Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies
Published: 1 September 2004
Alicia R. Folgueras, Alberto M. Pendás, Luis M. Sánchez and Carlos López-Otín
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University Institute of Oncology, Universidad de Oviedo, Spain.
Over the last years, the relevance of the matrix metalloproteinase (MMP) family
in cancer research has grown considerably. These enzymes were initially associated with the
invasive properties of tumour cells, owing to their ability to degrade all major protein components of the extracellular matrix (ECM) and basement membranes. However, further studies have
demonstrated the implication of MMPs in early steps of tumour evolution, including stimulation of
cell proliferation and modulation of angiogenesis. The establishment of causal relationships
between MMP overproduction in tumour or stromal cells and cancer progression has prompted
the development of clinical trials with a series of inhibitors designed to block the proteolytic activity of these enzymes. Unfortunately, the results derived from using broad-spectrum MMP
inhibitors (MMPIs) for treating patients with advanced cancer have been disappointing in most cases.
There are several putative explanations for the lack of success of these MMPIs including the recent finding that some MMPs may play a paradoxical protective role in tumour progression. These
observations together with the identification of novel functions for MMPs in early stages of cancer have made necessary a reformulation of MMP inhibition strategies. A better understanding of the functional complexity of this proteolytic system and global approaches to identify the relevant MMPs which must be targeted in each individual cancer patient, will be necessary to clarify whether MMP inhibition may be part of future therapies against cancer.