Matrix metalloproteinases: roles in cancer and metastasis.

The matrix metalloproteinase (MMP) family of extracellular proteinases play roles in normal physiological processes as well as in multiple disease settings including cancer. The link between MMP activity and cancer was considered strong enough to warrant considerable investment in pharmacological inhibitors of MMPs as a potential therapeutic modality, however, multiple large-scale clinical trials have all failed to reach their primary endpoints. This has led us to re-evaluate our thinking with respect to MMPs in cancer and shown that, most importantly, we need to understand the range of functions of these enzymes before we can effectively modulate them. The MMPs contribute to every stage of tumor progression, not just the later stages as was originally assumed. Additionally, through processing of their various substrates, MMP activity can have both pro- and anti-tumorigenic functions, thus their broad inhibition is likely to have unwanted consequences in some settings. Interactions between MMPs and proteinases of other classes are another important aspect of tumor biology and understanding these interactions is also necessary for development of effective therapeutic strategies. The aim of this article is to summarize recent findings in these areas and put them in the context of our growing understanding of how MMPs function in cancer development and progression.