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Serum MMP7, MMP10 and MMP12 Level As Negative Prognostic

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Serum MMP7, MMP10 and MMP12 Level As Negative Prognostic Klupp et al. BMC Cancer (2016) 16:494 DOI 10.1186/s12885-016-2515-7 RESEARCH ARTICLE Open Access Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients Fee Klupp1*, Lena Neumann1, Christoph Kahlert3, Johannes Diers1, Niels Halama2, Clemens Franz1, Thomas Schmidt1, Moritz Koch3ˆ, Juergen Weitz3, Martin Schneider1 and Alexis Ulrich1 Abstract Background: Matrixmetalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases which are involved in angiogenesis, tumor invasion and metastatic formation. Up to date, the prognostic relevance of MMPs in serum of patients with colon cancer remains unknown. Thus, we wanted to assess an expression pattern of MMPs in a homogenous cohort of colon cancer patients to assess their potential as prognostic biomarkers. Methods: Differences in the expression pattern of MMP7, MMP10 and MMP12 in 78 serum specimens of patients with an adenocarcinoma of the colon and serum specimens of a healthy control group were assessed using Luminex-100 technologies. Subsequently, we correlated these results with histopathological and clinical data of the patients. Results: Luminex based expression analysis revealed a significant overexpression of MMP7 and an overexpression of MMP10 and MMP12 in the sera of colon cancer patients compared to the healthy control group. Patients with vascular invasion showed a significantly higher MMP12 expression than V0-staged patients. Moreover overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera displayed a significantly impaired overall survival. Multivariate analysis revealed high MMP10 serum levels to be an independent adverse prognostic marker in colon cancer patients. Conclusions: Expression patterns of MMP7, MMP10 and MMP12 in colon cancer patients´ sera are different compared to serum specimens of healthy individuals. Furthermore, overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera correlates with a dismal prognosis and may help to stratify patients into different risk groups. Keywords: Colon cancer, Serum, MMP, Survival, Prognostic marker Background distant metastases [4]. Adjuvant chemotherapy in ad- Colorectal cancer (CRC) is one of the most prevalent vanced stages improves survival rates heavily, but with cancer entities and the second leading cause of cancer- the restrictions of general cytotoxity [5, 6]. It is known related death in the western world [1, 2]. For all stages that a percentage of patients is either under- respectively of CRC the 5-year survival rate is about 60 % [3]. Sur- overtreated due to the decision of adjuvant chemother- vival depends strongly on the histological stage with apy referring current clinical guidelines [7]. Therefore favorable survival rates in stage I and II whereas the out- individualized and tailored therapeutic strategies have come drastically decreases with lymph node positivity or turned into focus. Hence other predictive markers then eg. Dukes stage which influence tumor progression and survival were investigated like - to name only few - micro- * Correspondence: [email protected] satellite instability or cyclooxygenase-2 expression with ˆDeceased 1Department of General, Visceral and Transplantation Surgery, University of the aim to proceed a step towards new therapeutic strat- Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany egies additionally to chemo- and/or radiotherapy [8, 9]. Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Klupp et al. BMC Cancer (2016) 16:494 Page 2 of 9 Matrixmetalloproteinases (MMPs) comprise a family of at without any known comorbidities served as control serum least 25 secreted and cell surface zinc-dependent endo- group. A written informed consent of all patients and peptidases involved in tumor progression, angiogenesis, healthy donors was obtained and the study was approved invasion of surrounding tissue and metastatic formation by the ethics committee of the University of Heidelberg. and evasion of the immune system [10]. They are capable Clinical data included gender, date of birth, age at surgery, to degrade all components of the extracellular matrix and size, tumor location, histopathological diagnosis including even non-matrix proteins, necessarily needed for tumor TNM classification and UICC-stage, R-classification, grad- invasion and metastatic spread [11, 12]. According to their ing, adjuvant chemotherapy, postoperative