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The Antimetastatic Role of Thrombomodulin Expression in Islet Cell–Derived Tumors and Its Diagnostic Value

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The Antimetastatic Role of Thrombomodulin Expression in Islet Cell–Derived Tumors and Its Diagnostic Value Vol. 10, 6179–6188, September 15, 2004 Clinical Cancer Research 6179 The Antimetastatic Role of Thrombomodulin Expression in Islet Cell–Derived Tumors and Its Diagnostic Value Satoshi Iino,1,2 Kazuhiro Abeyama,2 ically useful molecular marker not only for identifying Ko-ichi Kawahara,2 Munekazu Yamakuchi,2 ␤-cell–origin islet cell tumors (i.e., insulinomas) but also for Teruto Hashiguchi,2 Sumika Matsukita,3 predicting disease prognosis of islet cell tumors. Suguru Yonezawa,3 Shotaro Taniguchi,2 Masanori Nakata,2 Sonshin Takao,1 INTRODUCTION Takashi Aikou,1 and Ikuro Maruyama2 Neuroendocrine neoplasms arising primarily from the pan- Departments of 1Surgical Oncology and Digestive Surgery, creatic islets of Langerhans (also termed islet cell tumors) are 2Laboratory and Vascular Medicine, and 3Human Pathology, quite rare, with an overall incidence of only 1 to 1.5 per 100,000 Kagoshima University Graduate School of Medicine and Dental in the general population (1, 2). Up to 50% of all of the islet cell Science, Kagoshima, Japan tumors secrete biologically active peptides, causing their sys- temic clinical symptoms; thus, such tumors are categorized as ABSTRACT “functional” islet cell tumors (i.e., insulinoma, glucagonoma, gastrinoma, somatostatinoma and VIPoma). By contrast, other Islet cell tumors, endocrine neoplasm arising from pan- islet cell tumors showing no substantial secretion of the peptide creatic islets of Langerhans, are histologically difficult to hormones are categorized as “nonfunctional” islet cell tumor. diagnose as benign or malignant. Molecular markers are Clinically, it is very difficult to diagnose islet cell tumors as associated with the clinical characteristics that most of in- “benign or malignant” by using histologic examination alone. sulinoma are usually benign tumors, whereas other islet cell To determine their malignant potentials, clinical features of islet tumors are malignant but have not been identified. In this cell tumors (i.e., lymph node metastasis or distant metastasis) context, we newly found that an endothelial anticoagulant must also be taken into consideration. According to the past thrombomodulin was expressed in the normal islet ␤ cells studies concerning the metastatic capacities of islet cell tumors, and insulinoma, but not of other islet components or non- more than 90% of insulinoma cases were clinically benign, insulinoma islet cell tumors. Clinically, all of the subjects whereas 40 to 60% of other functional islet cell tumors (1–4) of the insulinoma group showed no metastasis (15 ؍ n) and 80 to 90% of nonfunctional islet cell tumors (2, 5) were together with thrombomodulin expression in the lesions, malignant. Thus, most insulinoma cases are usually considered whereas the other islet cell tumor groups showed a high to be benign tumors in the clinical situations. Nevertheless, incidence of metastasis (82%) and a low expression rate of molecular markers clinically associated with the metastatic po- thrombomodulin (6%). To examine the functional role of tentials of islet cell tumors have not yet been identified. thrombomodulin, especially regarding the clinical charac- Thrombomodulin has been identified as an endothelial teristics of islet cell tumors, we tested the effect of exogenous membrane protein (6), and the thrombomodulin-protein C path- thrombomodulin overexpression on cell adhesiveness and way has become well recognized for its essential anticoagulant/ proliferation using MIN6 insulinoma cell line. In cell-based antithrombotic properties. The association of thrombin and experiments, thrombomodulin overexpression reduced cell -2؉ thrombomodulin on the endothelial surface blocks the proco proliferation and enhanced Ca -independent cell aggrega- agulant properties of thrombin and redirects substrate specificity tion, possibly through direct interaction with neural cell toward the activation of plasma protein C (6–12) as well as adhesion molecule. Taken together, these results are sug- toward the inhibitor of fibrinolysis, thrombin-activatable fibrin- gesting that thrombomodulin may act as antimetastatic mol- olysis inhibitor (13, 14). Activated protein C exerts additional ecule of insulinomas. In addition, thrombomodulin is a clin- anticoagulant effects by inactivating coagulant cofactors Va and VIIIa (7, 8, 12). Thrombomodulin is also expressed at extra- vascular sites, such as in syncytiotrophoblasts in the placenta, in Received 12/16/03; revised 5/3/04; accepted 5/18/04. the epithelial tissues of gingiva, in the skin, lungs and digestive Grant support: Ministry of Education and