Protective roles of matrix metalloproteinases: from mouse models to human cancer

Matrix metalloproteinases (MMPs) have long been linked to cancer progression owing to their ability to breakdown tissue barriers for metastatic spread. Accordingly, multiple studies have examined the potential value of these enzymes as targets for cancer therapy. Unfortunately, most clinical trials with MMP inhibitors have yielded negative results which has made necessary to re-evaluate the role of these proteases in cancer. Recent works mainly based on the use of mouse models deficient in specific MMPs have revealed that these enzymes play many roles in cancer distinct from matrix destruction, influencing early steps of tumor evolution, and expanding their pro-tumorigenic properties. However, these in vivo studies have also shown that, unexpectedly, some MMP family members like MMP8 may have paradoxical anti-tumor functions. Nevertheless, the final validation of these MMPs as bona fide tumor suppressors requested the identification of the putative genetic or epigenetic changes underlying their inactivation during cancer development. To this purpose, very recent large-scale genomic studies have explored the possibility that MMPs could be genetically altered in a panel of human malignant tumors from different sources. These studies have demonstrated that MMP8 is a frequently mutated gene in human melanoma. Functional analysis of the identified mutations has confirmed that all of them lead to the loss-of-function of MMP8 and enhance the progression of melanoma, thus providing definitive evidence that MMP8 is a tumor-suppressor gene. Parallel studies have extended these findings to other MMP-related metalloproteinases such as ADAMTS15, which has been found to be genetically inactivated in human colorectal cancer. This review describes the identification and validation of some MMPs and related enzymes as anti-tumor proteases and speculates about the molecular mechanisms underlying their protective roles in tumor development. Finally, the review explores the clinical applications derived from the identification of MMPs that favour the host instead of the tumor.