Integrin α4β1 involvement in stromal cell-derived factor-1α-promoted myeloma cell transendothelial migration and adhesion: role of cAMP and the actin cytoskeleton in adhesion

Abstract

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.

Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells

“…CXCL12 is involved in several aspects of MM pathogenesis, including transendothelial migration, bone marrow retention of plasma cells, angiogenesis and osteoclastic bone resorption. [6][7][8][9][10][11] Based on previous studies showing that hypoxia regulates CXCL12 expression in other cell systems, [22][23][24][25][26] we examined the role of hypoxia in inducing aberrant CXCL12 expression in MM plasma cells. Given the limited number of primary MM plasma cells that can be recovered from MM patients and the difficulty associated with their in vitro culture, MM plasma cell lines were used in this study.…”

“…[3][4][5] CXCL12 is highly expressed by MM plasma cells, 6 and circulating levels of CXCL12 are higher in the peripheral blood of MM patients than in age-matched normal donors and MGUS patients. 6,7 CXCL12 is an important mediator of several aspects of MM biology including transendothelial migration, 8,9 MM plasma cell migration and retention within the bone marrow, 10,11 angiogenesis, 7 and osteoclastic bone resorption. 6 Recent animal studies involving systemic injection of labeled MM plasma cells have also demonstrated that blocking the CXCL12/CXCR4 axis leads to a 20% reduction in bone marrow tumor burden.…”

Apoptosis of Multiple Myeloma

“…This chemokine plays a major role in homing, because MM cells express the SDF-1α receptor, CXCR4 (Figure 3). Once in the BM, integrin α 4 B 1 (VLA-4) mediates attachment of MM cells to the stroma [58], and this process confers the cells a survival advantage. Adhesion of MM cells to fibronectin (FN) is known to protect the cells from druginduced apoptosis [23].…”

Solitary plasmacytoma and multiple myeloma: adhesion molecule and chemokine receptor expression patterns

“…Our study confirmed strong expression of CXCR4 on MM plasma cells but suggested reduced expression by SP plasma cells, which may make them chemotactically less susceptible to SDF-1. Binding of CXCR4 to SDF-1 is also thought to transiently upregulate a4b1 (VLA-4) surface expression (Sanz-Rodriguez et al, 2001;Parmo-Cabanas et al, 2004). The lack of this interaction in SP plasma cells may contribute to the reduced expression of a4 demonstrated here.…”