A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, University of Toronto researchers review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis.
TIMPs at the apex of a complex biological hierarchy
Tissue inhibitors of metalloproteinases (TIMPs) control a variety of cell functions through overlapping but different metalloproteinase inhibitory profiles. In this figure, the hierarchy of the relationships between inhibitors, proteases, substrates and cellular processes is depicted at four levels.