Aaberg-Jessen Charlotte, Halle Bo, Jensen Stine S, Müller Sven, Rømer Unni Maria, Pedersen Christian B, Brünner Nils, Kristensen Bjarne W
Department of Pathology, Odense University Hospital, Winsløwparken 15, 3. Floor, 5000, Odense, Denmark.
Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark.
J Neurooncol. 2016 Dec;130(3):439-448. doi: 10.1007/s11060-016-2252-4. Epub 2016 Sep 12.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been associated with poor prognosis and resistance towards chemotherapy in several cancer forms. In a previous study we found an association between a low TIMP-1 tumor immunoreactivity and increased survival for glioblastoma patients, when compared to moderate and high TIMP-1 tumor immunoreactivity. The aim of the present study was to further evaluate TIMP-1 as a biomarker in gliomas by studying TIMP-1 gene copy numbers by fluorescence in situ hybridization (FISH) on 33 glioblastoma biopsies and by measuring levels of TIMP-1 in plasma obtained pre-operatively from 43 patients (31 gliomas including 21 glioblastomas) by enzyme-linked immunosorbent assay (ELISA). The results showed TIMP-1 gene copy numbers per cell ranging from 1 to 5 and the TIMP-1/CEN-X ratio ranging between 0.7 and 1.09, suggesting neither amplification nor loss of the TIMP-1 gene. The TIMP-1 protein levels measured in plasma were not significantly higher than TIMP-1 levels measured in healthy subjects. No correlation was identified between TIMP-1 tumor cell immunoreactivities and the TIMP-1 gene copy numbers or the plasma TIMP-1 levels. In conclusion, high immunohistochemical TIMP-1 protein levels in glioblastomas were not caused by TIMP-1 gene amplification and TIMP-1 in plasma was low and not directly related to tumor TIMP-1 immunoreactivity. The study suggests that TIMP-1 immunohistochemistry is the method of choice for future clinical studies evaluating TIMP-1 as a biomarker in glioblastomas.
金属蛋白酶组织抑制剂-1（TIMP-1）与多种癌症的预后不良和化疗耐药相关。在先前的一项研究中，我们发现与TIMP-1肿瘤免疫反应性中等和高的胶质母细胞瘤患者相比，TIMP-1肿瘤免疫反应性低的患者生存率更高。本研究的目的是通过对33例胶质母细胞瘤活检组织进行荧光原位杂交（FISH）研究TIMP-1基因拷贝数，并通过酶联免疫吸附测定（ELISA）测量43例患者（31例胶质瘤，包括21例胶质母细胞瘤）术前采集的血浆中TIMP-1的水平，进一步评估TIMP-1作为胶质瘤生物标志物的价值。结果显示，每个细胞的TIMP-1基因拷贝数为1至5，TIMP-1/CEN-X比值在0.7至1.09之间，提示TIMP-1基因既无扩增也无缺失。血浆中测量的TIMP-1蛋白水平并不显著高于健康受试者中测量的TIMP-1水平。未发现TIMP-1肿瘤细胞免疫反应性与TIMP-1基因拷贝数或血浆TIMP-1水平之间存在相关性。总之，胶质母细胞瘤中高免疫组化TIMP-1蛋白水平并非由TIMP-1基因扩增引起，血浆中的TIMP-1水平较低且与肿瘤TIMP-1免疫反应性无直接关系。该研究表明，TIMP-1免疫组化是未来临床研究中评估TIMP-1作为胶质母细胞瘤生物标志物的首选方法。
