title: Endogenous neurotrophins and Trk signaling in diffuse large B cell lymphoma cell lines are involved in sensitivity to rituximab-induced apoptosis.
abstract: BACKGROUND
  Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL.
  
  
  RESULTS
  In the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75(NTR)/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab.
  
  
  CONCLUSIONS
  Collectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.
authors.affiliation: Université de Limoges, EA3842, Limoges, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bellanger
authors.forename: Lydie
authors.initials: L
authors.lastname: Dubanet
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Lise
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Fauchais
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Jauberteau
authors.forename: Danielle
authors.initials: D
authors.lastname: Troutaud
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab; D014407:Tumor Cells, Cultured
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; D000069283:Rituximab; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC
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