Science of Japanese Gov- organs, and in the synovial lining cells (15–19). However, the ernment, Grant-in-Aid 13470324 and 14657627 (I. Maruyama) and functional role of thrombomodulin in the extra-vascular space, 13220016 (S. Yonezawa). apart from the possible limitation of thrombin generation at The costs of publication of this article were defrayed in part by the these sites, remains uncertain. Recent studies have shown that payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to thrombomodulin also attenuates inflammatory responses (20– indicate this fact. 22) and acts as an antimetastatic molecule against malignant Requests for reprints: Ikuro Maruyama, Department of Laboratory and tumor progression (23–27) beyond its anticoagulant activities. Vascular Medicine, Kagoshima University Graduate School of Medi- In the context of the antimetastatic properties of thrombo- cine and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan. Phone: 81-99-275-5437; Fax: 81-99-275-2629; E-mail: rinken@ modulin against tumor progression, we considered a possible m3.kufm.kagoshima-u.ac.jp. link between thrombomodulin and the benign character of in- ©2004 American Association for Cancer Research. sulinomas. In the present study, we first show the evidence that Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2004 American Association for Cancer Research. 6180 The Antimetastatic Role of Thrombomodulin Expression thrombomodulin is expressed dominantly in cases of insulinoma viously (16), and antimouse thrombomodulin rat IgG FM/TM as well as in normal ␤ cells in the pancreatic islets, which antibody was generously provided by Dr. Sumi Imada (Meiji negatively correlates with the clinical incidence of tumor me- Institute of Health Science, Odawara, Japan). tastasis. Furthermore, the results shown herein also demonstrate Cells and Cell Cultures. Dr. Susumu Seino (Chiba for the first time that thrombomodulin functions as a regulator University, Chiba, Japan) kindly donated the islet ␤ cell- for cell adhesion and proliferation in vitro. derived MIN6 line (29, 30). Cells were maintained in DMEM (high glucose; Life Technologies, Inc., Grand Island, NY) MATERIALS AND METHODS supplemented with 15% heat-inactivated fetal bovine serum, ␮ Tissue Samples. Surgical specimens were obtained from 100 units/ml penicillin, 100 g/ml streptomycin sulfate, 31 patients (14 men and 17 women) with islet cell tumor, who and 0.5% 2-mercaptoethanol at 37°C (5% CO2). To ob- underwent tumor resection in the Department of Surgical On- tain thrombomodulin-overexpressing MIN6, we produced cology and Digestive Surgery (Kagoshima University Graduate pTracer-CMV/Bsd Vector (Invitrogen Corp., Carlsbad, CA) School of Medicine and Dental Science) between 1977 and containing cDNA of the entire precursor of thrombomodulin 2003. The age of the patients ranged from 18 to 79 years, with (gift from Asahi Chemical Industry Co., Ltd.). MIN6 was an average age of 42 years. Type of tumor were as follows: (a) transfected with the vector construct using LipofectAMINE 15 patients were diagnosed with insulinoma; (b) 10 patients Reagent (Invitrogen). were diagnosed with nonfunctional islet cell tumor; (c) 1 patient Islet Isolation. Male ICR mice were housed in the was diagnosed with glucagonoma; (c) 2 patients were diagnosed pathogen-free facility of the Animal Resource Center, Ka- with gastrinoma; (d) 2 patients were diagnosed with soma- goshima University. All experiments involving animals were tostatinoma; and (e) 1 patient was diagnosed with VIPoma. Of conducted following the guidelines of the NIH and with the the 31 patients, 7 showed liver metastasis and 6 had lymph node approval of the Institutional Animal Care and Use Committee. metastasis (Table 1). The islets were isolated from 8-week-old male ICR mice as Immunohistochemistry. Immunohistochemical staining described previously (31). was performed using an ABC kit (Vector Laboratories, Burl- FACS Analysis. Briefly, cell suspension was incubated ingame, CA), as described previously (17, 28). Briefly, paraffin- with rabbit antiserum against thrombomodulin (1:50) for 30 embedded tissue samples were reacted with each antibody, as minutes. The samples were subsequently washed and reacted indicated in the presence of 1% BSA for 12 hours at 4°C. with fluorescence-conjugated antirabbit IgG antibody for 30 Biotinylated IgG was used as a second antibody. minutes. Fluorescent measurements were then performed using Reagents and Antibodies. Recombinant human soluble FACS (EPICS Profile, Beckman Coulter Inc., Fullerton, CA). thrombomodulin spanning the extracellular domain of the pro- Western Blotting. Western blotting analysis was per- tein was generously provided by Asahi Chemical Industry Co., formed as described previously (32). Briefly, lysates were sep- Ltd. (Tokyo, Japan). Recombinant neural cell adhesion
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