Cancer Biomarkers - Volume 14, issue 6

Authors: Baskic, Dejan | Popovic, Suzana | Bankovic, Dragic | Arsovic, Aleksandra | Vukovic, Vuk | Zelen, Ivanka | Djurdjevic, Predrag

Article Type: Research Article

Abstract: OBJECTIVE: The aim of this study was to evaluate the serum levels of IFN-γ , IL-18, NO and MDA, in patients with breast cancer and to assess their clinical significance as a novel diagnostic markers in breast carcinoma. METHODS: We examined IFN-γ , IL-18, NO and MDA in 18 healthy volunteers, 38 patients with primary invasive breast cancer, and 18 patients with distant metastatic breast cancer. Serum levels of NO were measured by the Griess method. Serum concentrations of IFN-γ and IL-18 were analyzed with ELISA assays. Concentration of MDA in serum was measured by a thiobarbituric …acid assay. The diagnostic value of inflammatory biomarkers was evaluated by receiver operating characteristic curves (ROC) and logistic regression models. RESULTS: ROC curve analyses demonstrated that only IFN-γ has the ability to distinguish either presence of breast cancer or breast cancer in localized or metastatic form, whereas IL-18 and NO can detect only metastasis. Using a logistic regression model with IL-18 and MDA we obtained a higher sensitivity and specificity regardless of disease status. A panel combining four markers, at least one “rule”, achieved the highest sensitivity of 95% and 100% for localized and metastatic cancer, respectively, and high specificity of 80%. CONCLUSION: The combination of four inflammatory biomarkers could be a novel panel of diagnostic markers in patients with breast cancer. Show more

Keywords: Interferon-gamma, interleukin-18, nitric oxide, malonyl-dialdehyde, receiver operating characteristic

DOI: 10.3233/CBM-140426

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 401-408, 2014

Authors: Swellam, Menha | Soliman, Hanan A. | Abdelmaksoud, Mohamed D.E. | Nageeb, Amira M. | El Arab, Lobna R. Ezz | Boshnak, Hussein

Article Type: Research Article

Abstract: BACKGROUND: Matrix metalloproteinase-9 and its tissue inhibitor TIMP-1 have been documented as putative tumor markers because of their involvement in cancer invasion and metastasis. OBJECTIVE: The aim of our study was to elucidate the diagnostic efficacy of proteolytic activity markers among traditional tumor markers (CEA and CA15.3) and clinicopathological variables. METHODS: Serum samples were withdrawn from 160 individuals (80 patients with primary breast cancer, 40 patients with benign breast lesions and 40 individuals serve as healthy controls). MMP-9 and TIMP-1 were measured by ELISA and gelatin zymography. RESULTS: The best cutoff points for MMP-9 …and TIMP-1 were depicted by receiver operating characteristic (ROC) curve. The positivity rates and the median levels for MMP-9 and TIMP-1 showed significant difference among the three investigated groups (P< 0.0001). MMP-9 and MMP-9/TIMP-1 were inversely related to clinical stage and lymph node involvement (P< 0.0001). TIMP-1 was significantly correlated with hormonal receptor status (ER, and PgR). MMP zymography results were comparable to those from ELISA. The sensitivity and the specificity of MMP-9, TIMP-1 and MMP-9/TIMP-1 were superior to traditional tumor markers (CEA and CA15.3) especially for early stages (T1) and low grade breast cancer patients. CONCLUSION: These findings indicate that investigated biomarkers are constructive for early diagnosis of breast cancer and MMP-9/TIMP-1 ratio might be a new significant marker in predicting breast cancer development. Show more

Keywords: Breast cancer, MMP-9, TIMP-1, zymography, early diagnosis

DOI: 10.3233/CBM-140428

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 409-417, 2014

Authors: Salis, Osman | Bedir, Abdulkerim | Kilinc, Veli | Alacam, Hasan | Gulten, Sedat | Okuyucu, Ali

