Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W
Department of Neurology, University of Tübingen, Medical School, Germany.
Cancer Res. 2001 Mar 15;61(6):2744-50.
Human malignant gliomas are highly lethal neoplasms. Involved-field radiotherapy is the most important therapeutic measure. Most relapses originate from the close vicinity of the irradiated target field. Here, we report that sublethal doses of irradiation enhance the migration and invasiveness of human malignant glioma cells. This hitherto unknown biological effect of irradiation is p53 independent, involves enhanced alphavbeta3 integrin expression, an altered profile of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9) expression and activity, altered membrane type 1 MMP and tissue inhibitor of metalloproteinases-2 expression, and an altered BCL-2/BAX rheostat favoring resistance to apoptosis. BCL-2 gene transfer and irradiation cooperate to enhance migration and invasiveness in a synergistic manner. Sublethal irradiation of rat 9L glioma cells results in the formation of a greater number of tumor satellites in the rat brain in vivo concomitant with enhanced MMP-2 and reduced tissue inhibitor of metalloproteinases-2 expression. Collectively, these data suggest that the current concepts of involved-field radiotherapy for malignant glioma need to be reconsidered and that the pharmacological inhibition of migration and invasion during radiotherapy may represent a new therapeutic approach to improve the therapeutic efficacy of radiotherapy for malignant glioma.
人类恶性胶质瘤是具有高度致死性的肿瘤。累及野放疗是最重要的治疗措施。大多数复发源于照射靶区的紧邻区域。在此，我们报告亚致死剂量的照射可增强人类恶性胶质瘤细胞的迁移和侵袭能力。这种迄今未知的照射生物学效应不依赖p53，涉及αvβ3整合素表达增强、基质金属蛋白酶-2和基质金属蛋白酶-9（MMP-2和MMP-9）表达及活性的改变、膜型1基质金属蛋白酶和金属蛋白酶组织抑制剂-2表达的改变，以及有利于抗凋亡的BCL-2/BAX变阻器的改变。BCL-2基因转移与照射协同以协同方式增强迁移和侵袭能力。对大鼠9L胶质瘤细胞进行亚致死照射导致在大鼠脑内形成更多数量的肿瘤卫星灶，同时伴有MMP-2表达增强和金属蛋白酶组织抑制剂-2表达降低。总体而言，这些数据表明，目前关于恶性胶质瘤累及野放疗的观念需要重新审视，并且在放疗期间对迁移和侵袭进行药理学抑制可能代表一种提高恶性胶质瘤放疗疗效的新治疗方法。
