There is a dynamic and complex regulation pattern of the activity

There is a dynamic and complex regulation pattern of the activity of meprin-�� in colorectal cancer. Increased zymogen activation contributes to higher proteolytic activity in primary else tumors stages I to IV (Fig. 5A), and the inhibitory activity against meprin-�� is reduced in the blood in colorectal cancer patients (Fig. 5B). The inefficient activation in liver metastases is in accordance with the previous observation that the uPA-system, a meprin-�� activator, is inactive in liver metastases, due to the lack of uPA activation and the over-expression of plasminogen activator inhibitor [27], [28]. Even though many matrix metalloproteases (MMPs) are known to be increased in invasive primary tumors in colorectal cancer [29], there are few analyses that include liver metastases.

In one such study, MMP-9 was shown to be increased in primary tumors but not liver metastases [30]. That study and our data point to significant differences between protease networks in primary tumors and liver metastases, which is relevant for therapeutic approaches using protease inhibitors. We studied cell migration in MDCK cells expressing meprin-�� at the cell surface bound in heterodimeric protein complexes with transmembrane meprin-�� [31]. Meprin-expressing cells migrated significantly faster on laminin-1 coated dishes in the presence of plasminogen and HGF. Meprin-�� might be activated at the cell surface by plasmin, generated from plasminogen through the activity of urokinase-type plasminogen activator (uPA) bound to its receptor (u-PAR), which both are known to be up-regulated by HGF in MDCK cells [32].

This system most probably also contributes to the activation of meprin-�� in tumors in vivo, as u-PA and u-PAR are up-regulated in colorectal cancer [33], [34], [35], [36]. In our migration assay, the pro-migratory effect is indeed due to meprin-��, as plasmin activates meprin-�� but not meprin-�� [7] and because actinonin, which reverses the pro-migratory effect, does inhibit meprin-�� with approximately 100-fold higher potency (Ki 2*10?8 M) than meprin-�� (Ki 2*10?6 M) GSK-3 [10]. Both laminin-1 and laminin-5 are cleaved by meprin-�� in vitro [37], and we speculate that meprin-�� might expose cryptic pro-migratory epitopes in a similar fashion as has been previously shown with laminin-5 and laminin-1 for MT1-MMP [38] and elastase [39], respectively. The uPA-plasminogen system is also crucially important in angiogenesis [23], [40], and plasmin in turn might activate meprin-�� as a downstream angiogenic effector in colorectal cancer. In line with our data, a pro-angiogenic effect of meprin-�� has also been observed in a morpholino knockdown in zebrafish [14].

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