Abstract
Multiple myeloma (MM) is a hematologic cancer characterized by uncontrolled growth of malignant plasma cells in the bone marrow and currently is incurable. The bone marrow microenvironment plays a critical role in MM. MM cells reside in specialized niches where they interact with multiple marrow cell types, transforming the bone/bone marrow compartment into an ideal microenvironment for the migration, proliferation, and survival of MM cells. In addition, MM cells interact with bone cells to stimulate bone destruction and promote the development of bone lesions that rarely heal. In this review, we discuss how Notch signals facilitate the communication between adjacent MM cells and between MM cells and bone/bone marrow cells and shape the microenvironment to favor MM progression and bone disease. We also address the potential and therapeutic approaches used to target Notch signaling in MM.
Highlights
Multiple myeloma (MM) is a cancer that forms in the bone marrow due to the growth and accumulation of clonal, terminally differentiated B lymphocytes
Vegf-A knockdown in osteocytes completely blocked the increased endothelial activity induced by MM cells or hypoxia[80]. These results demonstrate that osteocytes are a source of Vegf-A, and potentially other pro-angiogenic factors, in bones infiltrated with MM cells
Notch signaling regulates Rankl expression in MM cells[98]. Supporting this notion, we recently found that genetic deletion of Notch receptors 2 and 3 in MM cells or treatment with GSI significantly decreases Rankl expression and impairs their ability to stimulate osteoclastogenesis[58], Rankl expression in MM cells is stimulated by stromal cells, an effect depending on Notch activation[98]
Summary
Multiple myeloma (MM) is a cancer that forms in the bone marrow due to the growth and accumulation of clonal, terminally differentiated B lymphocytes. Notch signals may contribute to the development of resistance to mitoxantrone as inhibition of Notch signaling with GSI overcame the drug resistance to mitoxantrone induced by stromal cells[50] In this case the ligandreceptor requirements were not evaluated, this effect appeared to be mediated by the transcriptional activity of the Notch target gene Hes1[49]. Notch signaling regulates Rankl expression in MM cells[98] Supporting this notion, we recently found that genetic deletion of Notch receptors 2 and 3 in MM cells or treatment with GSI significantly decreases Rankl expression and impairs their ability to stimulate osteoclastogenesis[58], Rankl expression in MM cells is stimulated by stromal cells, an effect depending on Notch activation[98]. Ongoing pharmacokinetic and pharmacodynamics studies, as well as a full assessment of the safety profile, should provide a better picture of the potential of this new approach for the clinic
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