Article Type: Research Article

Abstract: N-myc downstream-regulated gene 1 (NDRG1) is defined as metastasis suppressor and can be downregulated in many types of cancers, and reported to be an indication of tumor progression in hepatocellular carcinomas. Several in-vivo and in-vitro studies have demonstrated that iron chelators such as Desferrioxamine (DFO) and 1–10 Phenanthroline (PHEN) are effective antitumor agents. It is suggested that these chelators deliver their antitumor activity by acting on the NDRG1 gene expression. It remains unclear why NDRG1 gene expression affects the tumors differently, or becomes affected differently. We consider that this different effect might be caused by variants. Based on this information, …we developed specific primers and probes for NDRG1 mRNA variants using bioinformatics analysis, and investigated how DFO and PHEN affected the dynamics of NDRG1 variant on the cell lines of Human Breast Adenocarcinoma (MCF-7) and Hepatocellular Carcinoma (HepG2) that demonstrate opposite action for the relationship NDRG1-metastasis. We administrated various doses of DFO and PHEN into the cells to monitor cell vitality and proliferation with Real time Cell Analyzer. We analyzed the gene expression levels of study groups with Quantitative RT-PCR as well as relative gene expression. Variants of NDRG1 mRNA were transcriptionally regulated after HepG2 and MCF-7 cells were treated by iron chelators, resulting in domination of NDRG1 mRNA Variant 1 (V1) in the HepG2 calls and domination of NDRG1 mRNA Variant 2 (V2) in the MCF-7 cells. Anti-proliferative and cytotoxic effects were observed in the MCF-7 cells whereas an increased proliferation was present in the HepG2 cells. Show more

Keywords: N-myc downstream-regulated gene 1, desferrioxamine, human breast adenocarcinoma and hepatocellular carcinoma

DOI: 10.3233/CBM-140422

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 419-426, 2014

Authors: Yi, Shan-Yong | Ruan, Jing | Zhao, Ling | Ke, Yang | Li, Xiang-Nan

Article Type: Research Article

Abstract: Recently, compelling evidence shows that cancer stem-like cells (CSLC) are thought to be critical for initiation and propagation of many types of cancers. Most of CSLC are dependent upon the vascular microenvironments that promote their long-term growth and self-renewal. However, it is not known if when we disrupted their vascular microenvironments, CSLC would be eliminated. Considering these possibilities, we have investigated the influence of different chemotherapy regimens on the CSLC population of hepatocarcinoma xenografts model. The mouse models of hepatocarcinoma were treated with different therapeutic regimens: low-dose metronomic (LDM) regimens, combination therapies of Bolus dose and low-dose metronomic regimens, for …the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose (MTD) chemotherapy using gemcitabine (GEM). All therapies produced a significant tumor growth delay. LDM GEM and Bolus+LDM GEM significantly reduced the tumor spheres, whereas MTD GEM had no effect on the tumor spheres. Furthermore, Bolus+LDM GEM could more significantly decrease both the population of CSLC and the levels of viable endothelial progenitor cells (EPC). Overall, our data indicate that Bolus+LDM GEM is a potent treatment regimen for inhibiting angiogenesis, attacking the tumor vascular microenvironments, and decreasing the population of CSLC. Targeting the unique microenvironment of CSLC may be the key to effective cancer therapy, and shows great promise for the clinical practice. Show more

Keywords: Metronomic chemotherapy, gemcitabine, tumor vascular microenvironment, cancer stem-like cells, hepatocarcinoma

