Serum levels of S100A6 are unaltered in patients with resectable cholangiocarcinoma
- Sven H. Loosen†1,
- Fabian Benz†1,
- Jennifer Niedeggen1,
- Maximilian Schmeding2,
- Florian Schüller1,
- Alexander Koch1,
- Mihael Vucur1,
- Frank Tacke1,
- Christian Trautwein1,
- Christoph Roderburg†1,
- Ulf P. Neumann†2 and
- Tom Luedde†1, 3Email author
© The Author(s) 2016
Received: 24 June 2016
Accepted: 10 September 2016
Published: 27 September 2016
Elevated expression levels of S100A6, a calcium-binding low-molecular-weight protein, were demonstrated in various malignancies. Moreover, increased serum levels of S100A6 were suggested as a novel biomarker for various inflammatory and malignant diseases including lung and gastric cancer. However, up to now, serum concentrations of S100A6 have not been analyzed in patients with cholangiocarcinoma (CCA).
S100A6 mRNA expression levels were analyzed in human and murine CCA tumor samples, using semi-quantitative reverse transcriptase PCR. S100A6 serum concentrations were measured using an enzyme-linked immunosorbent assay in 112 patients with CCA referred to surgery for curative resection and were compared to those of 42 healthy controls. Results were correlated with clinical data.
S100A6 mRNA expression levels were significantly up-regulated in tumor samples of CCA patients and in tumor tissue of a CCA mouse model. In contrast, serum levels of S100A6 were not significantly altered in patients with CCA compared to healthy controls. Whereas no differences became apparent within the different clinical subgroups of CCA, patients with primary sclerosing cholangitis (PSC)-based CCA displayed higher levels of S100A6 compared to the other patients. Nevertheless, patients with higher S100A6 serum concentrations showed a trend towards an impaired prognosis compared to patients with lower levels. Finally, within our cohort of patients both the diagnostic and prognostic potentials of S100A6 were similar to those of the clinically established biomarkers CEA and CA19-9.
Although S100A6 was expressed at significantly higher levels in human and murine CCA tumor samples, S100A6 serum levels were not regulated in patients with CCA and are thus not suitable for diagnosis of CCA. However, CCA-patients with elevated S100A6 displayed a trend toward an impaired prognosis compared to patients with lower S100A6 levels, supporting its further evaluation as a prognostic biomarker in CCA.
KeywordsS100A6 Cholangiocarcinoma (CCA) Cancer Biomarker Prognosis CA19-9 CEA
Cholangiocarcinoma (CCA) accounts for 10–15 % of all hepatobiliary malignancies and is therefore the second most common primary tumor of the liver . According to its location, CCA can be classified as intrahepatic, perihilar or extrahepatic CCA . The global incidence of CCA shows large geographical variations with incidence rates of 0.5–3.4/100,000 in Western Europe and the United States and up to 85/100,000 in Northeast Thailand . Although the incidence of extrahepatic CCA seems to decrease slightly over time, the overall incidence of CCA and especially the incidence of intrahepatic CCA have shown a strong increase over the last decades [4–6]. Surgical resection remains the only potentially curative treatment option for all types of cholangiocarcinoma, but is often not feasible due to an advanced disease stage at diagnosis . The standard therapy for patients with inoperable advanced stage CCA is a palliative chemotherapy with the substances gemcitabine and cisplatin [7–9].
The overall survival of CCA patients has remained fairly poor with a post-operative 5-year survival rate of 23–42 % after R0 resection and 0 % after R+ resection for intrahepatic CCA [10, 11] and 27–37 % for extrahepatic CCA, respectively [12, 13]. For advanced tumor stages, the 5-year survival rate has remained below 5 % [14, 15], highlighting the urgent need for biomarkers allowing an early diagnosis and prognosis of the disease. As cholangiocarcinoma can be considered one of the less common types of cancer, there are only a limited number of studies evaluating potential biomarkers for CCA. To date, no serum based marker detecting CCA with an appropriate sensitivity and specificity at early stages of disease could be established.
