title: HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment.
abstract: Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy. Electronic address: enrica.borsi2@unibo.it.
authors.forename: Enrica
authors.initials: E
authors.lastname: Borsi
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Hematology Department, Via Venezian 1, 20133 Milano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Perrone
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Terragna
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Martello
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Zamagni
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Tacchetti
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pantani
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Brioli
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Angela Flores
authors.initials: AF
authors.lastname: Dico
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Beatrice Anna
authors.initials: BA
authors.lastname: Zannetti
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Rocchi
authors.affiliation: Department of Experimental Diagnostic and Specialty Medicine (DIMES), "L. & A. Seràgnoli", Bologna University School of Medicine, S. Orsola׳s University Hospital, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
mesh_terms: D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010950:Plasma Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: C533794:EZN 2968; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense
keywords: Cell adhesion; HIF-1α; MAPKs; Multiple myeloma; Tumor microenvironment