Cancer Biomarkers - Volume 17, issue 3

Authors: Yin, Rui | Yang, Tongshu | Su, Hui | Ying, Li | Liu, Liyan | Sun, Changhao

Article Type: Research Article

Abstract: AIMS: The aims were to investigate the serum free fatty acid (FFA) and esterified fatty acid (EFA) profiles and to identify biomarkers that can be used to identify patients with epithelial ovarian cancer (EOC) based on the metabolomics approach. METHODS: We applied a targeted gas chromatography-mass spectrometry metabolomics approach to serum samples from 40 EOC patients and 35 healthy controls for achieving the FFA and EFA profiles. These metabolite profiles were processed using multivariate analysis to obtain potential biomarkers. And then, some independent samples were chosen to validate these potential biomarkers. RESULTS: …There were higher saturated fatty acids and lower unsaturated fatty acids in EOC patients when compared with the healthy controls. EFA (C16:0), EFA (C18:0) and FFA (C16:0) were identified as potential biomarkers that distinguished EOC from the healthy controls. The areas under the curve from the EFA (C16:0), EFA (C18:0) and FFA (C16:0) in validated study were 0.745, 0.701, 0.682, respectively. CONCLUSION: Our study provides useful information to bridge the gaps in our understanding to the fatty acids metabolic alterations associated with EOC, and this study has demonstrated saturated fatty acid biomarkers might be helpful for the detection and characterization of EOC patients. Show more

Keywords: Free and esterified fatty acids, epithelial ovarian cancer, Metabolomics, Biomarker, Gas chromatography-mass spectrometry

DOI: 10.3233/CBM-160638

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 259-269, 2016

Authors: Yang, Xiao-Ping | Zhou, Li-Xing | Yang, Qi-Jun | Liu, Ling | Cai, Yang | Ma, Sheng-Lin

Article Type: Research Article

Abstract: BACKGROUND: Vitronectin (VN) might be involved in the progression of hepatocellular carcinoma (HCC). OBJECTIVE: This study was designed to evaluate the diagnostic and prognostic value of serum vitronectin among HCC patients. METHODS: A total of 105 patients with HCC, 91 with liver cirrhosis, 102 with chronic hepatitis, and 100 healthy subjects were recruited. Serum VN and alpha-fetoprotein (AFP) levels were measured. RESULTS: Serum VN levels were significantly higher in HCC patients than in the other groups. Based on area under receiver operating characteristic curve, serum VN had …similar diagnostic value, compared with serum AFP, in distinguishing HCC from the groups, and also improved the diagnostic value of AFP alone. Serum VN levels were associated with the degree of histological differentiation, multiple foci, vascular tumor thrombosis and tumor node metastasis stage. Serum VN was an independent predictor for early recurrence and disease-free survival. Moreover, serum VN possessed similar prognostic predictive performance as compared to serum AFP and also significantly enhanced the prognostic value of AFP alone. CONCLUSIONS: Elevated serum VN levels represented high diagnostic value and had close relation to clinicopathological factors and early recurrence, suggesting that serum VN might be a useful diagnostic and prognostic marker for HCC. Show more

Keywords: Hepatocellular carcinoma, vitronectin, prognosis, diagnosis, biomarker

DOI: 10.3233/CBM-160639

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 271-279, 2016

Authors: Zhang, Kejun | Yu, Meiqin | Hao, Fengyun | Dong, Anbing | Chen, Dong

Article Type: Research Article

Abstract: Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. It is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. With conventional treatment, the median survival is about 6 months; therefore, new treatment options are needed. S100A4 is a calcium-binding protein related to the metastatic potential of carcinoma. Previous study has found S100A4 was overexpressed in human papillary thyroid carcinomas (PTC) tissues, and overexpression of S100A4 is associated with thyroid tumour invasion and metastasis. In the present study, we first examined S100A4 protein expression in 14 ATC tissues, …20 PTC tissues and 14 normal thyroid tissue by immunohistochemistry analysis. We then knocked down of S100A4 expression by RNA interference (S100A4 siRNA) and investigated its effects on growth and metastasis in two human ATC cell lines 8505C (BRAFV600E ) and Cal-62 (BRAFwt ) in vitro and in vivo. S100A4 and BRAFV600E protein expression was evaluated by western blot assay and immunohistochemistry analysis. Using immunohistochemistry, we found that high levels of S100A4 were detected in ATC specimens and PTC specimens. No S100A4 staining was observed in normal thyroid tissues. S100A4 siRNA significantly decreased proliferation and increased apoptosis, and inhibited the invasive potential of the two cells in vitro. In addition, S100A4 siRNA could effectively inhibit BRAFV600E expression in the 8505C cells, and treatment with 100 ng/ml human recombinant BRAF V600E in S100A4 siRNA/8505C cells could partly restore its proliferative and invasive ability. Results of implantation in vivo showed S100A4 shRNA could significantly inhibit abdominal cavity metastasis and tumor growth in vivo. Furthermore, knockdown of S100A4 has significant role on invasion, metastasis and growth inhibition in the 8505C cells than that of in the Cal-62 cells. These results support the hypothesis that S100A4 contributes significantly to growth and metastasis, and that down-regulation of S100A4 expression decreases the metastatic potential of ATC cells. Furthermore, down-regulation of S100A4 expression is more marked in BRAFV600E cells than that of in the BRAFwt cells. Show more

