Targeting of Adhesion Molecules as a Therapeutic Strategy in Multiple Myeloma
Nizar J. Bahlis.
Multiple myeloma (MM) is a clonal disorder of plasma cells that remains, for the most part, incurable despite
the advent of several novel therapeutic agents. Tumor cells in this disease are cradled within the bone marrow (BM)
microenvironment by an array of adhesive interactions between the BM cellular residents, the surrounding extracellular
matrix (ECM) components such as fibronectin (FN), laminin, vascular cell adhesion molecule-1 (VCAM-1),
proteoglycans, collagens and hyaluronan, and a variety of adhesion molecules on the surface of MM cells including
integrins, hyaluronan receptors (CD44 and RHAMM) and heparan sulfate proteoglycans. Several signaling responses are
activated by these interactions, affecting the survival, proliferation and migration of MM cells. An important consequence
of these direct adhesive interactions between the BM/ECM and MM cells is the development of drug resistance. This
phenomenon is termed ‘‘cell adhesion-mediated drug resistance’’ (CAM-DR) and it is thought to be one of the major
mechanisms by which MM cells escape the cytotoxic effects of therapeutic agents. This review will focus on the adhesion
molecules involved in the cross-talk between MM cells and components of the BM microenvironment. The complex
signaling networks downstream of these adhesive molecules mediated by direct ligand binding or inside-out soluble
factors signaling will also be reviewed. Finally, novel therapeutic strategies targeting these molecules will be discussed.
Identification of the mediators of MM-BM interaction is essential to understand MM biology and to elucidate novel
therapeutic targets for this disease.
Keywords: Adhesion, integrins, anti-adhesion agents, CAM-DR, microenvironment, multiple myeloma, Antibody-dependent cellular cytotoxicity, basic fibroblast growth factor, Fas-associated death domain-containing protein, Integrin linked kinase, Lymphocyte function-associated antigen 1, Monocyte chemoattractant protein 1, P-selectin Glycoprotein Ligand-1, Bone marrow microvascular density, Unfolded protein response.
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