Cancer Biomarkers - Volume 14, issue 5

Authors: Ghanjati, Foued | Beermann, Agnes | Hermanns, Thomas | Poyet, Cedric | Araúzo-Bravo, Marcos J. | Seifert, Hans-Helge | Schmidtpeter, Martin | Goering, Wolfgang | Sorg, Rüdiger | Wernet, Peter | Santourlidis, Simeon

Article Type: Research Article

Abstract: Urinary DNA is increasingly gaining importance in diagnosis of urological malignancies. Especially cell-free DNA originating from apoptotic and necrotic cells of the early tumor could become a key target for early stage tumor diagnosis. Aberrant DNA methylation forms tumor cell characteristic epigenetic profiles which are covalently established before any tumor related aberration at transcriptional or protein level has occurred. In addition, these epigenetic signatures are alterably adapted to and accompanying the individual stages of multistep, progressive tumorigenesis. Hence, they seem very promising for diagnosis as well as for monitoring the patient's follow-up care and even for decisions regarding personalized therapeutic …options. The essential prerequisite at this approach will be a reliable methodological handling of the biological material of interest. In this study we present detailed analyses of LINE-1 DNA methylation profiles and demonstrate the sensitive detection of LINE-1 DNA methylation differences as well as between cancer patients and healthy individuals, between urinary cellular and cell-free DNA. In addition, we show methylome differences between both DNA fractions from a healthy individual and bladder cancer patients. In conclusion, we demonstrate here the unrestricted amenability of urinary cell-free DNA for both, a detailed characterization of a distinct DNA methylation alteration and its sensitive detection and a comprehensive global, array-based screening for DNA methylation differences. Show more

Keywords: Cell-free DNA, DNA methylation, urine, diagnosis, bladder cancer

DOI: 10.3233/CBM-140407

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 295-302, 2014

Authors: Azab, Basem | Mohammad, Farhan | Shah, Neeraj | Vonfrolio, Steven | Lu, William | Kedia, Shiksha | Bloom, Scott W.

Article Type: Research Article

Abstract: Background: The neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) have been well studied as inflammatory markers and predictors for outcomes in colorectal cancer patients. Our aim was to determine the predictive value of both above ratios in colorectal cancer patients. Methods: This is a longitudinal retrospective study of a prospectively maintained database, included 580 patients, who had a complete blood count recorded before treatment (surgery or chemotherapy). We excluded patients presented with obstruction, infection, active hematological disease or those receiving steroid. The primary outcome (4-year cancer-related mortality) was obtained from our cancer registry. Results: …The 4-year cancer-related mortality rate in the 3rd tertile of NLR was 37% in comparison with 13% and 19% in lower tertiles, P value < 0.001. Similarly the 3rd tertile of PLR was 32% with 18% and 19% in lower tertiles, P value < 0.0005. In the multivariate survival analyses, elevated NLR was associated with higher mortality (a hazard ratio of 2.31(1.4–3.8) for the highest tertile and 5% increase in mortality for each unit increase in NLR, p < 0.001). Similarly, elevated NLR was a significant predictor for a worse disease-free survival. However, PLR was not significant predictor of mortality when adjusted for other confounding variables. Conclusion: Elevated pretreatment NLR is an independent predictor of both worse overall and disease free survival in colorectal cancer, whereas PLR was not after adjusting for confounding variables. Show more

Keywords: Colorectal cancer, survival, inflammation, neutrophil/lymphocyte, platelets/lymphocyte, NLR, PLR

DOI: 10.3233/CBM-140416

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 303-312, 2014

Authors: Tang, Hui | Mirshahidi, Saied | Senthil, Maheswari | Kazanjian, Kevork | Chen, Chien-Shing | Zhang, Kangling

