Department of Neurosurgery, Philipps University Marburg, Baldingerstrasse, D-35033 Marburg, Germany.
Department of Diagnostic and Interventional Radiology, Philipps University Marburg, Baldingerstrasse, D-35033 Marburg, Germany.
Biol Chem. 2020 Sep 11;402(2):195-206. doi: 10.1515/hsz-2020-0184. Print 2021 Jan 27.
Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer with a median survival of only 15 months. To complement standard treatments including surgery, radiation and chemotherapy, it is essential to understand the contribution of the GBM tumor microenvironment. Brain macrophages and microglia particularly contribute to tumor angiogenesis, a major hallmark of GBM. , a metalloprotease-disintegrin strongly expressed in tumor cells and associated immune cells of GBMs, is related to angiogenesis and correlates with poor clinical prognosis. However, the specific contribution of to GBM tumorigenesis remains elusive. Knockdown of in U87 glioma cells led to significantly decreased angiogenesis and tumor volumes of these cells after stereotactic injection into striate body of mice. We found that the angiogenic potential of in GBM cells and in primary macrophages is mediated by the regulation of osteopontin (OPN), an important inducer of tumor angiogenesis. By cell signaling analyses, we demonstrate that regulates OPN via JAK/STAT3 pathway in U87 cells and in primary macrophages. As is a dispensable protease for physiological homeostasis, we conclude that could be a tractable target to modulate angiogenesis in GBM with minor side-effects.
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑癌，中位生存期仅为 15 个月。为了补充手术、放疗和化疗等标准治疗方法，了解 GBM 肿瘤微环境的贡献至关重要。脑巨噬细胞和小胶质细胞特别有助于肿瘤血管生成，这是 GBM 的一个主要特征。ADAM17，一种在 GBM 肿瘤细胞及其相关免疫细胞中强烈表达的金属蛋白酶-解整合素，与血管生成有关，并与不良的临床预后相关。然而，ADAM17 对 GBM 肿瘤发生的具体贡献仍不清楚。在 U87 神经胶质瘤细胞中敲低 ADAM17 后，这些细胞在立体定向注射到纹状体后，血管生成和肿瘤体积明显减少。我们发现 ADAM17 在 GBM 细胞和原代巨噬细胞中的血管生成潜能是通过调节骨桥蛋白（OPN）介导的，OPN 是肿瘤血管生成的重要诱导剂。通过细胞信号分析，我们证明 ADAM17 通过 JAK/STAT3 通路在 U87 细胞和原代巨噬细胞中调节 OPN。由于 ADAM17 对于生理稳态不是必需的蛋白酶，我们得出结论，ADAM17 可以作为一个可行的靶点，通过最小的副作用来调节 GBM 的血管生成。
