Inhibition of matrix metalloproteinases by over‐expression of tissue inhibitor of metalloproteinase‐2 inhibits the growth of experimental hemangiomas

Abstract

Inhibitors of proteases prevent tumor‐associated matrix degradation, affecting tumor growth, angiogenesis and metastasis. Our study was designed to investigate the effect of inhibition of matrix metalloproteinases (MMPs) on the growth of experimental hemangiomas, using the model of murine endothelioma eEnd.1 cells. In nude mice, these cells generate hemangiomas, consisting mostly of host‐recruited endothelial cells, whose growth requires the activity of MMPs. In vitro, eEnd.1 cells produce factors that recruit endothelial cells and stimulate them to release MMPs. Over‐expression of TIMP‐2, following retrovirus‐mediated gene transfer, decreased tumor growth in vivo. The infected clone CR1, which produces high levels of TIMP‐2 (as assessed by Northern blot, ELISA and reverse zymography), formed slow‐growing tumors that did not grow beyond 0.4 g, while clone 1H, which produces little TIMP‐2, grew not dissimilarly to mock‐infected cells and parental e.End.1 cells. Histologically, control tumors presented the features of cavernous hemangiomas, while CR1 tumors had a more solid pattern, showing foci of apoptotic cells. In vitro, TIMP‐2 over‐expression had no autocrine anti‐proliferative effect on endothelioma cells but reduced their ability to recruit endothelial cells. CR1 cells lacked the capacity of mock‐infected or parental eEnd.1 cells to stimulate endothelial cell motility and invasiveness. Antibodies against TIMP‐2 restored the ability of CR1 to induce endothelial cell invasion. We conclude that, in this model, genetic increase of TIMP‐2 inhibits tumor growth, apparently by affecting the recruitment and organization of host endothelial cells by the transformed cells. © 2001 Wiley‐Liss, Inc.

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

“…Moreover, that increased amounts of TIMP-2 can promote MMP-2 activation and glioblastoma cell invasion is also not surprising. Although TIMP-2 was originally characterized as a suppressor of tumor invasion due to its ability to bind and inhibit MMP-2, 11 and overexpression of TIMP-2 was previously shown to reduce invasion and metastasis in a number of tumor cell models, [25][26][27] it is well known that TIMP-2 TIMP-2 promotes MMP-2 activation in glioblastoma KV Lu et al is also necessary for the efficient activation of proMMP-2. According to the model, a half molar ratio of TIMP-2 to MT1-MMP is theoretically optimal for MMP-2 activation.…”

Shedding of the Matrix Metalloproteinases MMP-2, MMP-9, and MT1-MMP as Membrane Vesicle-Associated Components by Endothelial Cells

“…20 After electrophoresis, gels were washed, incubated in collagenase buffer, and stained as described above. TIMP-1 and TIMP-2 appeared as dark bands at, respectively, 28 and 21 kd, corresponding to the areas where gelatin degradation by the gelatinases added to the gel is prevented by the inhibitors.…”

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

“…However, using the same inhibitor in in vivo studies with tumors implanted in mouse-models decreases tumor growth [9,17,[135][136][137][138][139][140][141][142]. It is not ruled out that the in vivo results might be obtained by negatively affecting tumor angiogenesis, resulting in decreased tumor growth.…”