complications substrate specificity or additional structural domain they and overall survival (time from operation up to death or are divided into subgroups like Collagenases, Gelatinases, last follow up). Median follow up time was 901 ± 469 days Stromelysins, Matrilysins and Membrane-type MMPs. (range: 6–1980 days). Synthesized as inactive zymogens, they become functional by proteolytic removal of the propeptide prodomain [13]. Tissue material and preparation The activity of MMPs is regulated by differential expres- Patients´ sera were obtained during surgery and imme- sion and post-translational processes. Activating factors diately stored at −80 °C. Likewise, healthy serum sam- include transcription factors such as LEF-1 (lymphoid en- ples were immediately stored at −80 °C after removal. hancer binding factor-1) or ß-catenin, other MMPs, serin Total protein concentration was measured using Pierce® proteinases, cytokines and growth factors [10, 13]. Coun- BCA Protein Assay Kit (Thermo Fisher Scientific Inc, terparts in terms of expressional inhibition are the tissue Rockford, IL, USA) and Infinite 200® PRO Reader (Tecan inhibitors of matrixmetalloproteinases (TIMPs), RECK Group Ltd., Männedorf, Switzerland) according to the (reversion-inducing cysteine-rich protein with Kazal mo- manufacturer’s protocol. Magellan™ Data Analysis Software tifs), α2-Macroglobulin or Thrombospondin [14–16]. (Tecan Group Ltd., Männedorf, Switzerland) was taken for Upregulation of several MMPs including MMP7, analysis of these data. All serum samples were diluted to a MMP10 and MMP12 in cancerous tissue and adverse concentration of 0.1 μg/μl of total protein. association with survival has been evaluated likewise in colorectal cancer [17, 18]. Moreover secretion of Luminex based multiplex assay MMPs into the bloodstream is proposed [19]. However Serum samples for the detection of MMP7, MMP10 prognostic impact of MMP expression in colorectal can- and MMP12 were processed using Milliplex MAP cer patients´ sera has only been assessed partially. In this Human MMP Assay Kits (Merck Millipore, Millipore study we have chosen three MMPs namely MMP7, Corporation, Billerica, MA, USA) according to the MMP10 and MMP12 for investigation. However, to our manufacturer’s protocol. The exact concentration of these knowledge until now there is no study assessing serum markers were detected in each sample by Luminex 100™ MMP10 and MMP12 level in a homogenous collective of reader (Luminex Corporation, Austin, Texas, USA). colon cancer patients’ sera in regard to overall survival. The prognostic impact of MMP7 serum level in advanced Statistics colorectal cancer has already been evaluated before [20]. Statistical analysis of the data and calculations were Therefore assessment of serum MMP7 level serves as a conducted with Excel 2010 (Microsoft Corporation, validation for underlining the representative study collective Redmond, WA) and SPSS version 21 (SPSS, IBM Cor- of patients. Hence, we investigated multiplex bead-based poration, Armonk, NY). immunoassay-technology measuring MMP7, MMP10 and Wilcoxon-signed rank test was used to determine dif- MMP12 serum level in a homogenous collective of 78 ferences in the expression pattern. Expression bars were patients suffering from colon cancer and a healthy control presented using mean concentration [pg/ml] + SEM. serum group to assess presumed differences in expression Kaplan-Meier method was employed to estimate cancer pattern and correlations with clinicopathological character- related survival. Differences between the survival curves istics and survival. were evaluated by log-rank test. For survival analysis Cox proportional hazards model was taken to calculate Methods survival related hazard ratios. Multivariate analysis was Patients performed using Cox proportional hazards regression Serum samples of 78 patients with primary adenocarcin- including the following covariates: age, gender, UICC oma of the colon were included in our current study. stage, TNM-classification, R-Stage, adjuvant chemother- Patients received surgical treatment at the Department of apy, anastomotic leakage and relative serum expression General, Visceral, and Transplantation Surgery, University of MMP7, MMP10 and MMP12 in colon cancer pa- of Heidelberg, Germany between September 2007 and tients´ sera vs. sera of healthy control serum group. The January 2012. Serum specimens of 38 healthy individuals comparison of clinical parameters and relative serum Klupp
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