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.