Article Type: Research Article

Abstract: Background and Objective: Deficiency of vitamin D could be a major cause of colon cancer as suggested as early as 1980 by Drs. Cedric and Frank Garland of the University of California and has recently been underscored by a large European case control study. Whether vitamin D deficiency is because of inadequate intake (food and sunshine) or because of vitamin D metabolism disorder in the patient body is unknown. A proteomics approach to identify protein pathways associated with vitamin D transportation and metabolism pathways will help us understand better the pathology of the colon cancer. Methods: Lysates of …colon adenocarcinoma tissues and their matched healthy tissues, from seven colon cancer patients, have been evaluated by quantitative proteomics and bioinformatics analysis to determine protein expression profiles. Unsupervised hierarchical clustering and principle component analysis (PCA) were utilized for protein expression profiling and biomarker identification, while the reporter ion ratios from tandem-mass-tagging (TMT) labeled peptides were used for quantification. Ingenuity Pathway Analysis (IPA) was used to analyze protein pathways. Results and Conclusion: Proteomics analyses demonstrated that the proteins involved in vitamin D/E binding, heme/iron binding and transportation, and lipid/steroid transportation/metabolic systems were down-regulated in colon cancer and the same set of proteins were down-regulated in the LXR/RXR activation and acute-phase response pathways, revealing a plausible mechanistic connection between vitamin D deficiency, iron homeostasis, and colon cancer. Show more

Keywords: Colorectal cancer, vitamin D, LXR/RXR, tandem-masstagging, mass spectrometry

DOI: 10.3233/CBM-140409

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 313-324, 2014

Authors: Yu, Li-Jun | Li, Yan | Li, Cong | Li, Hong | Wu, Mo-Li | Liu, Zhi-Li | Kong, Qing-You | Chen, Xiao-Yan | Liu, Xiao-Yu | An, Li-Jia | Liu, Jia

Article Type: Research Article

Abstract: Background: S100A4 promotes cancer metastasis but is frequently silenced in human cutaneous squamous cell carcinomas/c-SCCs due to DNA methylation, which may explain the less metastasized property of c-SCCs. Objective: This study aims to check 1) whether the metastatic potential of S100A4-negative human c-SCC cells could be enhanced when S100A4 expression is restored in COLO16 c-SCC cells with S100A4 methylation and 2) the correlation of S100A4 expression and the differentiation grades and invasiveness of human c-SCC tumors. Methods: The motility and invasion of parent and transfected COLO16 cells are examined by the use of 24-well modified Boyden …chambers, scratched wound healing assay and nude mouse transplantation tumor model. Meanwhile, the correlation of S100A4 expression with growth patterns and grade of differentiation of c-SCC surgical specimens are analyzed. Results: S100A4 expression is successfully restored in COLO16 cells after plasmid lipofectamine transfection. Transwell and scratched wound healing assays shows that the invasion and migration activities of S100A4-expressing transfectants are higher than that of parent COLO16 cells. Subcutaneous and foot pad c-SCC models are established by injecting 5 × 10 6 / 100 l parental and S100A4-expressing COLO16 cells to BALB/c-nu/nude mice, respectively. Histological examination confirms the differences of invasiveness between the parent cells and the transfectants. Regional lymph node metastases are found only in the mice bearing S100A4-expressing tumors. S100A4 expression levels and frequencies are significantly different (P< 0.001) between the well and the poorly differentiated c-SCCs and closely correlated with tumor invasion (P< 0.05). Conclusions: S100A4 confers invasive and metastatic potentials on human c-SCCs. The low incidence of metastasis of c-SCCs, especially the well differentiated ones, might be due to the infrequent S100A4 expression. S100A4 can be regarded as a negative prognostic biomarker or a metastasis-risk factor of human c-SCCs. Show more

Keywords: S100A4, cutaneous squamous cancer cells, invasion, metastasis, gene transfection

