Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-016-2252-4) contains supplementary material, which is available to authorized users.
Highlights
The current standard treatment of the highly malignant and most frequent brain tumor, the glioblastoma, includes surgery, radiotherapy and chemotherapy
A high tissue inhibitor of metalloproteinases-1 (TIMP-1) protein expression was found in the biopsy from patient 4 (Fig. 2c), whereas the TIMP-1 fluorescence in situ hybridization (FISH) analysis showed a low TIMP-1/CEN-X ratio of 0.7 (Table 1) in this biopsy
The TIMP-1 signals and CEN-X signals were counted in 60 cells per biopsy and the TIMP-1/CEN-X ratio was calculated
Summary
The current standard treatment of the highly malignant and most frequent brain tumor, the glioblastoma, includes surgery, radiotherapy and chemotherapy. The median overall survival has increased to 14.6 months and the 2-year survival has increased from 10.9 to 27.2 %, mainly due to the introduction of temozolomide [2]. This improved survival has increased the interest in prognostic and predictive biomarkers for this group of patients. In line with our report, high TIMP-1 protein expression levels in tumor tissue or in plasma obtained pre-operatively have been associated with poor prognosis in breast and colorectal cancer amongst others [4,5,6,7,8,9,10,11,12]
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