族一员,正常表达于人体的许多组织、器官和分泌物中.近年来研究发现其超乎寻常地表达于许多上皮性肿瘤中.MUC4是一种多功能蛋白,在肿瘤细胞的生长、浸润、转移中有重要作用.MUCA的特点使其可能成为一些肿瘤诊断的标记物,并为一些肿瘤的治疗提供新的途径.     

外周血miRNA作为肿瘤标志物的研究进展

miRNA是一类长度为20～24个核苷酸的非编码小分子RNA,与靶基因3'端非编码区不完全配对,从而抑制靶基因mRNA的翻译,影响个体发育、细胞凋亡、细胞增殖和分化等生命活动,与肿瘤的发生、转移和耐药等病理进程密切相关.近年来的研究发现,除了组织和细胞中的miRNA,外周血miRNA的表达也表现为显著的肿瘤相关性、组织特异性和表达稳定性,符合肿瘤标志物的要求.本文就外周血miRNA作为肿瘤标志物的研究进展进行综述.     

膀胱癌肿瘤标志物及其检测方法的研究进展

 膀胱癌是国内泌尿系统最常见的恶性肿瘤,易复发,发病率正逐年增高。目前膀胱镜检查和尿细胞学检查仍是膀胱癌诊断和随访的金标准。然而,膀胱镜检查为侵入性检查且费用较高,同时细胞学检查的敏感性低。随着对肿瘤在分子生物学特性的进一步理解,许多膀胱肿瘤分子标志物被研究。肿瘤标志物在肿瘤诊断、侵袭、转移、疗效判断和预后预测等方面具有重要作用。就近年来膀胱癌肿瘤标志物检测的研究进展作一综述。     

USP28 is a potential prognostic marker for bladder cancer

This study was conducted to analyze the expression of the ubiquitin-specific protease Usp28 and assess its clinical significance in human bladder cancer. mRNA and protein expression levels of Usp28 were determined by real-time polymerase chain reaction (PCR) and Western blot in 24 paired bladder cancers and the adjacent non-cancerous tissues. In addition, the expression of Usp28 protein in 186 bladder cancers was also determined by immunohistochemistry. The relationship between expression of Usp28 and clinico-pathologic features and prognosis was finally evaluated. Usp28 was expressed at a higher level in bladder cancers compared to adjacent non-cancerous tissues at both the mRNA and protein levels in 24 paired samples (all P?<?0.01). In immunohistochemical examination, 78 (41.9 %) of 186 cases displayed low Usp28 expression in cancerous tissues, whereas 108 (58.1 %) cases displayed high Usp28 expression. In the universal analysis, Usp28 correlated strongly with histopathological grade, clinical stage, tumor number and recurrence rate (P?=?0.0001, 0.0001, 0.0001 and 0.0051, respectively), but did not correlate with gender or age (P?=?0.5588 and 0.6574). After multiple analysis of the above factors and consideration of confounding factors, tumor number, histological grade, clinical stage, and recurrence were related to Usp28 expression (P?=?0.001, 0.001, 0.001 and 0.001, respectively). Finally, Usp28 expression was indentified as a independent predictors of survival (P?=?0.001). Usp28 protein expression is potentially valuable in prognostic evaluation of bladder cancer.     

Secreted CXCL1 is a potential mediator and marker of the tumor invasion of bladder cancer.

PURPOSE: The purpose of this study was to identify proteins that are potentially involved in the tumor invasion of bladder cancer. EXPERIMENTAL DESIGN: We searched for the candidate proteins by comparing the profiles of secreted proteins among the poorly invasive human bladder carcinoma cell line RT112 and the highly invasive cell line T24. The proteins isolated from cell culture supernatants were identified by shotgun proteomics. We found that CXCL1 is related to the tumor invasion of bladder cancer cells. We also evaluated whether the amount of the chemokine CXCL1 in the urine would be a potential marker for predicting the existence of invasive bladder tumors. RESULTS: Higher amount of CXCL1 was secreted from highly invasive bladder carcinoma cell lines and this chemokine modulated the invasive ability of those cells in vitro. It was revealed that CXCL1 regulated the expression of matrix metalloproteinase-13 in vitro and higher expression of CXCL1 was associated with higher pathologic stages in bladder cancer in vivo. We also showed that urinary CXCL1 levels were significantly higher in patients with invasive bladder cancer (pT1-4) than those with noninvasive pTa tumors (P = 0.0028) and normal control (P < 0.0001). Finally, it was shown that CXCL1 was an independent factor for predicting the bladder cancer with invasive phenotype. CONCLUSIONS: Our results suggest that CXCL1 modulates the invasive abilities of bladder cancer cells and this chemokine may be a potential candidate of urinary biomarker for invasive bladder cancer and a possible therapeutic target for preventing tumor invasion.     