DOI: 10.3233/CBM-140414

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 325-333, 2014

Authors: Nie, Fang | Zhao, Shi-Yi | Song, Fei-Xue | Li, Pei-Wu

Article Type: Research Article

Abstract: Background: Rac1, the better characterized Rac subfamily member, can regulate a large variety of different functions, including the organization of the actin cytoskeleton, cell migration, cell cycle progression, and cell survival through engagement of specific effectors. However, very little is currently known about the expression of Rac1 in colorectal cancer cells and the roles of Rac1 in the cell cycle progression and cell survival of human colorectal cancer cells. Objective: To assess the change of cytoskeleton and cell cycle in Lovo (human colorectal cancer) cell via deletion of Rac1 with RNA interference. Methods: Rac1 protein of …all selected human colorectal cancer cells and in human colorectal tissue was detected by Western blotting, Rac1-shRNA was used to silence the Rac1 to reduce its expression specifically in Lovo cells. Results: Rac1 protein was overexpressed in human colorectal cancer cells and in human colorectal tissue, RNA interference-mediated deletion of Rac1 strongly prolonged cell cycle progression and enhanced cell apoptosis of Lovo cells in vitro. Conclusions: depletion of Rac1 by the use of RNAi can arrest Lovo Cells in G0 /G1 and induce LoVo cells apoptosis. Show more

Keywords: Rac1, RNA interference, Cytoskeleton, cell cycle, cell apoptosis

DOI: 10.3233/CBM-140408

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 335-342, 2014

Authors: Eskandari-Nasab, Ebrahim | Hashemi, Mohammad | Ebrahimi, Mahboubeh | Amininia, Shadi | Bahari, Gholamreza | Mashhadi, Mohammad-Ali | Taheri, Mohsen

Article Type: Research Article

Abstract: Background: Recent evidence has demonstrated the implication of CC chemokine ligand 5 (CCL5) and CC chemokine receptor 5 (CCR5) in breast tumor initiation and progression. Objective: The purpose of this study was to investigate whether single nucleotide polymorphisms of CCL5 -403 G>A (rs2107538) and CCR5 Δ32 genes are associated with the breast cancer (BC) risk. Methods: A total of 439 subjects including on 236 BC patients and 203 healthy controls from the same area were recruited. The CCL5 -403 G>A and CCR5 Δ32 polymorphisms were genotyped by allele-specific polymerase chain reaction (AS-PCR) and PCR, respectively. …Results: Our data demonstrated that the CCL5 -403 GA and GA+AA genotypes, with a higher frequency in the BC patients compared to the control group, were associated with an increased risk of BC in the codominant (GG vs. GA OR=1.75, 95%CI=1.07–2.86, P=0.025) and dominant models (GG vs. GA+AA: OR=1.84, 95%CI=1.15–2.93, P=0.014), respectively. Additionally, the A allele of CCL5 -403 G>A variation was found more prevalent in the BC patients than in controls (14% vs. 8%) and was a risk factor for BC (G vs. A: OR=1.87, 95% CI=1.21–2.89, P=0.004). Conclusions: Our findings highlighted that the CCL5 -403 G>A polymorphism is a risk factor for BC in our population. Our findings suggest that the CCL5 -403 GA and GA+AA genotypes and the A allele were associated with an elevated risk of BC which may function as risk factor for breast carcinoma. Show more

Keywords: CCL5, CCR5, breast cancer, gene polymorphism

DOI: 10.3233/CBM-140411

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 343-351, 2014

Authors: Zhang, Yun | Liu, Lili | Li, Cui | Ai, Hao

Article Type: Research Article

Abstract: Background: The expressions of leptin and its receptor (ObR) have been observed in human endometrial cancer (EC) cells, and leptin can promote the proliferation of EC cells. However, the correlation between leptin and ObR expressions in EC and the clinicopathology of EC is still unclear. Objective: This study investigated the correlation between the expressions of leptin and ObR in EC and the clinicopathology of EC. Methods: Immunohistochemistry was used in this study. The correlation between the expressions of leptin and ObR in EC and the clinicopathology of EC was analyzed. Results: In the EC …specimens, the expressions of leptin and ObR were positively correlated with the invasiveness of the cancer and the obesity of patients, but inversely correlated with histological grade. The percentages of leptin and ObR were significantly higher in the patients with lymph node metastasis. Positive expression of leptin and ObR was associated with poorer prognosis (3-year survival rate). Moreover, the expression of leptin and ObR was associated with positive expression of estrogen receptor. Conclusions: Leptin and ObR are overexpressed in EC, and their expressions are associated with malignancy, invasion, and metastasis of EC. Thus, leptin and ObR may be important indicators in EC. Show more