DOI: 10.3233/CBM-140419

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 427-433, 2014

Authors: Gao, Xueren | Zhang, Shulong | Zhu, Zhansheng

Article Type: Research Article

Abstract: Background: Colorectal cancer (CRC) is the most common cancer worldwide. Both genetic and environmental factors play an important role in pathogenesis of CRC, susceptibility may be modified by functional polymorphisms in receptor tyrosine kinase genes, such as ErbB4. We here evaluated whether a 12-bp insertion/deletion (indel) polymorphism (rs6147150) in the 3’UTR of ErbB4 could potentially affect the occurrence of CRC in Chinese population. Methods: We studied the genotypic and allelic frequencies of ErbB4 polymorphism in 399 patients with CRC and 419 control participants using polymerase chain reaction and polyacrylamide gel electrophoresis method. Results: Under co-dominant model, …we found that the del/del genotype of indel was associated with a significantly increased risk of CRC compared with its homozygote ins/ins (adjusted OR=1.70, 95%CI=1.06–2.71). Under recessive model, carrying of del/del genotype conferred a significantly increased risk for CRC compared with ins/ins and ins/del genotype (adjusted OR=1.60, 95%CI=1.03–2.50). Presence of 12-bp deletion allele of ErbB4 seemed to confer higher risk for CRC when compared with non-carriers (adjusted OR=1.27, 95%CI=1.02–1.57). Further stratification analysis showed that this association was more pronounced in patients with drinking. Conclusion: Our data suggested that individuals in Chinese population with the ErbB4 12-bp deletion allele may be at higher risk for CRC, rs6147150 would potentially be a promising novel biomarker for CRC susceptibility. Further validation of our results in larger populations and studies with functional assays are required. Show more

Keywords: Colorectal cancer, ErbB4, polymorphism, susceptibility

DOI: 10.3233/CBM-140420

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 435-439, 2014

Authors: Yao, Jie | Wang, Jian-Ming | Wang, Zi-Lu | Wu, Yu-Nong

Article Type: Research Article

Abstract: Pin1 is a peptidylprolyl isomerase that specifically recognizes phosphorylated Pro-directed Ser/Thr (pSer/Thr-Pro) peptide sequences. Genetic variants in the Pin1 gene may alter protein function and cancer risk. In this study, we genotyped the two common promoter polymorphisms -842G/C (rs2233678) and -667T/C (rs2233679) in two independent hospital-based case-control studies conducted in Eastern Chinese populations, including 209 patients with oral squamous cell carcinoma and 444 cancer-free controls. We found -667TT heterozygotes had a significantly increased risk of oral squamous cell carcinoma (P=0.028, OR=1.66, 95%CI=1.02–2.69). However, there was no risk significant associated with the -842G/C polymorphism. Further large population-based studies are needed to …confirm these results. Show more

Keywords: Polymorphism, single nucleotide (SNP), peptidylprolyl isomerase pin1, oral squamous cell carcinoma (OSCC)

DOI: 10.3233/CBM-140421

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 441-447, 2014

Authors: Zhao, Dong-Yu | Cheng, LiYa | Yu, Jian | Shen, Hong

Article Type: Research Article

Abstract: Purpose: The purpose of this study is to investigate the associations of the x-ray repair cross-complementing 1 gene (XRCC1) single nucleotide polymorphisms (SNPs) Arg194Trp, Arg280His, and Arg399Gln with gastric cancer risk. Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, CINAHL, International Bibliography of the Social Sciences, and Social Sciences Citation Index were searched. Two authors independently searched for relevant studies in any language from 1966 to Jan 2013. Results: Seventeen studies with a total population of 10427 participants were identified. The results showed there were no associations of Arg399Gln polymorphism with gastric …cancer, no matter in the co-dominant model, dominant model or recessive model. For Arg194Trp and Arg280His polymorphism, still no significant differences were found between control groups and GC groups in samples regardless of race. However, significant associations between Arg194Trp polymorphism and gastric cancer were found in Asian. The Asia with mutant genotype (Trp/Trp+Arg/Trp) had a higher risk of GC compared with the Asian with wild genotype (Arg/Arg). Conclusion: Our meta-analysis indicates that genetic polymorphism of the XRCC1 Arg399Gln and Arg280His do not have an association with gastric cancer risk. However, for Arg194Trp polymorphism, mutant gene carriers had a higher GC risk in Asian. Show more

Keywords: XRCC1, genetic polymorphism, gastric cancer, Arg399Gln, Arg194Trp, Arg280His

DOI: 10.3233/CBM-140429

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 449-456, 2014

Authors: Roudi, Raheleh | Madjd, Zahra | Korourian, Alireza | Mehrazma, Mitra | Molanae, Saadat | Sabet, Mehrdad Nasrollahzadeh | Shariftabrizi, Ahmad

