Matrix metalloproteinases in tumorigenesis: an evolving paradigm

Abstract

Proteases are crucial for development, tissue remodeling, and tumorigenesis. Matrix metalloproteinases (MMPs) family, in particular, consists of more than 20 members with unique substrates and diverse function. The expression and activity of MMPs in a variety of human cancers have been intensively studied. MMPs have well-recognized roles in the late stage of tumor progression, invasion, and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis, e.g., in malignant transformation, angiogenesis, and tumor growth both at the primary and metastatic sites. Recent studies also suggest that MMPs play complex roles in tumor progression. While most MMPs promote tumor progression, some of them may protect the host against tumorigenesis in a context-dependent manner. MMPs have been chosen as promising targets for cancer therapy on the basis of their aberrant up-regulation in malignant tumors and their ability to promote cancer metastasis. Although preclinical studies testing the efficacy of MMP suppression in tumor models were so encouraging, the results of clinical trials in cancer patients have been rather disappointing. Here, we review the complex roles of MMPs and their endogenous inhibitors such as tissue inhibitors of metalloproteinase in tumorigenesis and strategies in suppressing MMPs.

Fig. 1

Complex roles for MMP in cancer. The multifunctional MMPs can not only degrade structural components within the extracellular matrix but also process growth factors and receptors (EGF, TGF-β, sFlt-1, etc.), cytokines and chemokines, and apoptosis-related molecules. Moreover, MMPs are involved in epithelial-mesenchymal transition. Therefore, MMPs have effects on cell growth and survival, angiogenesis, inflammation, invasion, and metastasis. These effects may be context-dependent. While MMPs can stimulate angiogenesis through release of angiogenic factors such as VEGF and bFGF, they are also involved in generating angiogenesis inhibitors such as angiostatin and endostatin

Fig. 2

Physiological and pharmacological regulation of MMP. The inactive pro-MMPs are synthesized from MMPs transcripts. The transcription of MMPs is regulated by transcription factors including Ets1, AP1, and NF-κB. The mechanisms underlying the activation of pro-MMPs are complex. Both MT1-MMP and MT3-MMP are involved in the activation of pro-MMPs. In addition, MMPs may be activated by plasmin and furin-like mechanism. Tissue inhibitors of metalloproteinase (TIMP) are endogenous MMP inhibitors that prevent the activation of pro-MMPs. TSP1 also inhibits the activation of MMPs. Paradoxically, TIMP-2 and TIMP-3 are involved in the activation of pro-MMP as well. The turnover of active MMPs may involve LRP-mediated endocytosis and clearance. α₂-Macroglobulin and TSP-2 act as endogenous MMP inhibitors through promoting LRP-mediated endocytosis and clearance of active MMPs. The pharmacological inhibitors of MMPs transcription include 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD), Gefitinib, NF-κB inhibitors, COX-2 inhibitors, and curcumin. In addition to hydroxamate-based MMP inhibitors (MMPIs), there are exosite MMPIs and mechanism-based MMPIs. Moreover, neutralizing antibodies to individual MMP are emerging as another choice for selective inhibition of MMP