Keywords: Endometrial cancer, leptin, ObR, clinicopathology

DOI: 10.3233/CBM-140415

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 353-359, 2014

Authors: Abols, A. | Ducena, K. | Zayakin, P. | Silina, K. | Kalnina, Z. | Sadovska, L. | Tars, J. | Vilmanis, J. | Narbuts, Z. | Eglitis, J. | Pirags, V. | Line, A.

Article Type: Research Article

Abstract: Background: Autoantibodies against tumor-associated antigens (TAAs) have been shown to serve as highly specific serological biomarkers for the diagnosis of various solid cancers. Although the autoimmunity against thyroid tissue specific antigens has been studied extensively, so far, the autoantibody responses against common TAAs such as cancer-testis antigens (CTAs), mutated or differentiation antigens have not been comprehensively analyzed in patients with thyroid cancer. Objective: The current study aims to characterize the frequency of autoantibody responses against common TAAs in patients with thyroid cancer and benign thyroid nodules. Methods: A phage-displayed antigen microarray comprising 65 TAAs was produced …and tested with sera from 53 patients with thyroid cancer, 90 patients with benign thyroid nodules and 96 cancer-free individuals, 100 melanoma, 54 breast cancer and 14 lung cancer patients as controls. Results: A panel of 6 TAAs was identified that preferentially reacted with sera from patients with thyroid cancer. The top ranked antigen in this panel was GAGE1 eliciting autoantibody response in 6% of patients with thyroid cancer but not with benign nodules, whereas no reactivity to other CTAs was detected in the sera from patients with thyroid cancer. Conclusions: Although six TAAs, including one CTA, showed thyroid cancer-associated reactivity, overall, spontaneous humoral immune responses against TAAs are rare in thyroid cancer and their utility for the development of non-invasive assay for the differential diagnosis of thyroid nodules is limited. Show more

Keywords: Phage-displayed antigen microarray, autoantibodies, thyroid nodules, thyroid cancer, cancer-testis antigens, biomarker

DOI: 10.3233/CBM-140413

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 361-369, 2014

Authors: Zou, Yingchang | Zhang, Xi | Chen, Xing | Hu, Yanjie | Ying, Kejing | Wang, Ping

Article Type: Research Article

Abstract: Background: Breath analysis became promising for noninvasive diagnosis of cancer with sophisticated spectrometry technology introduced. Objective: This study aimed to select volatile markers for lung cancer detection, which exclude the influences from non-malignant lung diseases. Methods: 171 subjects who were divided into three groups: patients with LC, patients with PNMD and healthy controls were enrolled in our studies as training cohort. The volatile organic compounds (VOCs) in their breath samples were analyzed with solid-phase micro-extraction/gas chromatography/mass spectrometry (SPME-GCMS). Markers were selected by receiver operating characteristic (ROC) curves. After that, 78 subjects with high morbidity of LC …were employed as validation cohort. Their breath samples were analyzed by thermal desorption instrument/gas chromatography/mass spectrometry (TD-GCMS). Results: Through a series of comparisons among lung cancer patients, pulmonary non-malignant diseases patients, and healthy participants in training cohort, Nonane,5-(2-methyl-)propyl-; phenol,2,6-di-tert-butyl-,4-methyl-; dodecane,2,6,11-trimethyl-; hexadecanal and pentadecane,8-hexyl- were selected as markers for lung cancer diagnosis. Principal component analysis was employ to process data from validation cohort. As results, satisfied distinctions have been obtained with detection of these five selected markers, although the detection method is not identical with that used for training cohort. Conclusions: In conclusion, with optimization method described in this paper, breath test could be an effective method for diagnosis of lung cancer and avoid the interference of pulmonary non-malignant diseases. Show more