Keywords: Anaplastic thyroid cancer, metastasis, S100A4, BRAF

DOI: 10.3233/CBM-160640

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 281-291, 2016

Authors: Polat, Ayfer Kamali | Soran, Atilla | Kanbour-Shakir, Amal | Menekse, Ebru | Levent Balci, Fatih | Johnson, Ronald

Article Type: Research Article

Abstract: BACKGROUND: Atypical Ductal Hyperplasia (ADH) is a disease of the proliferative breast lesion characterized with atypia and when diagnosed on core needle biopsy (CNB), excisional biopsy is the current management to exclude adjacent cancer, which may found 10 to 20%. OBJECTIVE: The purpose of the study is to investigate the role of biomarkers on surgical decision after the diagnosis of ADH on CNB. METHODS: Patients with pure ADH on core biopsy were retrospectively selected, and categorized according to final pathology after excision into three groups: Group I (n: 39) ADH; Group …II (n: 27) ductal carcinoma in situ (DCIS), and Group III (n: 9) invasive cancer (IC). Immunohistochemical analyses were performed using biomarkers MUC1, Ki67, Cyclin B1, and Cyclin D1. RESULTS: Only Cyclin D1 was significant in between group analysis by one-way ANOVA (64.74, 49.44, and 51.11, respectively; p= 0.01). However when appropriate cut-off levels (2%-50%) were used for each biomarkers using X2 test, no statistical significance was found. CONCLUSION: MUC1, Ki67, Cyclin B, and Cyclin D1have failed to predict adjacent cancer on core biopsy specimens with ADH. Further surgery is warranted for all ADH cases diagnosed on core biopsies until a new predictor is identified. Show more

Keywords: Atypical ductal hyperplasia, breast cancer, biomarker, MUC1, cyclin, Ki67

DOI: 10.3233/CBM-160641

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 293-300, 2016

Authors: Mirzaei, Alireza | Madjd, Zahra | Kadijani, Azade Amini | Tavakoli-Yaraki, Masoumeh | Modarresi, Mohammad Hossein | Verdi, Javad | Akbari, Abolfazl | Tavoosidana, Gholamreza

Article Type: Research Article

Abstract: BACKGROUND: DCLK1, as the most potential colorectal cancer stem cell (CSC) marker has been the core of many recent investigations. However, no study has been performed to evaluate the circulating cellular DCLK1 protein (CCDP) that might reflect the presences of colorectal CSC in circulation. OBJECTIVES: We aimed to evaluate CCDP in the peripheral blood mononuclear cells (PBMCs) of colorectal cancer (CRC) patients applying immunoassay based methods including PLA, IPCR and ELISA in order to introduce the method of choice for clinical detection of CCDP. METHODS: PBMCs were extracted from blood …samples of 58 CRC patients along with 58 blood samples of tumor free controls. Total protein of PBMC was extracted and the CCDP level was evaluated. The results of three applied immunoassay tests were compared and the best approach for clinical application was introduced, accordingly. In addition, the correlation of CCD Plevel with clincopathologic findings of CRC patients was assessed. RESULTS: The results of three immuneassay methods confirmed each other. Based on our finding, ELISA could be the most judicious method for clinical evaluation of CCDP considering its simplicity for clinical implications. Our results also showed a significant higher amount of CCDP in peripheral blood of CRC patients compared to control group which was also correlated with patients' clinicopathologic finding such as stage, grade and neoadjuvant history. CONCLUSION: CCDP could be applied for monitoring purposes in CRC patients. However, its application needs to be more elucidated in future investigations implementing larger samples. Show more

Keywords: DCLK1, circulating cancer stem cell, immunoassay, PLA, IPCR

DOI: 10.3233/CBM-160642

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 301-311, 2016

Authors: Wen, Xuemei | Lu, Renquan | Xie, Suhong | Zheng, Hui | Wang, Hongling | Wang, Yanchun | Sun, Jiajun | Gao, Xiang | Guo, Lin

