Cancer Biomarkers - Volume 7, issue 2

Authors: Nisman, Benjamin | Allweis, Tanir | Kaduri, Luna | Maly, Bella | Gronowitz, Simon | Hamburger, Tamar | Peretz, Tamar

Article Type: Research Article

Abstract: Aims: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis and an important proliferation marker. We explored the association of preoperative serum TK1 activity with clinicopathological parameters and prognosis in terms of recurrence-free survival (RFS) in breast cancer (BC) patients. Patients and methods: TK1 activity in serum of 120 healthy women and 161 BC patients was measured by quantitative ELISA. Results: Serum TK1 activity in BC patients was significantly higher than in healthy women (P < 0.0001). In BC patients elevated TK1 activity was significantly associated with advanced T stage (P = 0.015), higher …grade (P = 0.013), presence of tumor necrosis (P = 0.006), vascular invasion (P = 0.002), and lack of estrogen receptor (ER) and progesterone receptor (PR) expression (P = 0.0004 and P = 0.003). Higher TK1 activity was found in patients with BRCA1/2 mutations compared to those without the mutation (P = 0.004). Multivariate Cox proportional hazards analyses demonstrated that TK1, adjusted for stage, grade, necrosis, ER and PR negativity was retained as an independent predictor of disease recurrence (Hazard Ratio = 3.9, 95%CI 1.3–11.6, P = 0.013). Conclusion: Elevated serum TK1 is an important risk factor indicating a high proliferation potential of tumors at the time of excision. In multivariate analysis TK1 activity was found to be an independent prognostic factor for RFS. Show more

Keywords: Breast cancer, thymidine kinase 1 activity, prediction of recurrence, BRCA1/2 mutation

DOI: 10.3233/CBM-2010-0148

Citation: Cancer Biomarkers, vol. 7, no. 2, pp. 65-72, 2010

Authors: Schittenhelm, Jens | Thiericke, John | Nagel, Christoph | Meyermann, Richard | Beschorner, Rudi

Article Type: Research Article

Abstract: Objective: Wilms’ tumor protein (WT1) expression is usually absent in normal glial cells of the CNS but is highly upregulated in brain tumor cells and its expression correlates with tumor grade. However, knowledge on WT1 expression in tumors of the peripheral nerve system (PNS) is limited. As WT1 antibodies not only serve as biomarker for cancerous tissue but also are considered for cancer immunotherapy, knowledge of WT1 expression in tumorous and normal peripheral nerve tissue is important for therapeutical purposes. Methods: We analyze the immunohistochemical expression of WT1 in 101 samples consisting of 13 normal nerves, 10 neurofibromas, …69 schwannomas and 9 malignant peripheral nerve sheath tumors (MPNST). Tumor samples included 14 specimen from patients with a proven neurocutaneous disorder (neurofibromatosis type 1 and 2) and 3 cases of schwannomatosis. In 50 vestibular schwannomas tumor growth extension was correlated to WT1 expression. Results: WT1 expression is present in Schwann cells of the majority of normal human nerves (11/13). In peripheral nerve sheath tumors, cytoplasmic WT1 protein is expressed in the cytoplasm of the neoplastic cells in all tumors, including MPNST, neurofibromas and schwannomas. The WT1 expression is independent of tumor malignancy or tumor growth extension and is not associated with a neurocutaneous disorder. Conclusion: WT1 expression in normal and neoplastic tissue differs in the peripheral and the central nervous system. These findings may point to a different functional role of WT1 in the PNS and the CNS. Show more

Keywords: WT1, MPNST, schwannoma, neurofibroma

DOI: 10.3233/CBM-2010-0149

Citation: Cancer Biomarkers, vol. 7, no. 2, pp. 73-77, 2010

Authors: Trtková, Kateřina | Pašková, Lenka | Matiješčuková, Natálie | Kolář, Zdeněk

Article Type: Research Article

Abstract: Signaling through the androgen receptor (AR) plays a critical role in prostate cancer progression. The AR is a classical nuclear receptor (NR) providing a link between signaling molecule and transcription response. Histone deacetylase inhibitors (HDACI) have antiproliferative and proapoptotic effects on prostate cancer cells and their implication in silence AR signaling may have potential therapeutic use. We aimed to study the inhibitory effects of the corepressor SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptors) which forms a complex together with nuclear receptor corepressor (N-CoR) and with histone deacetylase 3 (HDAC3) on AR activity. The androgen-sensitive prostate cancer cell line …LNCaP and androgen-insensitive prostate cancer cell line C4-2 both AR-positive, and androgen-insensitive DU145 and PC3 prostate cancer cell lines were treated with two HDACIs, sodium butyrate (NaB) and/or trichostatin A (TSA). We amplified immunoprecipitated DNA by conventional PCR and in the following step we used the chromatin immunoprecipitation (ChIP) analysis coupled with quantitative PCR for monitoring NaB induced formation of AR-SMRT/N-CoR complex binding on the PSA promoter. The co-immunoprecipitation assay revealed increase in AR-SMRT formation in NaB treated cells. Simultaneously, the Western blot analysis showed a significant decrease in AR protein expression. Furthermore, we estimated the reduced presence of HDAC2 and HDAC3 proteins by NaB and TSA treatment in AR-negative DU145 cell line. In conclusion, the inhibitory effect of NaB on AR gene expression seems to be specific and unique for prostate cancer AR-positive cell lines and corresponds with its ability to stimulate AR-SMRT complex formation. We suggest that AR and SMRT/N-CoR corepressors may form a stable complex in vitro and NaB may facilitate the interaction between AR nuclear steroid receptor and SMRT corepressor protein. Show more

