Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment
Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment
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DOI：
10.1002/ijc.29376
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发表时间：
2015-07-01
影响因子：
6.4
通讯作者：
Heymann, Dominique
中科院分区：
文献类型：
--
作者：
Segaliny, Aude I.;Mohamadi, Amel;Heymann, Dominique
白细胞介素-34（IL-34）是近年来发现的一种M-CSF孪生细胞因子，调节骨髓细胞的增殖、分化和存活。最初怀疑M-CSF在肿瘤学中的意义是由于血管生成障碍导致基因敲除小鼠中转移性播散减少。在此基础上，我们研究了IL-34在骨肉瘤发病机制中的作用。在鼠临床前模型中评估了IL-34对组织血管和巨噬细胞浸润的体内作用，该模型基于对过度表达或不表达IL-34或M-CSF的人骨肉瘤细胞的并行接种。使用内皮细胞前体和成熟HUVEC细胞进行体外研究，以分析IL-34参与血管生成和骨髓细胞粘附。数据显示IL-34过表达与骨肉瘤的进展（肿瘤生长、肺转移）和新血管生成的增加相关。体外分析表明，IL-34刺激内皮细胞增殖和血管索形成。通过软骨素酶/肝素酶预处理内皮细胞减少了血管管的形成并消除了相关的细胞信号传导。此外，IL-34增加了M2肿瘤相关巨噬细胞在肿瘤组织中的体内募集。IL-34在体外增加单核细胞/CD 34（+）细胞在生理切应力条件下与活化的HUVEC单层的粘附。这项工作还表明，IL-34由骨肉瘤细胞表达，受TNF-α、IL-1的调节，并通过增加新血管生成和M2巨噬细胞的募集来促进骨肉瘤的生长。通过促进新血管形成和免疫细胞外渗，IL-34可能在肿瘤发展和炎性疾病中发挥关键作用。
Interleukin-34 (IL-34) was recently characterized as the M-CSF twin cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-, IL-1, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases.