Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.
Department of Biochemistry, University of Calgary, Calgary, AB, Canada.
Brain Pathol. 2021 Sep;31(5):e12947. doi: 10.1111/bpa.12947. Epub 2021 Mar 10.
Glioblastomas (GBMs) are highly aggressive, recurrent, and lethal brain tumors that are maintained via brain tumor-initiating cells (BTICs). The aggressiveness of BTICs may be dependent on the extracellular matrix (ECM) molecules that are highly enriched within the GBM microenvironment. Here, we investigated the expression of ECM molecules in GBM patients by mining the transcriptomic databases and also staining human GBM specimens. RNA levels for fibronectin, brevican, versican, heparan sulfate proteoglycan 2 (HSPG2), and several laminins were high in GBMs compared to normal brain, and this was corroborated by immunohistochemistry. While fibrinogen transcript was at normal level in GBM, its protein immunoreactivity was prominent within GBM tissues. These ECM molecules in tumor specimens were in proximity to, and surrounding BTICs. In culture, fibronectin and pan-laminin induced the adhesion of BTICs onto the plastic substratum. However, fibrinogen increased the size of the BTIC spheres by facilitating the adhesive property, motility, and invasiveness of BTICs. These features of elevated invasiveness were corroborated in resected GBM specimens by the close proximity of fibrinogen with matrix metalloproteinase (MMP)-2 and-9, which are proteases implicated in metastasis. Moreover, the effect of fibrinogen-induced invasiveness was attenuated in BTICs where MMP-2 and -9 have been inhibited with siRNAs or pharmacological inhibitors. Our results implicate fibrinogen in GBM as a mediator of the invasive properties of BTICs, and as a target for therapy to reduce BTIC tumorigenecity.
胶质母细胞瘤（GBM）是高度侵袭性、复发性和致命的脑肿瘤，由脑肿瘤起始细胞（BTIC）维持。BTIC 的侵袭性可能依赖于高度富集在 GBM 微环境中的细胞外基质（ECM）分子。在这里，我们通过挖掘转录组数据库和染色人类 GBM 标本来研究 GBM 患者中 ECM 分子的表达。与正常脑组织相比，纤维连接蛋白、短蛋白聚糖、 versican、硫酸乙酰肝素蛋白聚糖 2（HSPG2）和几种层粘连蛋白的 RNA 水平在 GBM 中较高，免疫组织化学也证实了这一点。虽然纤维蛋白原在 GBM 中的转录水平正常，但它的蛋白免疫反应性在 GBM 组织中很明显。肿瘤标本中的这些 ECM 分子与 BTIC 接近并环绕 BTIC。在培养中，纤维连接蛋白和泛层粘连蛋白诱导 BTIC 黏附在塑料基质上。然而，纤维蛋白原通过促进 BTIC 的黏附性、迁移性和侵袭性，增加了 BTIC 球体的大小。在切除的 GBM 标本中，纤维蛋白原与基质金属蛋白酶（MMP）-2 和 -9 的接近证实了这种侵袭性升高的特征，MMP-2 和 -9 是参与转移的蛋白酶。此外，用 siRNA 或药理学抑制剂抑制 MMP-2 和 -9 后，纤维蛋白原诱导的侵袭性的影响在 BTIC 中减弱。我们的研究结果表明，纤维蛋白原在 GBM 中作为 BTIC 侵袭性的介质，并作为减少 BTIC 致瘤性的治疗靶点。
