Integrin alpha4beta1 involvement in stromal cell-derived factor-1alpha-promoted myeloma cell transendothelial migration and adhesion: role of cAMP and the actin cytoskeleton in adhesion.
The chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is expressed by bone marrow (BM) stromal cells and plays key roles in cell homing to and retention into the bone marrow. In multiple myeloma, blood-borne malignant plasma cells home to the BM and accumulate in contact with stromal cells, implicating myeloma cell migration across endothelium. Myeloma cells express the SDF-1alpha receptor CXCR4, as well as the integrin alpha4beta1, which mediates their attachment to BM stroma. We show here that SDF-1alpha promotes transendothelial migration of purified BM myeloma cells and myeloma-derived NCI-H929 cells, involving a transient upregulation of alpha4beta1-dependent cell adhesion to the endothelium. Characterization of intracellular signaling pathways involved in the modulation by SDF-1alpha of alpha4beta1-mediated myeloma cell adhesion revealed that intracellular cAMP amounts associated with the activation of protein kinase A play key roles in this modulation. Furthermore, a functional link between cAMP actions on the dynamics of actin cytoskeleton, RhoA activation, and alpha4beta1-dependent cell adhesion in response to SDF-1alpha has been found. The regulation of alpha4beta1-mediated myeloma cell adhesion by SDF-1alpha could play key roles during myeloma cell homing into and trafficking inside the BM, and characterization of the molecular events involved in SDF-1alpha-activated modulation of this adhesion will contribute to a better understanding of mechanisms participating in cell migration.
Parmo-Cabañas
Marisa
M
Centro de Investigaciones Biológicas, Department of Immunology, Madrid, Spain.
Bartolomé
Rubén A
RA
Wright
Natalia
N
Hidalgo
Andrés
A
Drager
Angelika M
AM
Teixidó
Joaquin
J
D008841:Actin Cytoskeleton / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019718:Receptors, CXCR4 / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039041:Integrin alpha4beta1; D019718:Receptors, CXCR4; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020742:rhoA GTP-Binding Protein