Janus-Faced Effects of Broad-Spectrum and Specific MMP Inhibition on Metastasis

Abstract

In this chapter, we summarize the current knowledge of the effects of matrix metalloproteinase (MMP) inhibition on metastasis. While it was initially perceived that MMP inhibition should be the most potent therapeutic antimetastatic strategy, it has now been appreciated that more basic research has to be performed before another, more sophisticated, attempt should be made to use MMPs as targets in the clinic. The summary makes it evident that the complexity of preclinical models may obscure conclusive results. This may have led to the overestimated expectations and premature introduction of MMP inhibitors (MMPIs) into clinical trials. In addition to discussion of the options and limitations of different metastasis models in the search for improved strategies to inhibit MMPs, we emphasize the necessity to simplify the readout of models at this stage of research when the biology of interference with the proteolytic network is still not clear. Further, we stress the effects of MMP inhibition on the modulation of the host microenvironment, which critically influences the metastatic potential of tumor cells. This latter aspect is one of the new appreciations explaining the Janus-faced effects of broad-spectrum and specific MMP inhibition on metastasis.