MMP9: A Tough Target for Targeted Therapy for Cancer

Simple Summary MMP9, due to its proteolytic activity, plays a key role in tumorigenesis by regulating migration, epithelial-to-mesenchymal transition and survival of cancer cells, induction of immune response, angiogenesis and formation of tumor microenvironment. It seems to be an attractive target for anticancer therapies. However, on the one hand very complicated mechanism of regulation of expression, synthesis and activation of MMP9, which determines specific, often contradictory role of this enzyme, and on the other hand high homology with other members of MMP family, makes development of effective and safe MMP9 inhibitors as anticancer drugs extremely difficult. Recently, blocking antibodies that selectively inactivate MMP9 have raised hopes and are currently in clinical trials. However, there is still a need to deepen our understanding of the mechanisms by which MMP9 becomes an important part of the tumorigenesis process. The goal is to develop a new generation of therapies that target MMP9 for the treatment of cancer. Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.