Keywords: Androgen receptor, prostate cancer, acetylation, histone deacetylase inhibitor

DOI: 10.3233/CBM-2010-0150

Citation: Cancer Biomarkers, vol. 7, no. 2, pp. 79-90, 2010

Authors: Kalnina, Inta | Kurjane, Natalja | Kirilova, Elena | Klimkane, Laura | Kirilov, Georgii | Zvagule, Tija

Article Type: Research Article

Abstract: The fluorescent probe ABM was used to characterize lymphocyte membranes and blood plasma albumin from cancer patients suffering from colorectal cancer or gastric cancers at Stages II-IV. The aim of these studies was to evaluate the potential utility of measures of ABM fluorescence intensity as a standard tool in the analyses of host immune status and for a clinical interpretation of alterations in albumin per se and lymphocyte functional activity in cancer patients. The fluorescence intensity of ABM in the blood plasma decreased from control values and showed specific differences in each of the differing patients groups; these changes corresponded …to cancer stage. The significant decrease in ABM fluorescence in the plasma could be explained, in part, by a diminished binding capacity of the albumin of these patients. The lymphocyte distribution among the subsets of patients also differed. Interestingly, the ABM fluorescence in the cell suspension and blood plasma was also found to correlate with select immunological parameters (CD4+ : CD8+ ratios, lymphocyte counts, etc.) in the patients. These results obtained here showed that there was a strong agreement between changes in ABM spectral characteristics and both clinical and pathological estimates of disease (i.e., gastrointestinal cancers) severity. Thus, the use of ABM spectroscopy appears to be another tool that might be of some used by clinicians to monitor the course of certain diseases, such as gastrointestinal cancers. Show more

Keywords: Fluorescent probe, blood plasma albumin, immune status

DOI: 10.3233/CBM-2010-0151

Citation: Cancer Biomarkers, vol. 7, no. 2, pp. 91-99, 2010

Authors: Kohli, Manish | Rothberg, Paul G. | Feng, Changyong | Messing, Edward | Joseph, Jean | Rao, Sreevidya Sadasiva | Hendershot, Allison | Sahsrabudhe, Deepak

Article Type: Research Article

Abstract: Objectives: An association of a single nucleotide polymorphism (SNP) of the KLK2 gene (rs198977; c.748C>T; R250W) with risk for developing prostate cancer has been observed. We evaluated the role of R250W SNP for prognosis in prostate cancer. Methods: The c.748C>T SNP was genotyped from blood DNA of 182 patients after completing initial cancer treatments. For evaluating prognosis of genotype groups, associations were performed with Gleason score (GS) and biochemical recurrence free survival (bRFS) in patients demonstrating PSA-recurrence after initial cancer therapy. Results: Overall distribution of the CC, CT and TT genotypes for the SNP was 48%, …44% and 8%, respectively. The distribution of high (8–10), moderate (5–7) and low (2–4) GS among the genotype groups was 17%, 74% and 9% for CC group compared to 25%, 74% and 1% for the CT/TT (P=0.04). Median bRFS time for CT/TT group was 36.5 months compared to 44.5 months for the CC group (P=0.16), while genotype groups combined with morphology revealed significantly different bRFS (P=0.004). Conclusions: This exploratory analysis in prostate cancer patients revealed the W allele of the KLK2 R250W SNP to be less likely associated with low GS morphology. Further studies will be needed to confirm this observation in larger cohorts. Show more

Keywords: Prostatic neoplasm, kallikrein, polymorphism, prognosis

DOI: 10.3233/CBM-2010-0152

Citation: Cancer Biomarkers, vol. 7, no. 2, pp. 101-108, 2010

Authors: van den Broek, Irene | Sparidans, Rolf W. | Engwegen, Judith Y.M.N | Cats, Annemieke | Depla, Annekatrien C.T.M. | Schellens, Jan H.M. | Beijnen, Jos H.

Article Type: Research Article

Abstract: Increased total serum concentrations of human neutrophil peptide-1, -2 and -3 (HNP-1, -2 and -3) have been associated with colorectal cancer (CRC). Owing to a recently developed and fully validated liquid-chromatography coupled to tandem-mass spectrometry (LC-MS/MS) assay, individual serum concentrations of these antimicrobial peptides were quantified to evaluate their role as serum markers in CRC. Serum was obtained from patients with indications for colonoscopy, subsequently diagnosed as normal colon or hyperplastic polyp (CON; n= 368), adenomatous polyp (AP; n = 179) or colorectal cancer (CRC; n = 69). Comparison of HNP-1, -2 and -3 concentrations between CRC and …CON (130 ± 90 vs. 105 ± 80; 264 ± 140 vs. 206 ± 99 and 62 ± 56 vs. 54 ± 59 for HNP-1, -2 and -3, respectively) revealed that reported up-regulated total HNP-concentrations can be largely attributed to increased HNP-2 (P=0.0006) and HNP-1 (P=0.024) levels. Although receiver operating characteristics (ROC) analyses showed low specificity of the peptides for CRC and no significant changes in serum levels were observed after surgical removal of the tumor (n=23), the established differentiation between the HNP-subtypes may be particularly useful to completely elucidate the role of these antimicrobial peptides in CRC. Show more

Keywords: Human neutrophil peptides, colorectal cancer, serum markers, LC-MS/MS

DOI: 10.3233/CBM-2010-0153

Citation: Cancer Biomarkers, vol. 7, no. 2, pp. 109-115, 2010