CA 125: a potential tumor marker for gallbladder cancer

BACKGROUND: CA 125 is a glycoprotein and a commonly used tumor marker in ovarian carcinoma. Its use in gallbladder carcinoma (GBC) has not yet been reported. We have henceforth examined for the first time the diagnostic utility of CA 125 in patients with gallbladder diseases. PATIENTS AND METHODS: Serum CA 125 was measured in 64 patients with GBC, 47 Gallstone disease (GSD) and 23 healthy volunteers by ELISA. CA 125 level was compared between different cohorts by non-parametric test (Kruskal Wallis and Mann-Whitney test). Receiver operating characteristic curve (ROC) was constructed to see the diagnostic utility of CA 125. Its level was also correlated with age, sex and clinico-pathological parameters of the patients included in the study. RESULTS: Mean value of CA 125 in patients with GBC, GSD and healthy volunteers was 77.44 +/- 141.31 U/ml, 7.85 +/- 5.40 U/ml, and 8.08 +/- 3.26 U/ml respectively and showed a statistically significant difference (P < 0.001). CA 125 at cut off value of 11 U/ml yielded 64% sensitivity and 90% specificity in differentiating benign from malignant gallbladder disease. CA 125 level increased with stage and grade of the GBC though this was not statistically significant. A higher level of CA 125 was found in presence of gallbladder mass, weight loss, ascites and loss of appetite compared to patients with GSD. No association of CA 125 was apparent with either age or sex of the patients. CONCLUSION: CA 125 has a diagnostic potential for GBC and can differentiate GBC from GSD in light of other clinical details.     

An enzyme-linked immunosorbent assay for cancer procoagulant and its potential as a new tumor marker

Cancer procoagulant (CP) is a Mr 68,000 cysteine proteinase that initiates blood coagulation and is expressed by a variety of malignant cells but not by normally differentiated cells. Polyclonal immunoglobulin G and monoclonal immunoglobulin M antibodies were developed to purified CP and used to develop an enzyme-linked immunosorbent assay to analyze the antigen in human serum samples. The purpose of this preliminary study was to determine whether or not the analysis of CP in the serum might be a useful tumor marker. Pure CP was added to normal serum to establish a quantitative standard curve; the correlation coefficient of seven standard curves was 0.99. The upper limit of the normal range was established with 46 normal sera (mean +/- 2 SD = 0.57 microgram/ml). A total of 128 blinded serum samples were analyzed: 54 were from cancer patients (29 with gastrointestinal cancer, 22 with lung cancer, and three with urogenital cancer); 20 were from benign disease patients; and 54 were from normal individuals. All of the 13 early stage cancers were greater than 0.57 microgram/ml (positive), 31 of 41 (76%) of the late stage cancers were positive; overall, 44 of the 54 cancers (81%) were positive. Forty-nine of 54 (91%) of the normal sera and 16 of 20 (80%) of the benign disease sera were negative. Overall, the assay had a sensitivity of 81% and a specificity of 88%.     

MMP-7 as a prognostic marker in colorectal cancer

Matrix metalloproteinase-7 is capable of degrading many extracellular matrix proteins and cellular adhesions. In many malignancies, it is overexpressed, and it plays a role in cancer progression by enhancing tumor invasion and thereby metastatic potential. The purpose of this study was to evaluate the association between MMP-7 tissue expression and prognosis in colorectal cancer. From 623 patients who underwent surgery for colorectal cancer, surgical specimens were collected into tissue array blocks and stained by immunohistochemistry for MMP-7. Specimens from 545 patients were suitable for analysis. In specimens from 105 patients (19.3%), MMP-7 scored as high; in 103 (18.9%), as moderate; and in 134 (24.9%), as mild. In 203 cases (37.2%), immunoreactivity was negative. A significant correlation appeared between MMP-7 immunoexpression and tumor differentiation. High MMP-7 positivity associated with poor prognosis during a 5-year follow-up. During longer follow-up, the differences in survival between groups disappeared. MMP-7 is a potential target for tumor therapy, which should be evaluated in clinical trials.     

Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer

Prostaglandins, especially prostaglandin E₂ (PGE₂), and COX-2 play an important role in carcinogenesis of many tumors including bladder cancer (BCA). The PGE₂ receptors EP1-4 regulate tumor cell growth, invasion and migration in different tumor entities but EP expression in BCA remains to be determined. In the present study we examined the expression of EP1-4 in non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and normal urothelial tissue (NU) using immunohistochemistry. Nuclear and cytoplasmic EP1-4 expression was correlated with clinicopathological parameters and survival of BCA patients. EP1, EP2 and EP3 were significantly less expressed in the cytoplasm und nucleus of NMIBC and MIBC than in NU; EP4 cytoplasmic staining in MIBC was significantly higher compared to NU. The cytoplasmic staining was significantly more abundant in MIBC than in NMIBC in all investigated receptors except EP2. The level of EP staining in NMIBC was correlated with staging and grading, especially cytoplasmic EP1. Nuclear staining of EP1 was an independent predictor of BCA recurrence-free survival in NMIBC patients. EP receptors are dysregulated in BCA. The increase of EP1 may be used as prognostic parameter in NMIBC patients and its dysregulation could be targeted by specific EP1 inhibitors.     

Matrix metalloproteinase‐7 as a marker of metastasis and predictor of poor survival in bladder cancer

Matrix metalloproteinases (MMPs) play an important role in tumor progression and metastasis. Here, we investigated the prognostic relevance of MMP‐7 in urinary bladder cancer. MMP‐7 gene expression was measured in tissue samples of 101 patients using quantitative real‐time PCR. Circulating MMP‐7 serum levels of 98 individuals (79 patients and 19 controls) were analyzed by enzyme‐linked immunosorbent assay. The results were compared with the clinical follow‐up data, performing Kaplan–Meier log‐rank test as well as univariate and multivariate Cox analysis. In representative cases, immunohistochemical analysis for MMP‐7 was performed. We detected significantly elevated MMP‐7 levels both in tissue and serum samples of patients with metastatic disease (P = 0.001 and P = 0.002). Multivariate analysis revealed that high MMP‐7 tissue expression and serum concentration are stage‐ and grade‐independent predictors of both metastasis‐free (hazard ratio [HR] = 3.80, 95% confidence interval [CI], 1.29–11.23, P = 0.016, and HR = 2.53, 95% CI, 1.01–6.37, P = 0.048) and disease‐specific survival (HR = 1.89, 95% CI, 1.00–3.55, P = 0.050 and HR = 1.95, 95% CI, 1.03–3.71, P = 0.041). Based on these findings, we conclude that MMP‐7 is a promising marker to detect present and to predict future metastasis. Serum MMP‐7 analysis provides information about the risk of metastasis before surgery which could help to optimize therapeutic procedures. Furthermore, high MMP‐7 tissue and/or serum levels could identify patients most likely to benefit from early adjuvant chemotherapy. (Cancer Sci 2010; 101: 1300–1308)     

Evaluation of gamma-enolase as a tumor marker for lung cancer

The alpha-enolase and gamma-enolase in tumor tissues and sera of patients with lung cancer were determined with an enzyme immunoassay system. Tissue gamma-enolase in small cell carcinoma of the lung (SCCL, n = 11), large cell carcinoma (n = 11), and non-SCCL (except for large cell carcinoma) (n = 34) were enhanced approximately 35-fold, ninefold, and fourfold, respectively; tissue gamma/alpha + gamma value of SCCL was significantly higher than that of normal lung tissue (P less than 0.01). Serum gamma-enolase level was elevated (greater than 6.0 ng/ml) in 14/18, 3/10, and 15/60 patients with SCCL, large cell carcinoma, and non-SCCL (except for large cell carcinoma), respectively, and serum gamma/alpha + gamma value of SCCL was significantly higher than that of healthy subjects (P less than 0.01). Immunohistochemically, the gamma-enolase was positive in 29/31 of the lung cancers. Serum gamma-enolase value is a useful tumor marker for staging and monitoring treatment of patients with lung cancer, and serum gamma/alpha + gamma value may be useful for differential diagnosis of SCCL from non-SCCL or in differentiating lung cancers possessing neuroendocrine features from other lung cancers.     

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer

BackgroundIn early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making.Materials and methodsPatients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data.ResultsOf 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy.ConclusionctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.