title: VE-cadherin and PECAM-1 enhance ALL migration across brain microvascular endothelial cell monolayers.
abstract: OBJECTIVE
  Infiltration of the central nervous system (CNS) by leukemia is a problematic disease manifestation of acute lymphoblastic leukemia (ALL). The mechanisms by which leukocytes interact with human brain-derived microvasculature endothelial cells (HBMEC) and enter the CNS are largely derived from models of inflammation. However, our data indicate that ALL cells do not elicit an inflammatory phenotype by HBMEC. Our current investigation focuses on the contribution of the unique coexpression of vascular endothelial (VE)-cadherin and platelet endothelial cell adhesion molecule-1 (PECAM-1) by ALL in mediating leukemic cell interactions with HBMEC as an in vitro model of the blood-brain barrier.
  
  
  METHODS
  Primary ALL and ALL cell lines were evaluated for VE-cadherin and PECAM-1 expression. Lentiviral-mediated transduction of VE-cadherin and PECAM-1 into REH cells and antibody neutralization of VE-cadherin and PECAM-1 in SUP-B15 cells was used to delineate the role of these two proteins in mediating ALL adhesion to, and migration through, HBMEC monolayers.
  
  
  RESULTS
  Although cell line models indicate that VE-cadherin and PECAM-1 expression is found on the surface Philadelphia chromosome-positive ALL, evaluation of primary ALL demonstrates that VE-cadherin and PECAM-1 are expressed independent of Philadelphia status. Expression of VE-cadherin and PECAM-1 by ALL enhanced the adhesion of ALL to HBMEC, while expression of PECAM-1 enhanced ALL adhesion to, and migration through, HBMEC.
  
  
  CONCLUSIONS
  Expression of VE-cadherin and PECAM-1 by ALL cells positions them to interact with HBMEC. By increasing our understanding of molecular mechanisms through which ALL cells gain entry into the CNS, new strategies may be designed to prevent leukemia cell entry into the CNS.
authors.affiliation: Cancer Cell Biology Program, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Akers
authors.forename: Heather A
authors.initials: HA
authors.lastname: O'Leary
authors.forename: Fred L
authors.initials: FL
authors.lastname: Minnear
authors.forename: Michael D
authors.initials: MD
authors.lastname: Craig
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Vos
authors.forename: James E
authors.initials: JE
authors.lastname: Coad
authors.forename: Laura F
authors.initials: LF
authors.lastname: Gibson
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016086:Lentivirus; D010677:Philadelphia Chromosome; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods; D000099152:Cadherin 5
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D015820:Cadherins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5
references.citation: Ment Retard Dev Disabil Res Rev. 2006;12(3):184-91
references.pmid: 17061287
references.citation: Hematol Oncol Clin North Am. 2001 Feb;15(1):145-62
references.pmid: 11253605
references.citation: Folia Histochem Cytobiol. 2004;42(2):67-75
references.pmid: 15253128
references.citation: Pathol Oncol Res. 2003;9(3):147-58
references.pmid: 14530807
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Aug;293(2):G446-52
references.pmid: 17510197
references.citation: Am J Physiol Cell Physiol. 2007 Oct;293(4):C1309-18
references.pmid: 17670896
references.citation: Nat Rev Neurosci. 2006 Jan;7(1):41-53
references.pmid: 16371949
references.citation: Tissue Antigens. 2000 Aug;56(2):105-16
references.pmid: 11019910
references.citation: J Exp Med. 1993 Aug 1;178(2):449-60
references.pmid: 8340753
references.citation: Blood. 2005 Aug 1;106(3):903-5
references.pmid: 15831702
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Exp Cell Res. 2005 Feb 1;303(1):101-13
references.pmid: 15572031
references.citation: J Immunol. 1999 Mar 1;162(5):3022-30
references.pmid: 10072554
references.citation: Clin Dev Immunol. 2008;2008:384982
references.pmid: 18320011
references.citation: Physiol Rev. 2004 Jul;84(3):869-901
references.pmid: 15269339
references.citation: FEBS Lett. 2006 Jul 24;580(17):4252-60
references.pmid: 16828752
references.citation: J Clin Oncol. 1989 Jul;7(7):900-3
references.pmid: 2472471
references.citation: Oncogene. 2003 May 19;22(20):3070-5
references.pmid: 12789282
references.citation: FASEB J. 2005 Nov;19(13):1872-4
references.pmid: 16141364
references.citation: N Engl J Med. 1998 Aug 27;339(9):605-15
references.pmid: 9718381
references.citation: Cancer Res. 2008 Mar 1;68(5):1388-97
references.pmid: 18316602
references.citation: Blood. 2006 Jul 15;108(2):465-72
references.pmid: 16556888
references.citation: Blood. 2004 Aug 15;104(4):1010-6
references.pmid: 15126319
references.citation: J Immunol. 2003 May 1;170(9):4497-505
references.pmid: 12707326
references.citation: J Biol Chem. 1993 Oct 25;268(30):22883-94
references.pmid: 8226797
references.citation: Cancer. 1977 Sep;40(3):1304-6
references.pmid: 268999
references.citation: Ment Retard Dev Disabil Res Rev. 2006;12(3):174-83
references.pmid: 17061283
references.citation: Brain Pathol. 1991 Jan;1(2):97-105
references.pmid: 1669702
references.citation: Blood. 2007 Nov 1;110(9):3334-44
references.pmid: 17638851
references.citation: Clin Cancer Res. 2003 Oct 15;9(13):4674-81
references.pmid: 14581336
references.citation: Trends Immunol. 2005 Sep;26(9):485-95
references.pmid: 16039904
references.citation: J Clin Invest. 1997 May 1;99(9):2139-51
references.pmid: 9151786
references.citation: Hematology Am Soc Hematol Educ Program. 2006;:142-6
references.pmid: 17124053
references.citation: Nat Rev Immunol. 2003 Jul;3(7):569-81
references.pmid: 12876559
references.citation: J Neurooncol. 1999 May;43(1):19-25
references.pmid: 10448867