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

Exp Cell Res. 2004 Apr 1;294(2):571-80. doi: 10.1016/j.yexcr.2003.12.003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Bone Marrow Cells / metabolism*
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics*
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Endothelial Cells / metabolism
  • Humans
  • Integrin alpha4beta1 / metabolism*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / physiopathology
  • Receptors, CXCR4 / metabolism
  • Stromal Cells / metabolism*
  • Up-Regulation / genetics
  • rhoA GTP-Binding Protein / metabolism


  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Integrin alpha4beta1
  • Receptors, CXCR4
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • rhoA GTP-Binding Protein