Navone Stefania Elena, Guarnaccia Laura, Cordiglieri Chiara, Crisà Francesco Maria, Caroli Manuela, Locatelli Marco, Schisano Luigi, Rampini Paolo, Miozzo Monica, La Verde Nicla, Riboni Laura, Campanella Rolando, Marfia Giovanni
Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
World Neurosurg. 2018 Dec;120:e380-e391. doi: 10.1016/j.wneu.2018.08.080. Epub 2018 Aug 23.
Glioblastoma (GBM) is the most common and fatal human brain tumor, with the worst prognosis. The aberrant microenvironment, enhanced by the activation of proangiogenic mediators such as hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and their downstream effectors, sustain GBM malignancy. Proangiogenic signaling represents an attractive chemotherapeutic target. Recent evidence suggests a therapeutic benefit from aspirin (acetylsalicylic acid, or ASA) intake in reducing risk and cancer progression.
In the present study, human primary GBM-endothelial cells (ECs) were used to ascertain whether ASA could inhibit angiogenesis and improve cell sensitivity to drugs. The impact of ASA was observed by measuring cell viability, tube-like structure formation, migration, VEGF production, and proliferative, proangiogenic, and apoptotic modulators expression, such as HIF-1α/VEGF/vascular endothelial growth factor receptor/(VEGFR)-1/VEGFR-2, Ras/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/AKT signaling axis, and Bcl-2-associated X protein/B-cell lymphoma 2 (BCL-2) ratio. Furthermore, we evaluated the effect of ASA alone or in combination with temozolomide (TMZ), bevacizumab (BEV), and sunitinib (SUN).
Our data reported that ASA affected GBM-EC viability, tube-like structure formation, cell migration, and VEGF releasing in a dose-dependent manner and that combined treatments with TMZ, BEV, and SUN synergized to counteract proangiogenic cell ability. mRNA expression analysis displayed a marked effect of ASA in reducing VEGF, VEGFR-1, HIF-1α, RAS, mitogen-activated protein kinase kinase, AKT, and BCL-2, as well a combined anticancer effect of ASA together with TMZ, BEV, and SUN. Levels of HIF-1α, VEGFR-2, Bcl-2-associated X protein, and BCL-2 protein expression confirmed a positive trend.
ASA and antiangiogenic therapies showed synergetic anticancer efficacy in human primary GBM-ECs. Thus, the combination of conventional chemotherapy with ASA may offer a new strategy to counteract tumor malignancy.
胶质母细胞瘤（GBM）是最常见且致命的人类脑肿瘤，预后最差。由促血管生成介质如缺氧诱导因子-1α（HIF-1α）、血管内皮生长因子（VEGF）及其下游效应器激活所增强的异常微环境维持着GBM的恶性程度。促血管生成信号代表了一个有吸引力的化疗靶点。最近的证据表明，服用阿司匹林（乙酰水杨酸，或ASA）在降低风险和癌症进展方面具有治疗益处。
在本研究中，使用人原发性GBM内皮细胞（ECs）来确定ASA是否能抑制血管生成并提高细胞对药物的敏感性。通过测量细胞活力、管状结构形成、迁移、VEGF产生以及增殖、促血管生成和凋亡调节因子的表达，如HIF-1α/VEGF/血管内皮生长因子受体/（VEGFR）-1/VEGFR-2、Ras/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶、磷脂酰肌醇3-激酶/AKT信号轴以及Bcl-2相关X蛋白/B细胞淋巴瘤2（BCL-2）比值，观察ASA的影响。此外，我们评估了ASA单独或与替莫唑胺（TMZ）、贝伐单抗（BEV）和舒尼替尼（SUN）联合使用的效果。
我们的数据表明，ASA以剂量依赖的方式影响GBM-EC的活力、管状结构形成、细胞迁移和VEGF释放，并且与TMZ、BEV和SUN联合治疗协同抵消促血管生成细胞的能力。mRNA表达分析显示，ASA在降低VEGF、VEGFR-1、HIF-1α、RAS、丝裂原活化蛋白激酶激酶、AKT和BCL-2方面有显著作用，以及ASA与TMZ、BEV和SUN联合的抗癌作用。HIF-1α、VEGFR-2、Bcl-2相关X蛋白和BCL-2蛋白表达水平证实了积极趋势。
ASA和抗血管生成疗法在人原发性GBM-ECs中显示出协同抗癌疗效。因此，传统化疗与ASA联合可能提供一种对抗肿瘤恶性程度的新策略。
