title: N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation.
abstract: BACKGROUND
  Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma.
  
  
  METHODS
  Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation.
  
  
  RESULTS
  The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis.
  
  
  CONCLUSIONS
  Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.forename: Martin F M
authors.initials: MF
authors.lastname: de Rooij
authors.forename: Kinga A
authors.initials: KA
authors.lastname: Kocemba
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Reijmers
authors.forename: Anneke
authors.initials: A
authors.lastname: de Haan-Kramer
authors.forename: Marije B
authors.initials: MB
authors.lastname: Overdijk
authors.forename: Linda
authors.initials: L
authors.lastname: Aalders
authors.forename: Henk
authors.initials: H
authors.lastname: Rozemuller
authors.forename: Anton C M
authors.initials: AC
authors.lastname: Martens
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Kersten
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
mesh_terms: D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002450:Cell Communication; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D015820:Cadherins; D009363:Neoplasm Proteins