Musumeci Giuseppe, Magro Gaetano, Cardile Venera, Coco Marinella, Marzagalli Rubina, Castrogiovanni Paola, Imbesi Rosa, Graziano Adriana Carol Eleonora, Barone Fabio, Di Rosa Michelino, Castorina Sergio, Castorina Alessandro
Department of Biomedical Sciences and Biotechnologies, Section of Human Anatomy and Histology, School of Medicine, University of Catania, Via S. Sofia 87, 95125, Catania, Italy.
Department G.F. Ingrassia, Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele", Section of Anatomic Pathology, University of Catania, Via S. Sofia 87, 95125, Catania, Italy.
Cell Tissue Res. 2015 Oct;362(1):45-60. doi: 10.1007/s00441-015-2197-5. Epub 2015 May 7.
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans, whose invasiveness and proliferation are associated with poor prognosis. Matrix metalloproteinases (MMPs) and the related family of "a disintegrin and metalloproteinase" (ADAM) both contribute to increase cell invasion, and its substrate N-cadherin is involved in proliferation and metastatic capacities of tumor cells. However, these molecular determinants of aggressiveness have not been adequately characterized in GBM. In an attempt to better define these pathogenetic signatures, in the present study we evaluated the comparative expression of two main MMPs (MMP-2 and -9), as well as of ADAM-10 and N-cadherin in surgical samples from patients diagnosed with WHO grade IV GBM (n = 25) and in cortical tissue specimens obtained from untreatable epileptic patients (controls, n = 8) through a series of histopathological, immunohistochemical and biochemical tests. Our studies revealed that both MMP-2 and -9 immunoreactivities (IRs) were upregulated in 13 of 25 (52 %) and 19 of 25 (76 %) GBMs, respectively, and the extent of the increase was highly significant with respect to controls (p < 0.001). ADAM-10 IR was also found to be increased (p < 0.001) in 16 of 25 GBM specimens (64 %). Conversely, N-cadherin IR was remarkably decreased (p < 0.001) in almost the totality of tumor samples (22 of 25, 88 %). A similar trend was also obtained at the mRNA and protein level by qPCR and western blot analyses, respectively. Collectively, the current study provides a comprehensive molecular portrayal of some of the major pathological hallmarks of GBM aggressiveness, which could be exploitable as potential targets for a new therapeutic approach.
多形性胶质母细胞瘤（GBM）是人类最常见且侵袭性最强的原发性恶性脑肿瘤，其侵袭性和增殖与预后不良相关。基质金属蛋白酶（MMPs）和相关的“去整合素和金属蛋白酶”（ADAM）家族均有助于增加细胞侵袭，且其底物N-钙黏蛋白参与肿瘤细胞的增殖和转移能力。然而，这些侵袭性的分子决定因素在GBM中尚未得到充分表征。为了更好地定义这些致病特征，在本研究中，我们通过一系列组织病理学、免疫组织化学和生化检测，评估了两种主要MMPs（MMP-2和-9）以及ADAM-10和N-钙黏蛋白在诊断为世界卫生组织IV级GBM的患者手术样本（n = 25）和从无法治疗的癫痫患者获得的皮质组织标本（对照组，n = 8）中的相对表达。我们的研究表明，MMP-2和-9免疫反应性（IRs）在25个GBM中的13个（52%）和19个（76%）中分别上调，且相对于对照组，增加程度具有高度显著性（p < 0.001）。在25个GBM标本中的16个（64%）中也发现ADAM-10 IR增加（p < 0.001）。相反，在几乎所有肿瘤样本（25个中的22个，88%）中，N-钙黏蛋白IR显著降低（p < 0.001）。通过qPCR和蛋白质印迹分析分别在mRNA和蛋白质水平也获得了类似趋势。总体而言，本研究提供了GBM侵袭性一些主要病理特征的全面分子描述，这可作为新治疗方法的潜在靶点加以利用。
