Laboratory of Molecular Neurooncology, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, Zurich, Switzerland.
Clin Cancer Res. 2010 Aug 1;16(15):3851-9. doi: 10.1158/1078-0432.CCR-10-0705. Epub 2010 Jun 9.
Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-beta family. GDF-15 is necessary for the maintenance of pregnancy but has also been linked to other physiologic and pathologic conditions.
The expression of GDF-15 in glioma cell lines was assessed by quantitative reverse transcriptase-PCR and immunoblot. GDF-15 levels in situ and in the peripheral blood of glioma patients were examined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The effects of short hairpin RNA-mediated GDF-15 inhibition on proliferation and immunogenicity of SMA-560 glioma cells were investigated by [methyl-(3)H]thymidine incorporation and immune-mediated target cell lysis. The impact of GDF-15 on glioma growth in vivo was assessed in syngeneic mice.
GDF-15 is expressed by gliomas of different WHO grades as assessed by immunohistochemistry. The high expression of GDF-15 in tumor tissue translates into elevated GDF-15 serum levels in glioblastoma patients compared with healthy controls. GDF-15 mRNA and protein are also detectable in human and mouse glioma cells in vitro. Silencing of GDF-15 by RNA interference reduces the proliferation of malignant glioma cells. Immunologically, the depletion of glioma-derived GDF-15 enhances the susceptibility of mouse glioma cells towards syngeneic natural killer cells and splenocytes. This results in a reduced in vivo tumorigenicity and increased T-cell infiltration of GDF-15-deficient glioma cells in syngeneic mice.
Although previous studies focusing on ectopic overexpression of GDF-15 have proposed unclear or antitumorigenic effects of GDF-15 in glioma cells, we here show that GDF-15 at endogenous levels contributes to proliferation and immune escape of malignant gliomas in an immunocompetent host.
生长分化因子 15（GDF-15）是转化生长因子-β（TGF-β）家族的成员。GDF-15 是维持妊娠所必需的，但也与其他生理和病理状况有关。
通过定量逆转录酶-PCR 和免疫印迹评估 GDF-15 在神经胶质瘤细胞系中的表达。通过免疫组织化学和酶联免疫吸附试验分别检测 GDF-15 在神经胶质瘤患者原位和外周血中的水平。通过[甲基-(3)H]胸腺嘧啶掺入和免疫介导的靶细胞裂解研究短发夹 RNA 介导的 GDF-15 抑制对 SMA-560 神经胶质瘤细胞增殖和免疫原性的影响。通过在同种异体小鼠中评估 GDF-15 对体内神经胶质瘤生长的影响。
免疫组化评估显示，不同 WHO 分级的神经胶质瘤均表达 GDF-15。与健康对照组相比，胶质母细胞瘤患者肿瘤组织中 GDF-15 的高表达转化为血清 GDF-15 水平升高。体外还可检测到人源和鼠源神经胶质瘤细胞中的 GDF-15 mRNA 和蛋白。RNA 干扰沉默 GDF-15 可减少恶性神经胶质瘤细胞的增殖。免疫方面，耗尽胶质瘤来源的 GDF-15 可增强小鼠神经胶质瘤细胞对同种自然杀伤细胞和脾细胞的敏感性。这导致 GDF-15 缺陷型神经胶质瘤细胞在同种异体小鼠体内的致瘤性降低和 T 细胞浸润增加。
尽管之前的研究集中于 GDF-15 的异位过表达，但提出了 GDF-15 在神经胶质瘤细胞中作用不明确或具有抗肿瘤作用，我们在此表明，内源性水平的 GDF-15 有助于免疫活性宿主中恶性神经胶质瘤的增殖和免疫逃逸。