The S100 protein family consists of more than 25 low-molecular-weight proteins, characterized by Ca2+-binding EF-hand motifs . S100A6 (calcyclin) is a 90-amino-acid, 10.5 kDa protein that is predominantly expressed in the cytosol of numerous human cells, including fibroblast, epithelial cells, neuronal cells, lymphocytes, platelets, cardiomyocytes and smooth muscle cells [17–23]. A large number of studies have associated S100A6 with the development of cancer . As such, S100A6 was shown to be significantly up-regulated in the tumor tissue of cutaneous melanoma, colorectal adenocarcinoma, stomach and thyroid cancer, astrocytoma or pancreas ductal adenocarcinomas [24–29]. Functionally, S100A6 was shown to play a decisive role in different molecular processes in tumorigenesis. In renal cell carcinoma cells, knockdown of calcium-regulating S100A6 suppressed cell growth via induction of G2/M phase arrest, a finding that has previously been reported in other cell types , and significantly reduced tumor mass in an in vivo mouse model . Furthermore, S100A6 knockdown activated CXCL14-induced apoptosis in a renal cell carcinoma cell line . In acute lymphoblastic leukemia cell lines, up-regulation of S100A6 was associated with reduced apoptosis due to interactions with the p53-caspase 8-caspase 3 pathway . Pancreatic cancer cell lines showed significantly reduced cell proliferation and invasion after inhibition of S100A6 and different genes (e.g. human ovarian b-A inhibin, activin A and cytokine gro-b) that are known to be negative regulators of cell proliferation were shown to be up-regulated by S100A6 inhibition .
In cholangiocarcinoma, increased expression levels of S100A6 mRNA and protein were found in a small cohort of tissue specimens of intrahepatic CCA and it was suggested that S100A6 may help to differentiate between intrahepatic CCA and hepatocellular carcinoma (HCC) . Moreover, other representatives of the S100 family such as S100A4 and S100P were shown to be overexpressed in CCA tumor samples and were associated with increased tumor invasiveness [35–37].
Although the cause and exact mechanism of S100A6 secretion into the bloodstream is not fully understood, different studies revealed elevated serum levels of S100A6 in NSCLC, gastric cancer and urothelial carcinoma [38–40] and suggested its role as a diagnostic and/or prognostic biomarker. As an example, S100A6 serum levels were significantly elevated in patients with gastric cancer and correlated with lymph node metastasis or TNM stage as well as overall survival .
Despite the emerging role of S100A6 in the pathophysiology of different (gastrointestinal) cancers, no data on the potential use of this ligand as a biomarker for cholangiocarcinoma are available. In the present study, we therefore analyzed serum levels of S100A6 in a cohort of 112 CCA patients that were admitted for surgery in curative intention at University Hospital RWTH Aachen, in order to determine the potential role of S100A6 as a diagnostic and prognostic biomarker for cholangiocarcinoma.
Study design and patient characteristics
Characteristics of CCA study population
Age [median and range]
BMI [median and range]
Anatomic location of CCA [%]
Pain scale [%]
Levels of S100A6 and variant laboratory markers
CCA patients pre-op
CCA patients post-op
CA 19-9 [kU/l]
Determination of serum S100A6
S100A6 serum concentrations were analyzed using a commercial enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions (SEB769Hu by Cloud-Clone Corp., Houston, TX, USA). Evaluation of the ELISA absorbance values and calculation of the serum concentration was performed using a 4 Parameter Logistic (4PL) nonlinear regression model.
Semi-quantitative reverse transcriptase PCR (qPCR)
RNA isolation from tissue samples, cDNA synthesis and qPCR was performed as recently described in detail [41, 42]. The following primers for S100A6 were used: 1. For human S100A6: 5′-TCTTCCACAAGTACTCCGGC-3′, 2. Rev human S100A6: 5′-TCCGGTCCAAGT-CTTCCATC-3′, 3. For murine S100A6: 5′-ACTCTGGCAAGGAAGGTGAC-3′, 4. Rev murine S100A6: 5′-GGCGACATACTCCTGGAAGT-3′. All qPCR reactions were performed in duplicates. Data were generated and analyzed using the SDS 2.3 and RQ manager 1.2 software packages (Applied Biosystems).
CCA mouse model
For evaluation of murine S100A6 mRNA expression levels, tissue samples (tumor tissue, tumor microenvironment, healthy liver tissue from tumor-bearing mice and healthy liver tissue from untreated mice) from a recently published CCA mouse model were used . In brief, the left liver lobe of six to eight-weeks-old p53fl/fl mice (strain: C57BL/6) was electroporated with Sleeping Beauty-based oncogenic transposon plasmids. The combination of a targeted p53-knockout in hepatocytes and KRas-activation led to formation of a single intrahepatic cholangiocarcinoma within 3 weeks.
Statistical analyses have been performed as recently described in detail . In brief, data are given as median and range to reflect the skewed distribution of analysis on human samples. The Mann–Whitney-U-test and for multiple comparisons the Kruskal–Wallis-ANOVA was used. Box plot graphics display a statistical summary of the median, quartiles, ranges and extreme values. Correlations analyses were performed by using the Spearman correlation tests. The prognostic value of the variables was tested by univariate and multivariate analysis in the Cox regression model. Kaplan–Meier curves were plotted to display the impact on survival. ROC curves were generated by plotting sensitivity against one-specificity. All statistical analyses were performed with SPSS (SPSS, Chicago, IL, USA) and GraphPad Prism 5.0 (GraphPad Software Inc., La Jolla, CA, USA) .
S100A6 expression is up-regulated in tumor tissue of human and murine CCA
Serum S100A6 levels in patients with CCA
Correlation analysis between S100A6 and variant laboratory markers (R, Spearman coefficient; p, p value)
Postoperative serum levels of S100A6 do not reflect tumor characteristics
Serum S100A6 levels as prognostic biomarker for CCA
Comparison of serum S100A6 concentrations and CEA or CA19-9 serum levels
In clinical routine, measurements of CEA and CA19-9 are frequently performed in patients with CCA. We therefore compared the diagnostic and prognostic power of S100A6 measurements to those of CEA and CA19-9 in our cohort of patients with CCA. Similar to S100A6, both CEA and CA19-9 were not significantly elevated in patients with CCA. Concentrations of these markers did not differ in patients that succumbed to death and survivors (Additional file 5: Figure S4a and b). Notably, ROC curve analysis revealed that neither CEA nor CA19-9 were significantly superior to S100A6 measurements in prediction of patients' outcome (Additional file 5: Figure S4c).
Although the incidence of CCA is rising worldwide, knowledge on biomarkers for this heterogeneous disease allowing to non-invasively establish the diagnosis (e.g., in high-risk patients with cholestatic diseases) or to predict prognosis is scarce . In the present study, we demonstrate that S100A6 expression levels are significantly up-regulated in CCA tumor tissue but measurements of circulating S100A6 are not suitable for the diagnosis of CCA. Nevertheless, S100A6 serum levels might be indicative for the prognosis of patients with CCA. Of note, within our cohort of patients, measurements of S100A6 demonstrated a similar prognostic power than that of clinically established biomarkers such as CEA or CA19-9.
In humans, the S100 protein family consists of about 20 members that are characterized by a similar structure and all act as modulators of cellular responses towards injury and stress . Alterations in the expression of S100 family members represent a common feature of several cancers including gastrointestinal malignancies such as gastric cancer, pancreatic cancer and colorectal adenocarcinoma [25, 26, 39, 51]. While the expression of different S100 members is commonly up-regulated in malignant tumors, distinct and in part contradictory expression profiles were observed in many cancers and may be attributable to cancer subtype, disease stage, cellular distribution, or issues associated with S100 protein and/or mRNA detection. As an example, S100A11 expression is increased in NSCLC, but is decreased in small-cell lung cancer . Similarly, we did not detect a significant alteration in S100A6 serum levels in cholangiocarcinoma, while an up-regulation was described in other gastrointestinal cancers [25, 39]. In this context, it was recently suggested that differences in S100A6 expression might help to distinguish between cholangiocarcinoma and hepatocellular cancer as S100A6 expression levels were described to be up-regulated in CCA tumor tissue but normal in HCC tissue samples . In accordance with this finding, we showed that S100A6 is significantly overexpressed in human and murine CCA tissue samples, corroborating a pathophysiological role of S100A6 in cholangiocarcinoma. However, at least in our cohort of patients, these data were not reflected by concordant alterations in blood or serum levels (Fig. 2c), highlighting the complexity in the regulation of S100 family members in cancers.
We found slight alterations in S100A6 levels in patients that succumbed to death compared to survivors. Moreover, patients with S100A6 serum levels of less than 2234 ng/ml displayed a trend towards a better survival in Kaplan–Meier curve analysis, highlighting that S100A6 serum levels might reflect prognosis-relevant processes in patients with CCA. This justifies to further evaluate S100A6 in larger prospective trials, possibly alongside other promising biomarker candidates in order to develop new multi-parametric prognostic scores. Similar observations were made for S100A2 as a negative prognostic biomarker in pancreatic cancer . In line, S100 family members, including S100A6, have been demonstrated to regulate critical processes such as tumor growth, metastasis, angiogenesis and immune evasion [54–57].
Recently, serum levels of S100A2 and S100A6 were found to be higher in patients with NSCLC compared to controls . Moreover, also in patients with gastric cancer, serum S100A6 levels were elevated and significantly correlated with lymph node metastasis, TNM stage, perineural invasion and vascular invasion, supporting that S100A6 might represent a novel marker indicating patients prognosis independently of the examined tumor entity . We therefore hypothesized that also differences between pre- and postoperative levels in S100A6 levels might be of prognostic relevance. However, no significant difference became apparent when we compared pre- and postoperative concentration of S100A6. The results were not predictive for tumor or surgery specific factors such as complete tumor resection or tumor grading, which might have been expected as members of the S100 protein family have previously been shown to serve as a biomarker for the evaluation of response to surgical treatment and prediction of early relapse and survival in melanoma .
Recent data suggested a prognostic function of CA19-9 but not CEA in patients with CCA [59, 60]. In our cohort of patients no significant differences in survival for patients with elevated CEA or CA19-9 serum concentrations compared to those with lower levels became apparent. Importantly, both of these routinely used markers displayed a lower prognostic accuracy than S100A6, highlighting that new and innovative biomarkers might be superior in this setting than currently used markers. Beside S100A6 a prognostic function has also been described for cytokeratin-19 fragments (CYFRA 21-1), IL-6 and microRNA-21, but the available data suggest that panels of more than one biomarker are needed to reliably predict prognosis in patients with CCA [61–63].
Guiding early therapeutic decisions represents an important challenge in the treatment of patients with cholangiocarcinoma. In light of our findings that S100A6 concentrations might be indicative for an impaired prognosis, our results indicate that measurement of circulating S100A6 levels could be considered as a novel element in the diagnostic algorithm of patients with cholangiocarcinoma. Of note, although in our patients the prognostic value of S100A6 serum levels for overall survival was limited, it was similar to that of established prognostic markers such as CA19-9. As almost all of our patients underwent surgery for CCC and only few patients displayed a metastasized stage of disease already at the time-point of diagnosis, we cannot fully rule out that the findings of our study are only valid for this subgroup of patients and that S100A6 levels might be different in patients with metastases. Thus, future studies combining prospective clinical trials and experimental animal models are needed to further establish S100A6 measurements in the diagnosis of cholangiocarcinoma and to define the exact role of S100 family members in the pathophysiology of this devastating disease.
Our study, including 112 patients with histologically confirmed CCA, demonstrates that despite a significantly up-regulated expression of S100A6 in human and murine CCA tumor samples, S100A6 serum levels are not suitable as a biomarker for the diagnosis of CCA, which is in contrast to previous findings, suggesting a role of serum S100A6 as a biomarker in other gastrointestinal malignancies. CCA-patients with elevated S100A6 levels show a trend toward an impaired prognosis when compared to patients with lower S100A6 levels. This finding supports further evaluation of S100A6 as a prognostic biomarker in CCA.
S100 calcium-binding protein A6
primary sclerosing cholangitis
Union for International Cancer Control
Eastern Cooperative Oncology Group
International Normalized Ratio
non-small-cell lung carcinoma
white blood cell count
- CA 19-9:
body mass index
semi-quantitative reverse transcriptase PCR
CR, TL and UPN designed the study; MS and UPN recruited the patients; SHL, FB, FS, JN and MV performed experiments; CR, FB, SHL, TL performed statistical analysis and generated figures and tables; FT provided intellectual input; CR, SHL and TL drafted the manuscript. All authors read and approved the final manuscript.
Work in the lab of T.L. was supported by the German Cancer Aid (Deutsche Krebshilfe 110043 and a Mildred-Scheel-Professorship), the German-Research-Foundation (SFB-TRR57/P06 and LU 1360/3-1), the Ernst-Jung-Foundation Hamburg and a grant from the medical faculty of the RWTH Aachen. Moreover, this work was supported by project grants from the German Research Foundation (DFG RO 4317/4-1) and a START grant from the medical faculty RWTH Aachen to C.R.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study protocol was approved by the local ethics committee and conducted in accordance with the ethical standards laid down in the Declaration of Helsinki (ethics committee of the University Hospital Aachen, RWTH University, Aachen, Germany). Written informed consent was obtained from each patient.
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