title: Bortezomib-induced pro-inflammatory macrophages as a potential factor limiting anti-tumour efficacy.
abstract: Multiple myeloma (MM) is a chronic progressive malignancy of plasma cells. Although treatment with the novel proteasome inhibitor, bortezomib, significantly improves patient survival, some patients fail to respond due to the development of de novo resistance. We have previously shown that cytotoxic drugs can induce pro-tumorigenic host-mediated effects which contribute to tumour re-growth and metastasis, and thus limit anti-tumour efficacy. However, such effects and their impact on tumour cell aggressiveness have not been investigated using cytostatic agents such as bortezomib. Here we show that plasma from bortezomib-treated mice significantly increases migration, viability and proliferation of MM cells in vitro, compared to plasma from vehicle treated mice. In vivo, bortezomib induces the mobilization of pro-angiogenic bone marrow cells. Furthermore, mice treated with bortezomib and subsequently were used as recipients for an injection of MM cells succumb to MM earlier than mice treated with the vehicle. We show that bortezomib promotes pro-inflammatory macrophages which account for MM cell aggressiveness, an effect which is partially mediated by interleukin-16. Accordingly, co-inoculation of MM cells with pro-inflammatory macrophages from bortezomib-treated mice accelerates MM disease progression. Taken together, our results suggest that, in addition to the known effective anti-tumour activity of bortezomib, host-driven pro-tumorigenic effects generated in response to treatment can promote MM aggressiveness, and thus may contribute to the overall limited efficacy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.|Department of Haematology and BMT, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ofrat
authors.initials: O
authors.lastname: Beyar-Katz
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Magidey
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ben-Tsedek
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Alishekevitz
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Timaner
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Valeria
authors.initials: V
authors.lastname: Miller
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Moshit
authors.initials: M
authors.lastname: Lindzen
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.affiliation: Department of Haematology and BMT, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Avivi
authors.affiliation: Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
mesh_terms: D043925:Angiogenesis Inducing Agents; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D000069286:Bortezomib / Q000009:adverse effects / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D019410:Interleukin-16 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010950:Plasma Cells / Q000187:drug effects / Q000473:pathology; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D019410:Interleukin-16; D061988:Proteasome Inhibitors; D000069286:Bortezomib
keywords: bone marrow cells; cytokines; cytostatic drugs; haematological malignancies; macrophages; multiple myeloma