title: P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment.
abstract: Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in the pathogenesis of MM and in the development of drug resistance by MM cells. Selectins are involved in extravasation and homing of leukocytes to target organs. In the present study, we focused on adhesion dynamics that involve P-selectin glycoprotein ligand-1 (PSGL-1) on MM cells and its interaction with selectins in the BM microenvironment. We show that PSGL-1 is highly expressed on MM cells and regulates the adhesion and homing of MM cells to cells in the BM microenvironment in vitro and in vivo. This interaction involves both endothelial cells and BM stromal cells. Using loss-of-function studies and the small-molecule pan-selectin inhibitor GMI-1070, we show that PSGL-1 regulates the activation of integrins and downstream signaling. We also document that this interaction regulates MM-cell proliferation in coculture with BM microenvironmental cells and the development of drug resistance. Furthermore, inhibiting this interaction with GMI-1070 enhances the sensitization of MM cells to bortezomib in vitro and in vivo. These data highlight the critical contribution of PSGL-1 to the regulation of growth, dissemination, and drug resistance in MM in the context of the BM microenvironment.
authors.affiliation: Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Phong
authors.initials: P
authors.lastname: Quang
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Costas
authors.initials: C
authors.lastname: Pitsillides
authors.forename: Brian
authors.initials: B
authors.lastname: Thompson
authors.forename: Triona
authors.initials: T
authors.lastname: Chonghaile
authors.forename: John T
authors.initials: JT
authors.lastname: Patton
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Val
authors.initials: V
authors.lastname: Monrose
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Ludmila M
authors.initials: LM
authors.lastname: Flores
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.forename: John L
authors.initials: JL
authors.lastname: Magnani
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.forename: Ruben
authors.initials: R
authors.lastname: Carrasco
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006017:Glycolipids / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D006017:Glycolipids; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; C553182:rivipansel
references.citation: Cell Adh Migr. 2008 Jul-Sep;2(3):151-2
references.pmid: 19262108
references.citation: Bioorg Med Chem Lett. 2001 Jan 22;11(2):151-5
references.pmid: 11206447
references.citation: J Exp Med. 2003 May 19;197(10):1355-63
references.pmid: 12756271
references.citation: Cancer Res. 2007 Apr 1;67(7):2982-9
references.pmid: 17409404
references.citation: J Med Chem. 1999 Nov 18;42(23):4909-13
references.pmid: 10579852
references.citation: Ann N Y Acad Sci. 2004 Dec;1028:390-9
references.pmid: 15650264
references.citation: Blood. 2005 Sep 15;106(6):1901-10
references.pmid: 15890683
references.citation: Blood. 1998 Jan 1;91(1):154-64
references.pmid: 9414280
references.citation: J Med Chem. 2006 Oct 5;49(20):5988-99
references.pmid: 17004713
references.citation: Med Res Rev. 2002 Nov;22(6):566-601
references.pmid: 12369089
references.citation: Blood. 2009 Apr 30;113(18):4341-51
references.pmid: 19139079
references.citation: Arch Dermatol Res. 2006 Feb;297(8):345-51
references.pmid: 16362415
references.citation: Drug News Perspect. 2004 Nov;17(9):579-86
references.pmid: 15645015
references.citation: Lancet Oncol. 2005 Aug;6(8):632
references.pmid: 16054576
references.citation: Bioorg Med Chem Lett. 2001 Apr 9;11(7):923-5
references.pmid: 11294392
references.citation: J Am Chem Soc. 2001 Oct 17;123(41):10113-4
references.pmid: 11592897
references.citation: Glycobiology. 2010 Sep;20(9):1170-85
references.pmid: 20507883
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2193-8
references.pmid: 11854515
references.citation: Nature. 2005 Jun 16;435(7044):969-73
references.pmid: 15959517
references.citation: Acta Histochem. 2010;112(1):3-25
references.pmid: 19162308
references.citation: Blood. 2005 Oct 1;106(7):2276-9
references.pmid: 15961515
references.citation: Annu Rev Biomed Eng. 2009;11:177-202
references.pmid: 19413512
references.citation: J Med Chem. 2005 Jun 30;48(13):4346-57
references.pmid: 15974587
references.citation: Pulm Pharmacol Ther. 2006;19(4):233-41
references.pmid: 16140027
references.citation: Blood. 2009 Jul 16;114(3):619-29
references.pmid: 19443661
references.citation: Blood. 1999 Mar 1;93(5):1658-67
references.pmid: 10029595
references.citation: N Engl J Med. 1996 Jul 4;335(1):43-5
references.pmid: 8637541
references.citation: Inflamm Allergy Drug Targets. 2008 Jun;7(2):85-93
references.pmid: 18691137
references.citation: Mol Cancer Ther. 2002 May;1(7):539-44
references.pmid: 12479272
references.citation: Blood. 2007 Apr 1;109(7):2708-17
references.pmid: 17119115
references.citation: Curr Cancer Drug Targets. 2009 Aug;9(5):617-25
references.pmid: 19508173
references.citation: J Clin Invest. 1993 Feb;91(2):379-87
references.pmid: 7679406
references.citation: Expert Opin Biol Ther. 2010 Jun;10(6):863-73
references.pmid: 20367529
references.citation: News Physiol Sci. 2004 Feb;19:16-21
references.pmid: 14739398
references.citation: J Clin Invest. 2002 Apr;109(7):939-50
references.pmid: 11927621
references.citation: Science. 1996 Apr 5;272(5258):60-6
references.pmid: 8600538
references.citation: PLoS Pathog. 2010 Nov 04;6(11):e1001174
references.pmid: 21079683