Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms.

BACKGROUND: The increased synthesis of matrix metalloproteinases (MMPs) by aortic smooth muscle cells (SMCs) is thought to be involved in the etiopathogenesis of abdominal aortic aneurysms (AAAs), but the functional regulation and the activation states of these MMPs remain unclear. In this study, we assessed the expression levels and the functional regulation of several MMPs in the pathogenesis of AAAs. METHODS: Human healthy aorta and AAA specimens were homogenized, and the proteolytic activities of MMP-2 and MMP-9 and of the macrophage metalloelastase (MMP-12) were assessed with zymography. Protein expression of MMP-1, MMP-12, membrane-type 1 MMP (MT1-MMP), tissue inhibitor of MMP 1 (TIMP-1), TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed with electrophoresis on sodium dodecyl sulfate gels and immunoblotting. RESULTS: MMP-1, MMP-9, and MMP-12 zymogen levels and proteolytic activities were increased in AAAs when compared with healthy aorta. A severe reduction in alpha-actin--positive vascular SMCs was observed in all the AAA specimens and was correlated with an increase in TIMP-3 but not TIMP-1 or TIMP-2 potential activities. Although pro--MMP-2 activity was decreased, the extent of activated MMP-2 remained unaffected in the AAAs. In accordance with this result, a highly activated MT1-MMP form was also observed in AAAs. CONCLUSION: These data suggest that chronic aortic wall inflammation is mediated by macrophage infiltration, which may account for the destruction of medial elastin, as reflected by SMC down regulation, through increased levels of active MMP-1 and MMP-12. Moreover, altered MT1-MMP proteolytic turnover and differential regulation of TIMP expression in AAAs suggest that tight regulatory mechanisms are involved in the molecular regulation of MMP activation processes in the pathogenesis of AAAs.

Antitumor activity of fibroblast growth factors (FGFs) for medulloblastoma may correlate with FGF receptor expression and tumor variant.

Members of the fibroblast growth factor (FGF) family, which normally control cerebellar neuronal maturation, may represent more natural and less toxic tools with which to target medulloblastoma (MB), an embryonal brain tumor thought to arise from cerebellar neuronal precursors. In support of this, we found previously basic FGF/FGF-2 can inhibit MB progression by inducing neuronal-like differentiation, slowing the growth, and triggering apoptosis of a MB cell line we established from a histopathologically classic tumor (R. L. Kenigsberg et al., Am. J. Pathol., 151: 867-881, 1997). In the present study, the usefulness of this approach is additionally investigated. We report that of the five FGFs found in the developing cerebellum, only two, FGF-2 and FGF-9, possess antitumoral activity for MB. This activity is only noted for cell lines that originate from classic (UM-MB1 and SYR) rather than desmoplastic (HSJ) tumors. Whereas these FGFs inhibit proliferation of both classic cell lines, they only advance neuronal differentiation and induce apoptosis of one, UM-MB1. Consistent with these responses, after FGF treatment, levels of neurofilaments and the proapoptotic modulator Bax only increase in UM-MB1, whereas the cyclin-dependent kinase inhibitor p27/Kip1 (p27), which accumulates in cerebellar neuronal precursors before they exit the cell cycle, goes up in both UM-MB1 and SYR. Finally, although the histological variant of MB may help predict the sensitivity of MB to the FGFs, the selectivity, specificity, and type of response elicited may be dictated by, as evident by immunoprecipitation and Western blot analyses, the expression of certain FGF receptor types.