We have investigated the interaction between tumor cells and specific cells in their microenvironment using myeloma as a model. The role of myeloma-induced osteoclastogenesis in the disease was studied ex vivo. Myeloma plasma cells freshly purified from patients' bone marrow attracted committed osteoclast (OC) precursors (n = 9; P < 0.01) and in 22 experiments directly induced their differentiation to multinucleated, bone-resorbing OCs (P < 0.00002) in a receptor activator of nuclear factor-kappaB ligand-mediated mechanism that was inhibited by the receptor activator of nuclear factor-kappaB (RANK-Fc) in 13 experiments by 71 +/- 12% (P < 0.008). In contrast, myeloma cells did not induce differentiation of peripheral blood mononuclear cells. Myeloma plasma cells cocultured with OCs retained their viability and proliferative activity for >13 weeks. After 14 days in coculture, the plasma cells from 29 patients had higher viability (P < 2 x 10(-6)), fewer apoptotic cells (P < 4 x 10(-15)), and a higher bromodeoxyuridine labeling index (P < 0.0006) than controls. Physical contact between OCs and myeloma cells was required for these effects to take place. No differences were observed between OCs from healthy donors and those from myeloma patients. Blocking interleukin 6 activity, while reducing survival of myeloma cells, had no effect on their proliferative activity. These results support data obtained from animal models and clinical observations on the essential role of the microenvironment in tumor sustenance and progression.