Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo.

Tissue inhibitors of metalloproteinases (TIMPs) are negative regulators of matrix metalloproteinases (MMPs) which degrade major components of the extracellular matrix. The aberrant expression of TIMPs is believed to represent an important modulating factor in the invasive capacity of human tumors. In the present study we analyzed the expression of TIMPs in human brain tumor tissue samples by an enzyme-linked immunosorbent assay (ELISA) and by Northern blotting analysis. Quantitation of TIMP-1 and TIMP-2 by ELISA demonstrated low levels of TIMP-1 and TIMP-2 proteins in glioblastomas, and moderate levels in anaplastic astrocytomas compared with normal brain tissues low-grade gliomas and metastatic tumors (renal and breast carcinomas and melanomas). Northern blot analysis of TIMP-1 transcripts demonstrated higher expression in meningioma, normal brain tissues and other metastatic tumors than in anaplastic astrocytoma and glioblastoma. Two distinct transcripts of 1.0 and 3.5 kb were observed for TIMP-2 mRNA in normal brain tissue and in tumor extracts. In addition, TIMP-2 mRNA expression was lower in glioblastoma and anaplastic astrocytoma than in meningioma, normal brain tissues and metastatic tumors. These findings suggest that down-regulation of both TIMP-1 and TIMP-2 contributes significantly to the invasive potential of human glioblastoma multiforme and anaplastic astrocytomas.