The importance of the interaction of myeloma cells with bone marrow microenvironment has recently been recognized. Myeloma cells were found to interact with bone marrow stromal cells, osteoblasts, osteoclast precursors, and osteoclasts to trigger disease progression, and this knowledge is likely to be transferred into novel and, one hopes, more effective treatment strategies. Another important interaction of myeloma cells concerns bone marrow endothelial cells.FIG1
Folkman introduced the concept of angiogenesis in solid tumors 3 decades ago.1 Vacca et al were the first to show that bone marrow angiogenesis is increased in active compared with nonactive multiple myeloma.2 Recently, angiogenesis has been shown to be increased in a large variety of hematologic malignancies. Among them, myeloma was the first malignancy in which increased bone marrow angiogenesis was shown to be an independent prognostic factor for survival by Rajkumar et al3 and our group.4 This research field was also inspired by the work of Barlogie's group showing that thalidomide induces remissions in refractory myeloma patients, which was an important milestone in the treatment of multiple myeloma, even though this drug also has other properties besides its antiangiogenic action.5
In this issue of Blood, Vacca and colleagues (page ) provide new insights into the role of endothelial cells in multiple myeloma. The authors studied a variety of biologic features of endothelial cells extracted from bone marrow of patients with active multiple myeloma (MMECs) and compared these results with biologic features of human umbilical vein endothelial cells (HUVECs) as a model of normal quiescent endothelial cells. Genetic, phenotypic, functional, and ultrastructural features of endothelial cells are described. Vacca et al show that MMECs exist in subsets, secrete growth and invasive factors for myeloma cells, and can be inhibited by thalidomide. These results expand our understanding of the biology of MMECs and of the possible paracrine and cell-to-cell interactions of endothelial and myeloma cells.
Where do we go from here? Myeloma cells secrete a variety of angiogenic cytokines and activate multiple pathways to induce angiogenesis. Furthermore, different subsets of MMECs were found in the present study by Vacca et al. These results are consistent with the suggestion that the inhibition of a single signaling pathway in this complex system may be overcome by the activation of alternative pathways, and an appropriate combination of inhibitors may be necessary to achieve the desired goals in the treatment of multiple myeloma.
