MATRIX-METALLOPROTEINASES-2 AND MATRIX-METALLOPROTEINASES-9 ARE EXPRESSED IN HUMAN NEUROBLASTOMA - CONTRIBUTION OF STROMAL CELLS TO THEIR PRODUCTION AND CORRELATION WITH METASTASIS

Neuroblastoma, the second most common solid childhood tumor, can be a highly invasive and metastatic form of cancer. To assess the role of m atrix-degrading proteases in this cancer, we have examined the express ion of matrix metalloproteinases (TIMPs) and their corresponding tissu e inhibitors of metalloproteinases (TIMPs) in 7 human neuroblastoma ce ll lines and 24 primary untreated tumors. MMP-2 (gelatinase A) and MMP -9 (gelatinase B) were the only two MMPs expressed. MMP-2 was detected predominantly in an inactive preform in all tumor cell lines and tumo r tissue extracts. The lack of MMP-2 activation in cell lines was attr ibuted to the absence of expression of a membrane-type MMP (MT1-MMP), which activates proMMP-2, and to the abundant expression of TIMPs, par ticularly TIMP-2. Immunohistochemical analysis of tumor tissue samples indicated that MMP-2 was present in both tumor cells and stromal cell s. In contrast, MMP-9 was not expressed by neuroblastoma cell lines bu t was present in inactive and active forms in extracts from tumor tiss ues. Immunohistochemical analysis of positive specimens indicated that MMP-9 was predominantly present in stromal, vascular, and perivascula r cells surrounding nests of tumor cells. There was no correlation bet ween the levels of these MMPs and the MYCN copy number or the histopat hological phenotype, However, there were higher levels of MMP-2 and MM P-9 in stage IV (metastatic) disease when compared with stages I and I I (noninvasive and nonmetastatic) or IV-S (P < 0.05).