Dept Immunology and Inflammation, IRCCS Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
Eur J Cancer. 2010 Dec;46(18):3383-92. doi: 10.1016/j.ejca.2010.07.022. Epub 2010 Aug 19.
Human gliomas represent an unmet clinical challenge as nearly two-thirds of them are highly malignant lesions with fast progression, resistance to treatment and poor prognosis. The most severe form, the glioblastoma multiforme, is characterised by a marked and diffuse infiltration through the normal brain parenchyma. Given the multiple effects of chemokines on tumour progression, aim of this study was to analyse the expression of the chemokine CX3CL1 and of its specific receptor CX3CR1 in 36 human surgical glioma samples, with different degrees of histological malignancy and in glioblastoma-derived neurospheres. Herein we show that both ligand and receptor are expressed at the mRNA and protein levels in most specimens (31/36). While receptor expression was similarly detected in low or high grade tumours, the uppermost scores of CX3CL1 were found in grades III-IV tumours: oligodendrogliomas, anaplastic astrocytomas and glioblastomas. Accordingly, the expression of CX3CL1 was inversely correlated with patient overall survival (p = 0.01). Glioblastoma-derived neurospheres, containing a mixed population of stem and progenitor cells, were positive for both CX3CR1 and for the membrane-bound chemokine, which was further up-regulated and secreted after TNF-IFNγ stimulation. Confocal microscopy of 3D neurospheres showed that the ligand was primarily expressed in the outer layer cells, with points of co-localisation with CX3CR1, indicating that this ligand-receptor pair may have important intercellular adhesive functions. The high expression of CXC3L1 in the most severe forms of gliomas suggests the involvement of this chemokine and its receptor in the malignant behaviour of these tumours.
人类神经胶质瘤是一个未满足的临床挑战，因为近三分之二的神经胶质瘤是高度恶性的病变，具有快速进展、治疗耐药和预后不良的特点。最严重的形式是多形性胶质母细胞瘤，其特征是在正常脑组织中明显且弥漫性浸润。鉴于趋化因子对肿瘤进展的多种影响，本研究旨在分析 36 个人类手术神经胶质瘤样本中趋化因子 CX3CL1 及其特异性受体 CX3CR1 的表达情况，这些样本具有不同程度的组织学恶性程度和胶质母细胞瘤衍生的神经球。在此，我们表明，配体和受体在大多数标本中（31/36）在 mRNA 和蛋白质水平上均有表达。虽然在低级别或高级别肿瘤中均检测到受体表达，但在 3 级或 4 级肿瘤（少突胶质细胞瘤、间变性星形细胞瘤和胶质母细胞瘤）中，CX3CL1 的最高评分最高。因此，CX3CL1 的表达与患者总生存期呈负相关（p = 0.01）。包含干细胞和祖细胞混合群体的胶质母细胞瘤衍生的神经球对 CX3CR1 和膜结合趋化因子均呈阳性，TNF-IFNγ 刺激后，后者的表达上调并分泌。3D 神经球的共聚焦显微镜显示，配体主要在最外层细胞中表达，与 CX3CR1 有共定位点，表明该配体-受体对可能具有重要的细胞间黏附功能。在最严重形式的神经胶质瘤中 CXC3L1 的高表达表明，这种趋化因子及其受体参与了这些肿瘤的恶性行为。
