Role of the bone marrow microenvironment in multiple myeloma.
On June 26-27, 2001, the Sixth Research Roundtable in Multiple Myeloma, entitled "The Role of the Bone Microenvironment in Multiple Myeloma," was held and focused on the biology of cell-to-cell interactions, the mediators of bone disease, and novel treatment strategies for myeloma. Studies on cell-cell interactions showed that vascular cell adhesion molecule 1, expressed by local endothelial and stromal cells, binds to tumor cell surface integrins in which expression may be increased by tumor cell-derived chemokines such as macrophage inflammatory protein (MIP) 1alpha. These adhesive interactions increase production and release of vascular endothelial growth factor (VEGF). Studies on myeloma bone disease showed the ligand for receptor activator of nuclear transcription factor-kappaB (RANKL) was expressed on tumor cells and stromal cells associated with myeloma cells and was critical for osteoclast-induced osteolysis. Blockade of RANKL suppressed osteoclast maturation, bone resorption, and tumor development. Bisphosphonates, in addition to reducing osteoclast mobility and inducing osteoclast apoptosis, also decreased tumor cell adhesion to stroma. Immunomodulatory drugs such as thalidomide analogues targeted these tumor cell-stromal cell interactions, blocking both secretion of cytokines and activation of intracellular signaling pathways required for tumor survival and growth. These agents induced tumor cell apoptosis, decreased neovascularization, and potentiated natural killer cell activity. The proteasome inhibitor PS-341 also prevented expression of adhesion molecules and cytokines and triggered tumor cell apoptosis, even in drug-resistant cell lines, while showing minimal activity in healthy cells. In addition, potential therapeutic agents under investigation, which included RANKL antagonists, protein prenylation inhibitors, and osteoblast growth factors, were discussed.
Roodman
G David
GD
Center for Bone Biology, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pennsylvania 15261, USA.
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D016228:Endothelial Growth Factors / Q000378:metabolism; D006023:Glycoproteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010014:Osteolysis / Q000209:etiology; D053244:Osteoprotegerin; D011480:Protease Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000276:Adjuvants, Immunologic; D001897:Boronic Acids; D002352:Carrier Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004164:Diphosphonates; D016228:Endothelial Growth Factors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D011480:Protease Inhibitors; D011719:Pyrazines; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000069286:Bortezomib