title: Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways.
abstract: BACKGROUND
  There is increasing evidence that stromal cell interactions are required for the survival and drug resistance of several types of B-cell malignancies. There is relatively little information regarding the role of the bone marrow/lymphoid microenvironment in the pathogenesis of mantle cell lymphoma. In this study we investigated the interaction of primary mantle cell lymphoma cells with stromal cells in an ex vivo co-culture system.
  
  
  METHODS
  The murine stromal cell line MS-5 and human bone marrow mesenchymal stromal cells were each co-cultured with primary mantle cell lymphoma cells for up to 7 months. Mantle cell lymphoma cultures alone or combined with human stromal cells were analyzed for cell number, cell migration, nuclear factor-κB activation and drug resistance.
  
  
  RESULTS
  Co-culture of mantle cell lymphoma cells and human stromal cells results in the survival and proliferation of primary mantle cell lymphoma cells for at least 7 months compared to mantle cell lymphoma cells cultured alone. Mantle cell lymphoma-human stromal cell interactions resulted in activation of the B-cell activating factor/nuclear factor-κB signaling axis resulting in reduced apoptosis, increased mantle cell lymphoma migration and increased drug resistance.
  
  
  CONCLUSIONS
  Direct mantle cell lymphoma-human stromal cell interactions support long-term expansion and increase the drug-resistance of primary mantle cell lymphoma cells. This is due in part to activation of the canonical and non-canonical nuclear factor κB pathways. We also demonstrated the ability of B-cell activating factor to augment CXCL12- and CXCL13-induced cell migration. Collectively, these findings demonstrate that human stromal cell-mantle cell lymphoma interactions play a pivotal role in the pathogenesis of mantle cell lymphoma and that analysis of mantle cell lymphoma-human stromal cell interactions may help in the identification of novel targets for therapeutic use.
authors.affiliation: The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA. medinadj@umdnj.edu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Medina
authors.forename: Lauri
authors.initials: L
authors.lastname: Goodell
authors.forename: John
authors.initials: J
authors.lastname: Glod
authors.forename: Céline
authors.initials: C
authors.lastname: Gélinas
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Rabson
authors.forename: Roger K
authors.initials: RK
authors.lastname: Strair
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053264:B-Cell Activating Factor / Q000378:metabolism*; D002450:Cell Communication; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000378:metabolism; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D053264:B-Cell Activating Factor; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; D016328:NF-kappa B