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      MMP28 (epilysin) as a novel promoter of invasion and metastasis in gastric cancer

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          Abstract

          Background

          The purpose of this study was to investigate invasion and metastasis related genes in gastric cancer.

          Methods

          The transwell migration assay was used to select a highly invasive sub-line from minimally invasive parent gastric cancer cells, and gene expression was compared using a microarray. MMP28 upregulation was confirmed using qRT-PCR. MMP28 immunohistochemistry was performed in normal and gastric cancer specimens. Invasiveness and tumor formation of stable cells overexpressing MMP28 were tested in vitro and i n vivo.

          Results

          MMP28 was overexpressed in the highly invasive sub-cell line. Immunohistochemistry revealed MMP28 expression was markedly increased in gastric carcinoma relative to normal epithelia, and was significantly associated with depth of tumor invasion, lymph node metastasis and poorer overall survival. Ectopic expression of MMP28 indicated MMP28 promoted tumor cell invasion in vitro and increased gastric carcinoma metastasis in vivo.

          Conclusions

          This study indicates MMP28 is frequently overexpressed during progression of gastric carcinoma, and contributes to tumor cell invasion and metastasis. MMP28 may be a novel therapeutic target for prevention and treatment of metastases in gastric cancer.

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          Most cited references26

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          How matrix metalloproteinases regulate cell behavior.

          The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regulating some of these processes in vivo. Our knowledge in the field of MMP biology is rapidly expanding, yet we still do not fully understand how these enzymes regulate most processes of development, homeostasis, and disease.
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            Epidemiology of gastric cancer.

            The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socio-economic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socio-economic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori (H pylori) infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.
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              Recurrence following curative resection for gastric carcinoma.

              The diagnosis and treatment of recurrent gastric cancer remains difficult. The aim of this study was to determine the risk factors for recurrence of gastric cancer and the prognosis for these patients. Of 2328 patients who underwent curative resection for gastric cancer from 1987 to 1995, 508 whose recurrence was confirmed by clinical examination or reoperation were studied retrospectively. The risk factors that determined the recurrence patterns and timing were investigated by univariate and multivariate analysis. The mean time to recurrence was 21.8 months and peritoneal recurrence was the most frequent (45.9 per cent). Logistic regression analysis showed that serosal invasion and lymph node metastasis were risk factors for all recurrence patterns and early recurrence (at 24 months or less). In addition, independent risk factors involved in each recurrence pattern included younger age, infiltrative or diffuse type, undifferentiated tumour and total gastrectomy for peritoneal recurrence; older age and larger tumour size for disseminated, haematogenous recurrence; and older age, larger tumour size, infiltrative or diffuse type, proximally located tumour and subtotal gastrectomy for locoregional recurrence. Other risk factors for early recurrence were infiltrative or diffuse type and total gastrectomy. Reoperation for cure was possible in only 19 patients and the mean survival time after conservative treatment or palliative operation was less than 12 months. The risk factors for each recurrence pattern and timing of gastric cancer can be predicted by the clinicopathological features of the primary tumour. Since the results of treatment remain dismal, studies of perioperative adjuvant therapy in an attempt to reduce recurrence are warranted.
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                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2011
                26 May 2011
                : 11
                : 200
                Affiliations
                [1 ]Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, China
                [2 ]Hillman Cancer Center Lab, Department of Pathology, Pittsburgh University, G21 5117 Center Ave. Pittsburgh, PA 15206, USA
                [3 ]Department of Cell and Molecular Biology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
                [4 ]Translational Research Center, Second Hospital, The Second Clinical School, Nanjing Medical University, Nanjing, China
                Article
                1471-2407-11-200
                10.1186/1471-2407-11-200
                3115915
                21615884
                799ceb0b-3e64-4484-b4c6-11f50f11cdd7
                Copyright ©2011 Jian et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 October 2010
                : 26 May 2011
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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