Control of matrix metalloproteinase activity in cancer

Remodelling of extracellular matrix (ECM) and basement membranes is a key component of the process of tumour cell invasion and metastasis. Matrix metalloproteinases (MMPs) are one of the major classes of enzymes involved in degrading ECM, having different substrate specificities and being inhibited by naturally occurring tissue inhibitors (TIMPs). Elevated levels of MMPs have been associated with poor prognosis for a variety of malignancies. However, the expression and effective action of MMPs are influenced by multiple factors: most are synthesized by stroma rather than tumour cells, suggesting tumour cell-stromal cell co-operation; receptors (MT-MMPs) have to be present on tumour cells for binding and activation of MMP; co-ordination of tissue proteolysis and subsequent integrin binding will aid cell movement through a matrix; integrin receptors can directly moderate the production of MMP. These various components need to be considered when trying to determine the key events regulating matrix proteolysis and hence invasion.