Article Type: Research Article

Abstract: Backgroud: According to the cancer stem cell theory, tumors originate from a subset of cells known as cancer stem cells (CSCs) that are responsible for tumor initiation, resistance and relapse. CD44 is a cell adhesion molecule that can aid in the identification of CSCs in various malignancies. Objective: The purpose of the current study is to evaluate the expression level and clinical significance of CD44 in lung cancer samples. Methods: One hundred and ninety-five lung tumor samples including 74 (38%) squamous cell carcinomas (SCC), 61 (31%) adenocarcinomas (ADC), 23 (12%) large cell carcinoma (LCC) in non-small …cell lung cancer (NSCLC) group and 37 (19%) small cell lung cancer (SCLC) samples were examined for the expression of CD44 using immunohistochemistry method. The correlation of CD44 expression with clinicopathological parameters as well as Ki-67 status was also assessed. Results: Univariate analysis demonstrated that CD44 expression was significantly higher in NSCLC compared to SCLC (P < 0.001). Among NSCLC, higher level of CD44 expression was found in SCC compared to ADC (P< 0.001) and LCC (P=0.046). Increased expression of CD44 was significantly correlated with higher grade tumors which correspond to poor prognosis in SCC (P=0.012) and the lower level of CD44 expression was more often found in well differentiated ADC tumors (P=0.03). In addition, high expression of CD44 was significantly associated with decreased level of proliferative marker Ki-67 (P=0.04). CONCLUSIONS: CD44 could be a valuable tool for the study of lung CSCs and provide a novel therapeutic target for treatment of the patients with lung cancer in combination with conventional therapy. Show more

Keywords: Cancer stem cells, non-small cell lung cancer, small cell lung cancer, CD44, Ki-67

DOI: 10.3233/CBM-140424

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 457-467, 2014

Authors: Liao, Chen | Yu, Zubin | Guo, Wei | Liu, Qingyun | Wu, Yanan | Li, Yafei | Bai, Li

Article Type: Research Article

Abstract: Introduction: Inflammation has been recognized as an important contributing factor in the development and progression of lung cancer. However, the relationship between the magnitude of inflammation and prognosis in patients with lung cancer remains unclear. This meta-analysis aimed to investigate the association between levels of circulating inflammatory factors and clinical survival in patients with non-small cell lung cancer(NSCLC). Methods: We conducted a meta-analysis of cohort studies to evaluate the prognostic effect of circulating inflammatory factors. Twenty-three studies were eligible and included in our meta-analysis. The pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were used to …assess the predictive ability of circulating inflammatory factors on overall survival (OS) in patients with NSCLC. Results: In overall analysis, high circulating C-reactive protein (CRP) and interleukin-6 (IL-6) level were significantly associated with shorter OS in NSCLC. However, either in CRP or IL-6 subgroup analysis by treatment, significant association with poor prognosis was observed in (radio)chemotherapy group (HR[95% CI]:1.30 [1.09–1.54] and 1.80 [1.32–2.46]; respectively), but not in surgery group. Additionally, there was no significant association between circulating IL-8, IL-10, TNF-ɑ level and OS. Conclusion: Increased circulating CRP and IL-6 levels were significantly associated with poor prognosis especially in patients with unresectable NSCLC. Show more

Keywords: Non-small cell lung cancer, circulating inflammatory factor, C-reactive protein, interleukin-6, prognosis

DOI: 10.3233/CBM-140423

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 469-481, 2014

Authors: Yu, Wanjia | Jiang, Xueyan | Bai, Tuya | Lv, Xiaoli | Chang, Fuhou

Article Type: Research Article

Abstract: Background: +936C>T polymorphism of vascular endothelial growth factor (VEGF) is one of the most investigated polymorphisms, it has been suggested that it plays a vital role in tumorigenesis. Intensive studies centering on the association between VEGF +936C>T polymorphism and lung cancer risk or lung cancer patients’ overall survival were conducted in recent years, but with inconclusive and ambiguous results. Objective and Methods: We investigated whether VEGF +936C>T polymorphism influences lung cancer risk and lung cancer patients’ overall survival (OS) using pooled odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence intervals (CI) under different genetic …models. Results: A total of 12 eligible studies were included. In the overall analysis, we didn’t find any statistical evidence that +936C>T polymorphism was related to the risk of lung cancer in any genetic model. However, increased lung cancer risk was detected in adenocarcinoma subgroup (OR=1.532, 95%CI: 1.016–2.312, P=0.042). For an aggregate result of survival analysis, +936C>T polymorphism was linked to an unfavorable OS (HR=2.248, 95%CI: 1.257–4.017, P=0.006) under homozygous model (TT/CC). Show more

