Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation
Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation
复制标题
DOI：
10.1158/2159-8290.cd-14-0096
复制
发表时间：
2014-12-01
期刊：
影响因子：
28.2
通讯作者：
Hoepken, Uta E.
中科院分区：
文献类型：
--
作者：
Heinig, Kristina;Gaetjen, Marcel;Hoepken, Uta E.
在人类慢性淋巴细胞白血病（CLL）发病机制中，B细胞抗原受体信号传导似乎对白血病B细胞个体发育很重要，而微环境影响B细胞活化、肿瘤细胞沉积和抗原刺激的提供。使用小鼠E mu-Tcl 1 CLL模型，我们证明了CXCR 5控制的滤泡树突状细胞的访问赋予白血病B细胞的增殖刺激。活体成像显示边缘带B细胞样白血病细胞运输途径。小鼠和人CLL细胞通过光敏素-β-受体激活间接刺激驻留的间充质基质细胞，导致CXCL 13分泌和基质室重塑。抑制光敏素/光敏素-β-受体信号传导或CXCR 5信号传导可延缓白血病进展。因此，CXCR 5活性链接肿瘤细胞归巢，形成一个生存的小生境，并获得本地化的增殖stimulation.Significance：CLL和其他惰性淋巴瘤是不可治愈的，通常治疗后复发，在这个过程中，肿瘤微环境起着至关重要的作用。我们剖析了CXCR 5依赖性肿瘤细胞倒伏和LT β R依赖性基质-白血病细胞相互作用的连续步骤;此外，我们提供了治疗方案来干扰这种相互的肿瘤-基质串扰。(C)2014年AACR。
In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment influences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine E mu-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell trafficking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-beta-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-beta-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli.SIGNIFICANCE: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LT beta R-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk. (C) 2014 AACR.