Production and Correlation with Metastasis Neuroblastoma: Contribution of Stromal Cells to Their Matrix Metalloproteinases-2 and -9 Are Expressed in Human

Neuroblastoma, the second most common solid childhood tumor, can he a highly invasive and metastatic form of cancer. To assess the role of matrix-degrading proteases in this cancer, we have examined the expres sion of matrix metalloproteinases <MMIM and their corresponding tissue inhibitors of metalloproteinases (TIMPs) in 7 human neuroblastoma cell lines and 24 primary untreated tumors. \l\IP-2 (gelatinase A) and MMP-9 (gelatinase B) were the only two MMPs expressed. MMP-2 was detected predominantly in an inactive profumi in all tumor cell lines and tumor tissue extracts. The lack of MMP-2 activation in cell lines was attributed to the absence of expression of a membrane-type MMP (MT1MMP), which activates proMMP-2, and to the abundant expression of TIMPs, particularly TIMP-2. Immunohistochemical analysis of tumor tissue samples indicated that MMP-2 was present in both tumor cells and stromal cells. In contrast, MMP-9 was not expressed by neuroblastoma cell lines but was present in inactive and active forms in extracts from tumor tissues. Immunohistochemical analysis of positive specimens indi cated that MMP-9 was predominantly present in stromal, vascular, and perivascular cells surrounding nests of tumor cells. There was no corre lation between the levels of these MMPs and the MYCN copy number or the histopathological phenotype. However, there were higher levels of MMP-2 and MMP-9 in stage IV (metastatic) disease when compared with stages I and II (noninvasive and nonmetastatic) or IV-S (P < 0.05).