Membrane associated proteases and their inhibitors in tumour angiogenesis

Abstract

Cell surface proteolysis is an important mechanism for generating biologically active proteins that mediate a range of cellular functions and contribute to biological processes such as angiogenesis. Although most studies have focused on the plasminogen system and matrix metalloproteinases (MMPs), recently there has been an increase in the identification of membrane associated proteases, including serine proteases, ADAMs, and membrane-type MMPs (MT-MMPs). Normally, protease activity is tightly controlled by tissue inhibitors of MMPs (TIMPs) and plasminogen activator inhibitors (PAIs). The balance between active proteases and inhibitors is thought to determine the occurrence of proteolysis in vivo. High concentrations of proteolytic system components correlate with poor prognosis in many cancers. Paradoxically, high (not low) PAI-1 or TIMP concentrations predict poor survival in patients with various cancers. Recent observations indicate a much more complex role for protease inhibitors in tumour progression and angiogenesis than initially expected. As knowledge in the field of protease biology has improved, the unforeseen complexities of cell associated enzymes and their interaction with physiological inhibitors have emerged, often revealing unexpected mechanisms of action.

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC)

“…The finding of a positive correlation between ADAM-12 and VEGF-A 121 and VEGF-A 165 isoforms, which are proangiogenic, in all tumour samples reinforce the hypothesis of a specific role for ADAM-12 in tumour-associated angiogenic process. The potential effect of ADAM-12 on angiogenesis could occur either directly by activating some mediators implicated in angiogenesis as demonstrated for some MMPs or by inactivating angiogenesis inhibitors (Munaut et al, 2003;Maquoi et al, 2004;Noel et al, 2004). Alternatively and as suggested for other proteases, ADAMs could release proangiogenic factors trapped in the extracellular matrix by degrading its components (Werb et al, 1999).…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Angiogenesis process is under the dependence of a balance of pro-and antiangiogenic factors [93][94][95]. Proteinases have been initially considered as positive regulators of angiogenesis but recent studies have evidenced complex and sometimes opposite roles of MMPs, ADAMs and ADAMTSs in regulating tumoral angiogenesis [5,83,[95][96][97][98]. Interestingly, ADAMTS-1 and ADAMTS-8 have been proven to be antiangiogenic factors [99].…”

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases

“…This conversion of pro-MMP into activated form can be performed in vitro by reactive oxygen radicals or physical conditions like pH or temperature (Nagase, 1997). In vivo, MMP activation involves other MMPs or serine proteases (Noel et al, 2004). For instance, activation of proMMP-2 is performed by membrane bound membrane type-1 MMP (MT1-MMP) (Lewalle et al, 1995;Zucker et al, 2003).…”

“…Matrix metalloproteinases (MMPs), or matrixins, belong to the metzincin superfamily of metalloproteinases, also including astacins, ADAMs (a protein with a disintegrin and metallopro-tease domain) and ADAM-TS proteases (ADAM with a thrombospondin-like motif) (Sternlicht and Werb, 2001;Folgueras et al, 2004;Handsley and Edwards, 2005;Noel et al, 2004). MMPs are proteolytic enzymes believed to be implicated in many physiological and pathological processes including embryonic development, morphogenesis, reproductive processes, bone remodeling, wound healing, cancer, arthritis, atherosclerosis, MMPs are zinc and calciumdependent enzymes being able to degrade virtually all extracellular matrix components.…”