EXPRESSION OF TIMP-1, TIMP-2, 72-KDA AND 92-KDA TYPE-IV COLLAGENASE TRANSCRIPTS IN HUMAN ASTROCYTOMA CELL-LINES - CORRELATION WITH ASTROCYTOMA CELL INVASIVENESS

Malignant astrocytomas are highly invasive neoplasms which infiltrate diffusely into regions of normal brain. As evidence to support one mec hanism by which tumor cells are known to invade, we have previously sh own that astrocytoma cell lines secrete a variety of matrix metallopro teinases (MMPs) and metalloproteinase inhibitors (Apodaca et al: Cance r Res 50: 2322-2329, 1990). In the present study we determined the exp ression of tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, 72- kDa and 92-kDa type IV collagenase transcripts among human astrocytoma cell lines. In addition, we sought to correlate MMP and TIMP transcri pt levels with astrocytoma invasiveness. RNA from seven well character ized human astrocytoma cell lines was extracted before and after phorb ol ester treatment and Northern blot analyses were performed using cDN A probes for the MMPs and TIMPs. All astrocytoma cell lines and normal human leptomeningeal cells were tested for their relative invasive po tential using an in vitro invasion assay. There was variable expressio n of MMP and TIMP transcripts among astrocytoma cell lines. SF-188 was the only cell line to demonstrate a relative abundance of 72- and 92- kDa type IV collagenase transcripts over TIMP-1 and TIMP-2 transcript levels. Interestingly, this cell line was the most highly invasive in the in vitro invasion assay system. U 343 MG-A demonstrated relative a bundance of TIMP-1 and -2 transcripts over 72- and 92-kDa type IV coll agenase transcripts and was the least invasive cell line. Prior treatm ent of astrocytoma cell lines with phorbol ester upregulated TIMP-1 an d 92-kDa type IV collagenase transcripts, but not TIMP-2 and 72-kDa ty pe IV collagenase transcripts. We conclude that there is only partial correlation between MMP and TIMP transcript levels and in vitro cell i nvasiveness among the astrocytoma cell lines studied. Our analysis has led to the identification of an astrocytoma cell line, SF-188, which appears to overexpress the 72-kDa and 92-kDa type IV collagenase trans cripts relative to low level TIMP-1 and TIMP-2 transcripts. This parti cular cell line will continue to be of considerable value in dissectin g some of the molecular mechanisms involved in astrocytoma cell invasi on.