Background: Multiple Myeloma (MM) is a chronic relapsing malignancy of plasma cells. The introduction of the highly effective proteasome inhibitor, bortezomib, has led to a significant improvement in patients’ survival, however some patients fail to respond, or progress very shortly after completing therapy. Previous studies performed in solid tumors demonstrated that chemotherapy promotes host-driven pro-tumorigenic effects by means of increased angiogenesis and tumor cell invasion. Such host effects lead to the acceleration of tumor outgrowth in preclinical models. However, the impact of cytostatic targeted drugs, such as bortezomib on the reactive host, and the importance of these host-induced responses in hematological malignancies, has not been elucidated.
Methods: Plasma from non-tumor and MM bearing mice was obtained and further evaluated for angiogenesis, migration, invasion and proliferation of endothelial and MM cells, using several in-vitro assays. Furthermore, mice bearing CAG-MM cells were assessed for tumor expansion in the presence of bortezomib therapy.
Results: Plasma obtained from non-tumor bearing mice after being treated with bortezomib, significantly increased migration, invasion and proliferation of MM cells, compared with plasma from non-bortezomib exposed mice. Furthermore, mice treated with bortezomib exhibited an increased number of circulating endothelial cells and hemangiocytes compared with vehicle treated mice. In terms of MM outgrowth, mice primed with bortezomib and subsequently intravenously injected with CAG MM cells revealed extended bone-marrow involvement compared with mice treated with vehicle. MM growth effects were profoundly demonstrated in the mice treated with bortezomib 4 hours before MM cell inoculation.
Conclusions: The presented results suggest that bortezomib induces host effects, which in turn promote MM outgrowth by means of increased angiogenesis, MM cell invasion, and bone-marrow involvement. These results may explain, at least in part, the contribution of the host to the development of bortezomib-resistance MM cells in a substantial number of MM patients.
