Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas.
BACKGROUND
Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines.


METHODS
We analysed expression of NGF, BDNF, and their receptors (Trk, p75(NTR)) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75(NTR) axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies.


RESULTS
A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75(NTR), TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75(NTR) was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model.


CONCLUSIONS
This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups.
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Lydie
L
Dubanet
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Hafidha
H
Bentayeb
Laboratoire d'Anatomie-Pathologique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.
Barbara
B
Petit
Structure Régionale de Référence des Lymphomes du Limousin, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.|Service d'Hématologie Clinique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.
Agnès
A
Olivrie
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Sofiane
S
Saada
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Miguel A
MA
de la Cruz-Morcillo
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Fabrice
F
Lalloué
Structure Régionale de Référence des Lymphomes du Limousin, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.|Service d'Hématologie Clinique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.
Marie-Pierre
MP
Gourin
Structure Régionale de Référence des Lymphomes du Limousin, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.|Service d'Hématologie Clinique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.|UMR CNRS 7276, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland 87025, Limoges Cedex, France.
Dominique
D
Bordessoule
UMR CNRS 7276, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland 87025, Limoges Cedex, France.
Nathalie
N
Faumont
Laboratoire d'Anatomie-Pathologique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.
Manuela
M
Delage-Corre
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Anne-Laure
AL
Fauchais
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Marie-Odile
MO
Jauberteau
EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
Danielle
D
Troutaud
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001706:Biopsy; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D000069283:Rituximab / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009419:Nerve Tissue Proteins; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor; D000069283:Rituximab; D042461:Vascular Endothelial Growth Factor A; D000099183:Sortilin; C484065:NGFR protein, human; C049985:staurosporine aglycone