Keywords: VEGF, +936C>T, polymorphism, lung cancer, meta-analysis

DOI: 10.3233/CBM-140427

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 483-492, 2014

Authors: Jia, Ming | Wang, Zhu-Jun | Li, Jing-Yuan | Yang, Shi-Long | Zhao, Hai-Zhao | Cheng, Yu-Ping | Luo, Ze-Bin | Tang, Yong-Min

Article Type: Research Article

Abstract: Background: Various studies have reported that IKZF1 deletion (IKZF1-d) is a poor prognostic factor for acute lymphoblastic leukemia (ALL) patients, however they do not agree on the level of significance for this deletion. Objective: To provide a quantitative assessment of this correlation, an updated meta-analysis of cohort studies was performed to derive a more precise estimation of the prognostic significance of IKZF1-d. Methods: Relevant studies were identified in PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang databases until January 31, 2014. A total of 15 published studies including 5021 patients were …eligible for this meta-analysis. Combined hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with random-effects model. Results: Combined hazard ratios suggested that IKZF1 deletion (IKZF1-d) had an unfavorable impact on event-free survival (EFS) (HR=2.32, 95%CI: 1.97–2.74) and overall survival (OS) (HR=2.56, 95%CI: 1.75–3.74) in patients with ALL. The significant role of IKZF1-d in the prognosis of ALL was also observed among different subgroups stratified by statistical methodology, ethnicity, age, detection method, risk group and duration of follow up. Conclusions: The findings from this meta-analysis suggest that IKZF1 deletion can be used to serve as an independent predictive factor in patients with ALL. Show more

Keywords: Acute lymphoblastic leukemia, IKZF1, prognosis, meta-analysis

DOI: 10.3233/CBM-140425

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 493-503, 2014

Authors: Huang, Juan | Ma, Xuelei | Chen, Xiangjun | Liu, Xiaoxiao | Zhang, Binglan | Minmin, Li | Nie, Wen | Zhang, Lei | Liu, Lei

Article Type: Research Article

Abstract: Background: Many studies have shown that microvessel density (MVD) could play a potential value as prognostic biomarkers of tumors. The aim of this systematic review and meta-analysis is to evaluate the association between MVD and survival in patients with bladder cancer. Methods: Relevant literature was identified using PubMed and EMBASE. The eligible studies were assessed for quality using REMAPK (REporting recommendations for tumor MARKer prognostic studies (REMARK)). The patients’ clinical characteristics and survival outcomes in eligible studies were extracted. And then, data were synthesized to evaluate the prognostic role of the MVD in bladder cancer with hazard ratio …(HR), while the heterogeneity among studies was examined using the I2 . Results: This meta-analysis included 10 eligible studies conducted between 1998 and 2011 dealing with bladder cancer. The combined HRs and 95% confidence interval [95% CI] for disease-free survival (DFS) was 2.24 [1.20,4.17], for overall survival (OS) was 1.16 [1.02,1.33] and 1.68 [1.15,2.45] for disease-specific survival (DSS). There was evidence heterogeneity between studies, and the disease stage was a key factor for heterogeneity in subgroup analysis. Conclusions: Our studies suggested that high MVD was significantly associated with poor survival and MVD could serve as a prognostic biomarker in patients with bladder cancer. Show more

Keywords: Bladder cancer, disease-free survival(DFS), disease-specific survival(DSS), microvessel density, overall survival (OS)

DOI: 10.3233/CBM-140417

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 505-514, 2014

Article Type: Other

DOI: 10.3233/CBM-140438

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 515-517, 2014

Article Type: Other

DOI: 10.3233/CBM-2014-14614

Citation: Cancer Biomarkers, vol. 14, no. 6, pp. 519-524, 2014