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  • Review Article
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TIMPs: versatile extracellular regulators in cancer

Key Points

  • Tissue inhibitors of metalloproteinases (TIMPs) control diverse metalloproteinases and their wide range of substrates, regulating tissue homeostasis.

  • TIMPs are tightly involved in the development of most cancer hallmarks.

  • TIMP-regulated proteolytic processing affects major signalling pathways.

  • TIMP genetic models suggest TIMPs have a role in adult stem cell niches.

  • TIMP1 and TIMP3 have contrasting correlations with prognosis in human cancers: TIMP1 increase and TIMP3 reduction indicate poor prognosis.

  • TIMPs have the potential to function as biomarkers in patient body fluids.

Abstract

A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we 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.

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Figure 1: TIMPs at the apex of a complex biological hierarchy.
Figure 2: Tertiary structure of a TIMP protein.
Figure 3: Changes in TIMP expression during human cancer progression.
Figure 4: TIMP influence on key aspects of the tumour microenvironment.
Figure 5: TIMPs regulate metalloproteinases to affect signal transduction.

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Acknowledgements

The Khokha laboratory has been supported by funding from Canadian Institutes of Health Research, Canadian Cancer Society Research Institute, Canadian Breast Cancer Foundation and Genome Canada. H.W.J. received a Studentship from the Canadian Breast Cancer Foundation.

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Correspondence to Rama Khokha.

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DATABASES

Cn3D

PBD ID 1BR9

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Supplementary information (XLSX 24 kb)

Glossary

Metzincin superfamily

Includes enzymes with zinc ion-binding methionine-turn sequences, such as astacins, serralysins, adamalysins, matrix metalloproteinases, snapalysins and leishmanolysins.

Protease subsites

Contiguous pockets of the protease active site, each responsible for binding to the consecutive amino acids of a target substrate.

Haemopexin domains

210 amino acid regions in most human matrix metalloproteinases (MMPs), except MMP7, MMP23 and MMP26, with a role in high-affinity binding by tissue inhibitors of metalloproteinases (TIMPs).

AB loop

A tissue inhibitor of metalloproteinase (TIMP) structural feature that partly determines TIMP specificity for individual metalloproteinases, especially a disintegrin and metalloproteinases (ADAMs).

Podosomes

Actin-rich dynamic cellular protrusions on the outer surface of a cell's plasma membrane that promote focal proteolysis of extracellular matrix.

Mitogenic

Substances that trigger mitosis including growth factors, cytokines and endotoxins.

CpG islands

Short regions at transcription start sites with higher concentrations of CG dinucleotides, often methylated as part of transcriptional regulation.

Mechanotransduction

The processes through which cells sense and respond to mechanical stimuli by converting physical forces into biochemical signals that elicit specific cellular responses.

γδ T cells

Low abundance 'unconventional' T cells with one γ and one δ chain. Rapid responders to pathogens in gut and intra-epithelial locations.

M2 macrophages

Macrophages involved in wound healing and tissue repair that can dampen immune activation by producing high levels of transforming growth factor-β (TGFβ) and interleukin-10 (IL-10).

M1 macrophages

Proinflammatory macrophages, activated by lipopolysaccharide (LPS) and interferon-γ (IFNγ) and that express tumour necrosis factor (TNF). M1 macrophages kill pathogens and cells with reactive oxygen species and nitric oxide.

Cardiac challenge

Constriction of the aorta to generate a pressure overload and mechanical stress on the heart.

S2 cleavage

The second cleavage step required for NOTCH activation preceding the final γ-secretase mediated S3 cleavage, release of the intracellular domain and signal transduction.

DMBA

7,12-Dimethylbenz[a]anthracene. A polcyclic aromatic hydrocarbon commonly used as a carcinogen for the initiation of multiple research models of cancer.

SILAC-iTRAQ-TAILS

A mass spectrometry based workflow used to gain insight into protease activity in complex cellular compartments. Stable isotope labelling by amino acids in cell culture (SILAC)-isobaric tag for relative and absolute quantification (iTRAQ)-terminal amine isotopic labelling of substrates (TAILS).

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Jackson, H., Defamie, V., Waterhouse, P. et al. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 17, 38–53 (2017). https://doi.org/10.1038/nrc.2016.115

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