Aaberg-Jessen Charlotte, Fogh Louise, Sørensen Mia Dahl, Halle Bo, Brünner Nils, Kristensen Bjarne Winther
Department of Pathology, Odense University Hospital, J.B. Winsloew vej 15, DK-5000, Odense, Denmark.
Department of Nuclear Medicine, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense, Denmark.
Pathol Oncol Res. 2019 Jan;25(1):59-69. doi: 10.1007/s12253-017-0312-5. Epub 2017 Sep 30.
The multifunctional protein - tissue inhibitor of metalloproteinases-1 (TIMP-1) - has been associated with a poor prognosis in several types of cancers including glioblastomas. In addition, TIMP-1 has been associated with decreased response to chemotherapy, and especially the efficacy of the family of topoisomerase (TOP) inhibitors has been related to TIMP-1. As a second line treatment of glioblastomas, the vascular endothelial growth factor (VEGF) antibody bevacizumab is administered in combination with the TOP1 inhibitor irinotecan and glioblastoma cell levels of TIMP-1 could therefore potentially influence the efficacy of such treatment. In the present study, we aimed to investigate whether a high TIMP-1 expression in glioblastoma cell lines would affect the sensitivity to TOP inhibitors, and whether TIMP-1 overexpressing cells would have alterered growth and invasion. We established TIMP-1 overexpressing subclones from two human glioblastoma cell lines. TIMP-1 overexpressing U87MG cells were significantly more resistant than low TIMP-1 expressing clones and parental cells when exposed to SN-38 (TOP1 inhibitor) or epirubicin (TOP2 inhibitor). No significant differences were observed for the TIMP-1 transfected A172 cells. Implantation of both U87MG and A172 spheroids into organotypic brain slice cultures revealed a reduced growth of TIMP-1 overexpressing U87MG spheroids, however, no significant differences in invasion were observed. The present study suggests that TIMP-1 overexpression reduces the effect of TOP inhibitors in glioblastoma. TIMP-1 also appeared to reduce spheroid growth, but did not influence invasion. Whether TIMP-1 plays a role in irinotecan resistance and has a predictive potential in glioblastoma patients remains to be elucidated.
多功能蛋白——金属蛋白酶组织抑制剂-1（TIMP-1）——与包括胶质母细胞瘤在内的多种癌症的不良预后相关。此外，TIMP-1与化疗反应降低有关，尤其是拓扑异构酶（TOP）抑制剂家族的疗效与TIMP-1有关。作为胶质母细胞瘤的二线治疗方法，血管内皮生长因子（VEGF）抗体贝伐单抗与TOP1抑制剂伊立替康联合使用，因此胶质母细胞瘤细胞中的TIMP-1水平可能会影响这种治疗的疗效。在本研究中，我们旨在调查胶质母细胞瘤细胞系中高TIMP-1表达是否会影响对TOP抑制剂的敏感性，以及过表达TIMP-1的细胞是否会改变生长和侵袭。我们从两个人类胶质母细胞瘤细胞系中建立了过表达TIMP-1的亚克隆。当暴露于SN-38（TOP1抑制剂）或表柔比星（TOP2抑制剂）时，过表达TIMP-1的U87MG细胞比低表达TIMP-1的克隆和亲本细胞具有显著更高的抗性。对于转染TIMP-1的A172细胞，未观察到显著差异。将U87MG和A172球体植入器官型脑片培养物中，发现过表达TIMP-1的U87MG球体生长减少，然而，未观察到侵袭方面的显著差异。本研究表明，TIMP-1过表达降低了TOP抑制剂在胶质母细胞瘤中的作用。TIMP-1似乎也降低了球体生长，但不影响侵袭。TIMP-1是否在伊立替康耐药中起作用以及在胶质母细胞瘤患者中是否具有预测潜力仍有待阐明。
