VE-cadherin and PECAM-1 enhance ALL migration across brain microvascular endothelial cell monolayers.
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.
Akers
Stephen M
SM
Cancer Cell Biology Program, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
O'Leary
Heather A
HA
Minnear
Fred L
FL
Craig
Michael D
MD
Vos
Jeffrey A
JA
Coad
James E
JE
Gibson
Laura F
LF
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
D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D015820:Cadherins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5
Ment Retard Dev Disabil Res Rev. 2006;12(3):184-91
17061287
Hematol Oncol Clin North Am. 2001 Feb;15(1):145-62
11253605
Folia Histochem Cytobiol. 2004;42(2):67-75
15253128
Pathol Oncol Res. 2003;9(3):147-58
14530807
Am J Physiol Gastrointest Liver Physiol. 2007 Aug;293(2):G446-52
17510197
Am J Physiol Cell Physiol. 2007 Oct;293(4):C1309-18
17670896
Nat Rev Neurosci. 2006 Jan;7(1):41-53
16371949
Tissue Antigens. 2000 Aug;56(2):105-16
11019910
J Exp Med. 1993 Aug 1;178(2):449-60
8340753
Blood. 2005 Aug 1;106(3):903-5
15831702
Methods. 2001 Dec;25(4):402-8
11846609
Exp Cell Res. 2005 Feb 1;303(1):101-13
15572031
J Immunol. 1999 Mar 1;162(5):3022-30
10072554
Clin Dev Immunol. 2008;2008:384982
18320011
Physiol Rev. 2004 Jul;84(3):869-901
15269339
FEBS Lett. 2006 Jul 24;580(17):4252-60
16828752
J Clin Oncol. 1989 Jul;7(7):900-3
2472471
Oncogene. 2003 May 19;22(20):3070-5
12789282
FASEB J. 2005 Nov;19(13):1872-4
16141364
N Engl J Med. 1998 Aug 27;339(9):605-15
9718381
Cancer Res. 2008 Mar 1;68(5):1388-97
18316602
Blood. 2006 Jul 15;108(2):465-72
16556888
Blood. 2004 Aug 15;104(4):1010-6
15126319
J Immunol. 2003 May 1;170(9):4497-505
12707326
J Biol Chem. 1993 Oct 25;268(30):22883-94
8226797
Cancer. 1977 Sep;40(3):1304-6
268999
Ment Retard Dev Disabil Res Rev. 2006;12(3):174-83
17061283
Brain Pathol. 1991 Jan;1(2):97-105
1669702
Blood. 2007 Nov 1;110(9):3334-44
17638851
Clin Cancer Res. 2003 Oct 15;9(13):4674-81
14581336
Trends Immunol. 2005 Sep;26(9):485-95
16039904
J Clin Invest. 1997 May 1;99(9):2139-51
9151786
Hematology Am Soc Hematol Educ Program. 2006;:142-6
17124053
Nat Rev Immunol. 2003 Jul;3(7):569-81
12876559
J Neurooncol. 1999 May;43(1):19-25
10448867