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首页> 外文期刊>British Journal of Cancer >Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas
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Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas

机译：神经营养蛋白在弥漫性大B细胞淋巴瘤中的抗凋亡作用及其临床意义

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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)on-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.
机译：背景：弥漫性大B细胞淋巴瘤（DLBCL）是一种致命的恶性肿瘤，需要确定新的靶点以寻求其他治疗选择。这项研究旨在阐明DLBCL活检样品和细胞系中内源性神经营养蛋白（神经生长因子（NGF）和脑源性神经营养因子（BDNF））的临床和生物学意义。方法：通过免疫组织化学，免疫荧光和免疫印迹分析51种活检和细胞系中NGF，BDNF及其受体（Trk，p75〜（NTR））的表达。为了研究BDNF / TrkB / p75〜（NTR）轴的生物学作用，确定了神经营养蛋白信号传导抑制对肿瘤细胞存活和血管内皮生长因子（VEGF）分泌的影响。药理性Pan-Trk抑制剂K252a用于体外和体内研究。结果：BDNF / TrkB轴均在所有活检组织中表达，与生发中心B细胞（GCB）/非GCB谱无关。 p75〜（NTR），TrkB和BDNF肿瘤评分显着相关，NGF高表达与MUM1 / IRF4和非GCB亚型显着相关。弥漫性大B细胞淋巴瘤细胞系共表达神经营养蛋白及其受体。在所有细胞系中均发现了全长TrkB受体，该受体也在Tyr-817处被磷酸化。 p75〜（NTR）与Trk有关，而与细胞死亡共受体sortilin无关。在体外，抑制神经营养蛋白信号传导诱导细胞凋亡。 K252a引起细胞凋亡，VEGF分泌减少和利妥昔单抗增强作用，特别是在对利妥昔单抗敏感的细胞中。在体内，K252a在GCB-DLBCL异种移植模型中显着降低了肿瘤的生长，并增强了利妥昔单抗的作用。结论：这项工作证明了内源性神经营养蛋白在DLBCLs中具有生存作用，而抑制Trk信号传导可能是利妥昔单抗耐药亚组的潜在治疗策略。

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