Studies on the roles of the membrane-associated matrix metalloproteinase regulator BECK in angiogenesis

点击翻译按钮获取中文摘要

We have discovered that forced expression of RECK in the HT1080 fibrosarcoma cells affects the processing of pro-MMP-2 in the culture supernatant and that mice lacking RECK expression die around embryonic day 10.5 with hemorrhage. We investigated the mechanisms of these phenomena and found that RECK inhibits both MT1-MMP and MMP-2 in vitro and that in mice lacking RECK expression, pro-MMP-2 processing is accelerated and collagen fibrils are dramatically reduced. Thus, the blood vessel disruption and mesenchymal disarray found in these mice may be due to the increased MMP-2 activation and this notion was further supported by the finding that MMP-2/RECK double mutant mice showed milder tissue damage and longer survival (0.5 day) (Oh et al. Cell 2001). In another line of studies which uses clinical samples, we found that RECK expression in several types of cancer (such as hepatocellular-carcinoma, pancreatic ductal carcinoma, non-samll cell Lung carcinoma), RECK expression in tumor tissues positively correlates with better prognosis (longer survival) and negatively correlates with activation of pro-MMP-2, invasiveness, and blood vessel density in tumors (Furumoto et al. Hepatology 2001; Masui et al. Clin. Cancer Res. 2003; Takanaka et al. Eur. J. Cancer 2004). We have also generated MMP-2/MT1-MMP double null mice, which are probably similar in effect to RECK-overexpressing mice, and found that they show peri-natal death with defects in blood vessel enlargement and muscle development (Oh et al. Oncogene 2004). The finding unexpectedly demonstrate that two MMPs with distinct molecular nature and subcellular localization are functionally redundant in vivo and that MMPs are indeed essential for extracellular matrix remodeling during mammalian embryonic development.