title: Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo.
  
  
  METHODS
  Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression.
  
  
  RESULTS
  We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens.
  
  
  CONCLUSIONS
  Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Yamamoto
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohnuma
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hatano
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Komiya
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Division of Hematology/Oncology, University of Florida, 1600 SW Archer Road, Box 100278, Room MSB M410A, Gainesville, FL 32610, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Dang
authors.affiliation: Department of Medical Oncology and Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, 685 Higashi-Kiwa, Ube, Yamaguchi 755-0241, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Aoe
authors.affiliation: Department of Respiratory Medicine, Okayama Rosai Hospital, 1-10-25 Chikkomidorimachi, Okayama Minami-ku, Okayama 702-8055, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000627:therapeutic use*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D010997:Pleural Neoplasms / Q000188:drug therapy*; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054697:Cytostatic Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D018819:Dipeptidyl Peptidase 4
references.citation: Lung Cancer. 2009 Nov;66(2):191-7
references.pmid: 19232771
references.citation: Cancer Res. 2005 Mar 1;65(5):1973-83
references.pmid: 15753397
references.citation: Biochem Biophys Res Commun. 2012 Mar 16;419(3):529-36
references.pmid: 22369943
references.citation: Immunology. 2002 Nov;107(3):325-33
references.pmid: 12423308
references.citation: Mol Endocrinol. 1997 Jul;11(8):1062-9
references.pmid: 9212054
references.citation: J Biol Chem. 2002 Aug 9;277(32):28431-8
references.pmid: 12045195
references.citation: Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3470-7
references.pmid: 16740772
references.citation: Clin Cancer Res. 2012 Mar 1;18(5):1447-56
references.pmid: 22261805
references.citation: J Biol Chem. 2004 Dec 10;279(50):52338-45
references.pmid: 15448155
references.citation: Mol Cell Endocrinol. 2008 May 14;286(1-2):40-8
references.pmid: 17913342
references.citation: Ann N Y Acad Sci. 1994 Sep 15;733:138-46
references.pmid: 7978861
references.citation: Cell Signal. 2009 Sep;21(9):1396-414
references.pmid: 19426801
references.citation: PLoS One. 2013 Apr 29;8(4):e62304
references.pmid: 23638030
references.citation: Biochem Biophys Res Commun. 2011 Jan 14;404(2):735-42
references.pmid: 21163253
references.citation: Surg Oncol Clin N Am. 2013 Apr;22(2):345-55
references.pmid: 23453339
references.citation: Clin Cancer Res. 2007 Jul 15;13(14):4191-200
references.pmid: 17634548
references.citation: Science. 1998 Oct 23;282(5389):737-40
references.pmid: 9784130
references.citation: Endocr Pathol. 2007 Summer;18(2):79-85
references.pmid: 17916997
references.citation: Cancer Cell Int. 2009 Jun 26;9:17
references.pmid: 19555512
references.citation: Trends Immunol. 2008 Jun;29(6):295-301
references.pmid: 18456553
references.citation: N Engl J Med. 2005 Oct 13;353(15):1591-603
references.pmid: 16221782
references.citation: Nat Rev Drug Discov. 2003 Dec;2(12):999-1017
references.pmid: 14654798
references.citation: PLoS One. 2014 Jan 23;9(1):e86671
references.pmid: 24466195
references.citation: Front Neuroendocrinol. 1999 Jul;20(3):157-98
references.pmid: 10433861
references.citation: Immunol Rev. 1998 Feb;161:55-70
references.pmid: 9553764
references.citation: Stem Cells. 2011 Mar;29(3):389-96
references.pmid: 21425402
references.citation: J Biol Chem. 2002 Aug 16;277(33):30079-90
references.pmid: 12034717
references.citation: Clin Cancer Res. 2001 Jul;7(7):2031-40
references.pmid: 11448921
references.citation: Eur J Nucl Med. 2001 Jul;28(7):836-46
references.pmid: 11504080
references.citation: J Biol Chem. 2007 Mar 30;282(13):10117-10131
references.pmid: 17287217
references.citation: Respiration. 2012;83(6):481-93
references.pmid: 22710421
references.citation: Biopolymers. 2002;66(3):161-83
references.pmid: 12385036
references.citation: Cancer Res. 2005 Aug 1;65(15):6950-6
references.pmid: 16061680
references.citation: Semin Oncol. 2002 Feb;29(1):18-25
references.pmid: 11836665
references.citation: Clin Chest Med. 2013 Mar;34(1):99-111
references.pmid: 23411061
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4350-5
references.pmid: 9539740
references.citation: Cell Oncol. 2008;30(6):473-82
references.pmid: 18936524
references.citation: J Biol Chem. 1989 Feb 25;264(6):3596-601
references.pmid: 2563382
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14186-91
references.pmid: 15353589
references.citation: J Biol Chem. 1979 Oct 25;254(20):9982-5
references.pmid: 489616
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12138-43
references.pmid: 11593028
references.citation: Curr Opin Pulm Med. 2012 Jul;18(4):377-81
references.pmid: 22617814
references.citation: Front Biosci. 2008 Jan 01;13:1634-45
references.pmid: 17981655
references.citation: Oncol Rep. 2011 Dec;26(6):1369-75
references.pmid: 21894438