title: Immature dendritic cells from patients with multiple myeloma are prone to osteoclast differentiation in vitro.
abstract: OBJECTIVE
  Recent studies demonstrated that the interactions of immature dendritic cells (iDCs) with myeloma cells enhance the clonogenic capacity of tumor cells while iDCs undergo osteoclast (OC) transformation. Here, we investigated these interactions as well as iDC behavior in terms of both migration and OC differentiation.
  
  
  METHODS
  We studied 12 patients with multiple myeloma (MM) and 5 with monoclonal gammopathy of undetermined significance. Chemokine receptors, tumor-mediated chemotaxis, and a proliferation-inducing ligand (APRIL) expression were investigated in iDCs, whereas receptor activator of nuclear factor κB ligand (RANKL) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) levels were measured in primary plasma cells. Furthermore, cocultures of myeloma cells with autologous iDCs were installed to verify OC differentiation of these cells. Finally, the role of RANK/RANKL in such OC differentiation was investigated by inhibiting this molecular pathway.
  
  
  RESULTS
  Peripheral and marrow iDCs from MM showed high CXCR4 expression and were augmented in bone marrow of MM patients with respect to monoclonal gammopathy of undetermined significance. Also, iDCs expressed APRIL, whereas RANKL and TACI were upregulated by malignant cells. The cellular contact of myeloma cells with iDCs enhanced the clonogenic effect on tumor growth, whereas iDCs were directly primed to undergo OC transformation. These iDCs, indeed, exerted typical bone resorption that was abrogated by disabling the RANK/RANKL pathway signals. By contrast, plasma cells from monoclonal gammopathy of undetermined significance patients were ineffective in transforming autologous iDCs.
  
  
  CONCLUSIONS
  Our results emphasize the marrow cross-talk of iDCs with myeloma cells as an additional mechanism that upregulates osteoclastogenesis in MM, and suggest that such a RANKL-mediated OC differentiation of iDCs observed in vitro may also occur in vivo.
authors.affiliation: DIMO, Department of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Bari, Italy. m.tucci@dimo.uniba.it
authors.forename: Marco
authors.initials: M
authors.lastname: Tucci
authors.forename: Sabino
authors.initials: S
authors.lastname: Ciavarella
authors.forename: Sabino
authors.initials: S
authors.lastname: Strippoli
authors.forename: Oronzo
authors.initials: O
authors.lastname: Brunetti
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
authors.forename: Franco
authors.initials: F
authors.lastname: Silvestris
mesh_terms: D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000276:immunology* / Q000378:metabolism; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D053245:RANK Ligand; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; C108467:TNFRSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13