Keywords: Lung cancer, volatile markers, breath test, pulmonary non-malignant disease

DOI: 10.3233/CBM-140418

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 371-379, 2014

Authors: Yu, Xinnian | Chen, Baoan | Cheng, Jian | Gao, Chong | Zhang, Xiaoping | Bao, Wen

Article Type: Research Article

Abstract: Objective: The Interleukin-10 (IL-10) gene polymorphism (–1082 A>G) has been linked to the risk of developing lymphoma, but the available results were inconsistent. To derive a more precise estimation, we performed a meta-analysis. Methods: A comprehensive search was conducted to examine all the eligible studies about IL-10-1082A>G polymorphism and lymphoma risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Results: We included 12 studies, including 5847 cases and 6016 controls. The overall results suggested that the IL-10-1082G allele was associated with a borderline significantly increased risk of …lymphoma (G vs. A: OR=1.07, 95% CI=1.01–1.12; GG vs. AA: OR=1.14, 95% CI=1.02–1.26; and AG+GG vs. AA: OR=1.10, 95% CI=1.02–1.19). Stratifying by ethnicity (Caucasian and mixed), tumor type [non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL)], sample size (> 1000 and ≤ 1000 subjects) and Hardy-Weinberg equilibrium (HWE) in controls, similar results were found in mixed subgroup, NHL subgroup, large studies and the subgroup conforming to HWE. Conclusions: In conclusion, the meta-analysis suggests that the IL-10-1082A>G polymorphism is weakly associated with altered susceptibility to lymphoma. Further studies with haplotype analysis and on larger population of mixed ethnicity are warranted for a more definitive conclusion. Show more

Keywords: Lymphoma, meta-analysis, interleukin-10, polymorphism, susceptibility

DOI: 10.3233/CBM-140406

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 381-388, 2014

Authors: Yu, Min | Wang, Qian | Ding, Jiang-Wu | Yang, Zhen | Xie, Chuan | Lu, Nong-Hua

Article Type: Research Article

Abstract: Background: Loss of Raf kinase inhibitor protein (RKIP) may contribute to metastasis in a variety of human cancers. Many studies have evaluated whether loss of RKIP expression is a prognostic factor for survival in cancers of the digestive system, however, its predictive value remains controversial. Thus, we performed a meta-analysis to obtain a more comprehensive estimate of the prognostic value of RKIP expression in digestive system cancers. Methods: Studies were identified by searching multiple electronic databases through December 12, 2013, and by reviewing reference lists of obtained articles. Studies reported hazard ratios (HRs) with 95% confidence intervals (CIs) …for the association between RKIP and overall survival (OS) and disease-free survival (DFS) in cancers of the digestive system were eligible, including esophageal cancer, gastric cancer, colorectal cancer and pancreatic cancer. Results: Nineteen studies involving approximately 3700 participants were included in the final analysis. The pooled results suggested that loss of RKIP expression was associated with unfavorable OS (HR 0.55, 95% CI 0.46–0.65) and DFS (HR 0.46, 95% CI 0.30–0.62) among patients with digestive system cancers, whereas the difference was not statistically significant in pancreatic cancer specifically (OS, HR 0.76; 95% CI 0.51–1.01; DFS, HR 0.71; 95% CI 0.28–1.13). Conclusions: Loss of RKIP expression might be an independent indicator of poor prognosis in patients with digestive tract cancers, which includes esophageal cancer, gastric cancer and colorectal cancer. More studies are needed to further clarify the prognostic value of RKIP in pancreatic cancer. Future studies, preferably large prospective studies utilizing formal marker assessment processes, are needed to establish the prognostic value of RKIP before these results can be clinically applied. Show more

Keywords: Cancers of the digestive system, raf kinase inhibitor protein (RKIP), overall survival (OS), disease-free survival (DFS), meta-analysis

DOI: 10.3233/CBM-140410

Citation: Cancer Biomarkers, vol. 14, no. 5, pp. 389-400, 2014