Matrix metalloproteinases in tumorigenesis: an evolving paradigm

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.