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      Suppression of metastasis of human pancreatic cancer cells to the liver by small interfering RNA-mediated targeting of the midkine gene

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          Abstract

          The present study aimed to ascertain whether suppression of midkine (MK) expression in pancreatic cancer cells inhibits metastasis to the liver. Human pancreatic cancer AsPC-1 cells were transfected with small interfering RNA (siRNA) targeting MK. siRNA against MK was observed to reduce the expression of MK mRNA and protein in a concentration- and time-dependent manner, and to decrease the number of migrating and tissue-penetrating cells in a concentration-dependent manner (P<0.005). Extracellular vascular endothelial growth factor (VEGF) concentrations were markedly reduced for the siRNA-transfected cells compared with those that were non-siRNA-transfected. The liver transmission rate and tumor nodule number in the animals harboring the siRNA-transfected cells were lower compared with those in the animals harboring the non-siRNA-transfected cells (P<0.005). These data indicate that metastasis of pancreatic cancer cells to the liver requires the expression of MK. The downregulation of VEGF expression is essential to the mechanism whereby suppression of MK expression constrains the metastasis of pancreatic cancer cells to the liver.

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          High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma.

          Y Seo, Elio Baba, M Takashima … (2000)
          Vascular endothelial growth factor (VEGF), a recently identified growth factor with significant angiogenic properties, is a multifunctional angiogenic cytokine that is expressed in many tumors. High VEGF expression has been shown to correlate with the incidence of metastasis and poor prognosis in various cancers. In this study, the authors investigated VEGF expression and microvessel density (MVD) in ductal pancreatic adenocarcinoma and examined the correlations among VEGF expression, clinicopathologic factors, and clinical outcome. The authors especially focused on the correlation between VEGF expression and liver metastasis. Paraffin embedded tumor specimens of 142 surgically resected pancreas carcinoma were immunohistochemically stained for VEGF and MVD. The correlations among VEGF expression and MVD, clinicopathologic factors, and clinical outcome were then statistically analyzed. One hundred thirty-two (93%) of 142 ductal pancreatic adenocarcinomas were positive for VEGF protein by immunohistochemistry. A significant correlation was observed between VEGF positivity and MVD (P < 0.0001). Multivariate logistic regression analysis indicated a significant association between high VEGF expression and liver metastasis (P = 0.010) but no other factors, such as age, tumor size, histologic type, lymph node metastasis, venous invasion, neural invasion, peritoneal metastasis, or local recurrence. Patients with tumors that showed moderate or high VEGF expression had significantly shorter survival than patients with low VEGF expression or none at all in their tumors (P < 0.05). These results indicate that VEGF expression is closely correlated with MVD and seems to be an important predictor for both liver metastasis and poor prognosis in ductal pancreatic adenocarcinoma.
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            Resection of Primary Pancreatic Cancer and Liver Metastasis: A Systematic Review

            Christoph W Michalski, Mert Erkan, Norbert Hüser … (2009)
            Resection of liver metastases for locally resectable pancreatic cancer has rarely been performed. Recently, promising results regarding morbidity and mortality as well as long-term survival have been shown. Thus, we conducted a systematic review of the literature on pancreatic cancer resection with associated liver metastasis resection. There are 3 case reports and 18 studies including less than 10 patients. Only three studies are larger series with 10 or more patients in whom pancreatic resections and hepatic metastasectomies were performed. Here, morbidity and mortality ranged from 24.1 to 26% and from 0 to 4.3%, respectively. Median survival was reported to be between 5.8 and 11.4 months. In total, all identified studies included 103 patients in whom a metastasis resection was performed. Liver metastasis resection for locally resectable pancreatic cancer can be performed in selected cases with low morbidity and mortality. Overall survival in cases with one or few liver metastases which are concomitantly resected seems to be comparable to cases without evidence of metastasis. Therefore, randomized controlled clinical trials will have to be initiated to determine the value of such resections and to identify factors which will allow for selection of patients in whom the extension of the resectability criteria might confer a survival benefit.
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              Midkine, a retinoic acid-inducible heparin-binding cytokine in inflammatory responses: chemotactic activity to neutrophils and association with inflammatory synovitis.

              T Muramatsu, K Toriyama, X Song … (1997)
              Midkine (MK) is a retinoic acid-inducible heparin-binding cytokine. In the inflammatory synovitis of rheumatoid arthritis and osteoarthritis, MK was detected in synovial fluid, synoviocytes, and endothelial cells of new blood vessels. Normal synovial fluid and noninflammatory synovial tissue did not contain detectable MK. Therefore, MK showed inflammation-associated expression in these cases. Furthermore, MK was found to promote chemotaxis of neutrophils in the range of 10 ng/ml. The mode of action of MK was found to be haptotactic; the substrate-bound form of MK was the active one. MK is also known to promote fibrinolysis. These activities of MK are in agreement with the modes of MK expression in various pathological statuses, and thus MK is proposed to be an important molecule regulating inflammatory responses.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncol Lett
                Journal ID (iso-abbrev): Oncol Lett
                Journal ID (publisher-id): OL
                Title: Oncology Letters
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-1074
                ISSN (Electronic): 1792-1082
                Publication date (Print): November 2013
                Publication date (Electronic): 12 September 2013
                Publication date PMC-release: 12 September 2013
                Volume: 6
                Issue: 5
                Pages: 1338-1342
                Affiliations
                [1 ]Zhenjiang Key Laboratory of Molecular Endocrinology, Zhenjiang, Jiangsu 212001, P.R. China
                [2 ]Cancer Institute, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
                [3 ]Department of General Surgery, Jiangsu Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
                Author notes
                Correspondence to: Dr Da Wei, Department of General Surgery, Jiangsu Cancer Hospital, No. 42 Baiziting, Nanjing, Jiangsu 210009, P.R. China, E-mail: 13605184569@ 123456163.com
                Article
                Publisher ID: ol-06-05-1338
                DOI: 10.3892/ol.2013.1572
                PMC ID: 3813521
                PubMed ID: 24179520
                SO-VID: b878a5f0-e3ce-4181-a1c8-53f52eaadae0
                Copyright © Copyright © 2013, Spandidos Publications
                License:

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Date received : 31 January 2013
                Date accepted : 18 July 2013
                Categories
                Subject: Articles

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: aspc-1 cells,liver metastasis,midkine,pancreatic cancer,small interfering rna,vascular endothelial growth factor
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: aspc-1 cells, liver metastasis, midkine, pancreatic cancer, small interfering rna, vascular endothelial growth factor

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