Article Type: Research Article

Abstract: BACKGROUND: Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme that is involved in DNA repair and the redox regulation of transcription factors. Blocking these functions leads to cell-growth inhibition, apoptosis and other effects. Previous studies have demonstrated that high expression levels of the APE1 protein are associated with the progression and chemoresistance of cancers. We hypothesized that APE1 silencing in ovarian cancer cells might have anticancer effects mediated by cell-growth inhibition and an increase in drug-sensitivity. OBJECTIVE: In this study, we explored the consequences of APE1 silencing in ovarian cancer cells. …METHODS: Immunohistochemistry (IHC) was used to detect the APE1 protein levels in tissue samples from twelve ovarian cancer (OC) patients and eleven non-OC patients. APE1 knockdown was achieved via the stable transfection of SKOV3 and A2780 cells with a construct encoding a short hairpin DNA directed against the APE1 gene. Then, cell proliferation, colony formation, cell cycle and apoptosis assays were performed to reveal the consequences of APE1 silencing in ovarian cancer cells. Additionally, the SKOV3 and A2780 cells were subjected to the treatment with camptothecin (CPT) and ultraviolet rays (UV) to assess the possible link between the APE1 protein and drug-resistance. RESULTS: Our results revealed that the APE1 protein was overexpressed in OC tissues. APE1 knockdown in A2780 and SKOV3 cells reduced cell proliferation, arrested cell cycle progression, repressed colony formation and weakly promoted cell apoptosis through the BAX and BCL-2 apoptotic pathways. Additionally, the down-regulation of APE1 significantly enhanced the sensitivity of ovarian cancer cells to the CPT/UV treatment. CONCLUSION: Our study suggested that the APE1 protein is important for the proliferation and growth of ovarian cancer cells. APE1 silencing might enhance drug-sensitivity, and thus APE1 might serve as a novel anti-OC therapeutic target. Show more

Keywords: Apurinic/apyrimidinic endonuclease 1, ovarian cancer, proliferation, apoptosis

DOI: 10.3233/CBM-160643

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 313-322, 2016

Authors: Adam, Julien | Sourisseau, Tony | Olaussen, Ken A. | Robin, Angélique | Zhu, Chang Q. | Templier, Alexandre | Civet, Alexandre | Girard, Philippe | Lazar, Vladimir | Validire, Pierre | Tsao, Ming S. | Soria, Jean-Charles | Besse, Benjamin

Article Type: Research Article

Abstract: BACKGROUND: Resectable non-small cell lung cancer (NSCLC) treatment options most often consist of surgical resection along with adjuvant chemotherapy (ACT). The benefit of ACT however is modest and is accompanied by important side effects. OBJECTIVE: One central quest in the field is therefore the identification of a predictive marker of the response to ACT. METHODS: We applied an unbiased approach based on high content analysis of expression data generated from a discovery patient cohort. RESULTS: We identified MMS19, a component of the cytoplasmic Iron-Sulfur Assembly (CIA) machinery …important for the Nucleotide Excision Repair (NER) pathway as a pivotal gene for cisplatin toxicity. We then confirmed the association between MMS19 expression and the response to Cisplatin treatment in a panel of NSCLC cell lines. Finally we validated these pre-clinical data in a subgroup of JBR.10 trial patients through a hypothesis-driven analysis, and showed that MMS19 levels associated with ACT benefit. CONCLUSIONS: We therefore propose the expression level of MMS19 as a candidate predictive marker of ACT benefit in resected NSCLC patients. Show more

Keywords: Non-small-cell lung cancer, adjuvant chemotherapy, DNA repair

DOI: 10.3233/CBM-160644

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 323-333, 2016

Authors: Formica, Vincenzo | Morelli, Cristina | Ferroni, Patrizia | Nardecchia, Antonella | Tesauro, Manfredi | Pellicori, Stefania | Cereda, Vittore | Russo, Antonio | Riondino, Silvia | Guadagni, Fiorella | Roselli, Mario

Article Type: Research Article

Abstract: BACKGROUND: High Neutrophil/Lymphocyte ratio (NLR), as a measure of enhanced inflammatory response, has been negatively associated with prognosis in patients with localized pancreatic ductal adenocarcinoma (PDA). OBJECTIVE: In the present study, we aimed at investigating the prognostic value of NLR in two homogeneous groups of chemotherapy-naïve metastatic PDA patients. Patients were treated with either gemcitabine (GEM) or gemcitabine/oxaliplatin (GEMOXA). We also assessed whether NLR could identify patients benefiting from the use of oxaliplatin. METHODS: Consecutive PDA patients treated at the Medical Oncology Unit of Tor Vergata University Hospital of Rome with …either GEM or GEMOXA were included (n= 103). NLR was assessed before and during chemotherapy and correlated with outcome together with common clinical and biochemical variables. RESULTS: Among 17 analyzed variables NLR, Karhofsky Perfomance Status (KPS), d-dimer and erythrocyte sedimentation rate were found to be significantly associated with median Overall Survival (mOS) at the univariate analysis. Only NLR and KPS were independent prognosticator at multivariate analysis, with NLR displaying the highest statistical significance. NLR was also predictive of oxaliplatin activity, as only patients with NLR > 2.5 (cutoff determined upon ROC analysis) derived benefit from GEMOXA over GEM. CONCLUSIONS: NLR is both an independent prognostic and predictive factor in metastatic PDA, since only patients with high NLR seem to benefit from the addition of oxaliplatin. NLR may help select patients for whom a particularly poor prognosis might justify more intensive, yet less tolerable, combination regimens. Show more

Keywords: Neutrophil/lymphocyte ratio, pancreatic ductal adenocarcinoma, gemcitabine, oxaliplatin

DOI: 10.3233/CBM-160645

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 335-345, 2016

Authors: Portich, Júlia Plentz | Gil, Mirela Severo | dos Santos, Rafael Pereira | Goulart, Bruno Kilpp | Ferreira, Maria Beatriz Cardoso | Loss, Jiseh Fagundes | Gregianin, Lauro José | Brunetto, Algemir Lunardi | Brunetto, André Tesainer | Roesler, Rafael | de Farias, Caroline Brunetto

Article Type: Research Article

Abstract: BACKGROUND: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related receptor kinase B (TrkB) are involved in the maturation of B lymphocytes in the bone marrow (BM), promote cell differentiation in B-cell malignancies, and are associated with poor prognosis in adults with acute leukemia (AL). However, the role of BDNF in pediatric AL remains poorly understood. OBJECTIVE: We carried out a cohort observational study to evaluate BDNF levels in BM or peripheral blood (PB) samples from children with AL. METHODS: BM or PB samples were collected from 57 children and adolescents with …acute lymphoid leukemia (ALL), 14 children and adolescents with acute myeloid leukemia (AML), and 44 healthy individuals (HI) of the same age range. RESULTS: BDNF levels at diagnosis in AL patients were significantly lower when compared to HI. Samples from patients in complete remission from disease had higher levels of BDNF compared to those obtained from patients with malignant cells. Moreover, BDNF levels at diagnosis in patients who died were significantly lower compared to those found in survivors. CONCLUSIONS: These findings provide the first evidence for a possible role of BDNF as a marker of active disease and poor prognosis in pediatric AL. Show more

Keywords: Brain-derived neurotrophic factor, neurotrophin, acute lymphoid leukemia, acute myeloid leukemia

DOI: 10.3233/CBM-160646

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 347-352, 2016

Authors: Shahbazi, Shirin | Khorasani, Maryam | Mahdian, Reza

Article Type: Research Article

Abstract: OBJECTIVES: The ectopic expression of coagulation Factor VII has been shown in various cancers. Recently, F7 gene has been identified as a direct target of the androgen receptor in breast cancer. In this study, we examined the mRNA expression of F7 and AR in clinical sample series of prostate cancer and BPH. MATERIAL AND METHODS: All the prostate cancer patients were new cases with no medical history of surgery or chemotherapy. The tissue samples were assigned as either prostate cancer tumor (n= 45) harboring at least 80% tumor cell content, or BPH (n= 36). …Relative AR and F7 mRNA expression in each tissue sample was normalized to the mean of the Ct values determined for GAPDH and PSA genes. RESULTS: Mean plasma level of prostate specific antigen (PSA) was 17.82 ± 3.71 ng/ml and 7.71 ± 1.28 ng/ml (Mean ± SEM) in PCa and BPH group, respectively. AR mean expression was up-regulated 22.468 fold in clinical tumor sample cohort (S.E., 0.175-2,916, 95% CI: 0.001-126,764, P= 0.001). The mean expression of F7 gene in tumor tissues relative to PBH samples was 6.981 (S.E., 0.099-413.001, 95% CI: 0.002-34,183, P= 0.012). ANOVA analysis of the gene expression results showed significant correlation between F7 and AR mRNA expression in tumor samples (p< 0.001). CONCLUSIONS: Our study findings suggest a link between FVII and AR in prostate cancer pathogenesis. F7 gene expression could be up-regulated via various AR mediators affecting the promoter region of the F7 gene. Should this be confirmed by further studies, it may be suggested as a potential contributing factor in prostate cancer. Show more

Keywords: Prostate cancer, FVII, F7 gene, androgen receptor, AR gene, gene expression

DOI: 10.3233/CBM-160647

Citation: Cancer Biomarkers, vol. 17, no. 3, pp. 353-358, 2016