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New functions for the matrix metalloproteinases in cancer progression

Key Points

  • The matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases that consist of more than 21 human MMPs and numerous homologues from other species. They can be divided into eight structural classes, three of which are membrane bound.

  • The MMPs are synthesized as inactive zymogens and activated by proteinase cleavage. Their activity is regulated by endogenous inhibitors, including α2-macroglobulin; tissue inhibitors of metalloproteinases (TIMPs); small molecules with TIMP-like domains; and the membrane-bound inhibitor RECK (reversion-inducing cysteine-rich protein with kazal motifs).

  • Direct evidence for a role of MMPs in tumour progression comes from xenograft experiments using cancer cells with decreased and increased expression levels of MMPs or TIMPs, and from carcinogenesis experiments with mice that either lack a specific Mmp or Timp-1 or have organ-specific Mmp or Timp-1 overexpression.

  • MMPs are upregulated in almost every type of human cancer, and their expression is often associated with poor survival. Whereas some of the MMPs (for example, MMP-7) are expressed by the cancer cells, other MMPs (for example, MMP-2 and MMP-9) are synthesized by the tumour stromal cells, including fibroblasts, myofibroblasts, inflammatory cells and endothelial cells.

  • MMPs can promote cancer progression by increasing cancer-cell growth, migration, invasion, metastasis and angiogenesis. MMPs exert these effects by cleaving a diverse group of substrates, which include not only structural components of the extracellular matrix, but also growth-factor-binding proteins, growth-factor precursors, receptor tyrosine kinases, cell-adhesion molecules and other proteinases.

  • Several synthetic MMP inhibitors are undergoing Phase III clinical trials. Although a few encouraging results have been reported, some trials were prematurely terminated due to either lack of benefits or major adverse effects.

  • The clinical trials have so far focused on patients with advanced-stage disease. Based on animal experiments, we would expect, however, that clinical efficacy might be improved either by using MMP inhibitors in the treatment of early disease (in combination with conventional therapy), or as preoperative and postoperative treatment to prevent surgical-induced micrometastatic spread and recurrence of the disease.

Abstract

Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?

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Figure 1: The protein structure of the MMPs.
Figure 2: Properties of MMPs in models of cancer.
Figure 3: Expression of MMPs and TIMPs in breast tumours.
Figure 4: Functions of MMPs in cancer progression.

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Acknowledgements

We thank B. Wiseman and M. Sternlicht for their helpful comments on the manuscript and apologize for omission of many significant references due to space constraints. This work was supported by grants from the National Cancer Institute and from the Danish Cancer Society.

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Supplementary information

Online Table 1: The matrix metalloproteinases (MMPs) and their substrates (PDF 28 kb)

Online Table 2: Properties of the tissue inhibitors of matrix metalloproteinases (TIMPs) (PDF 40 kb)

41568_2002_BFnrc745_MOESM3_ESM.pdf

Online Table 3: Expression and clinical relevance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human cancer (PDF 58 kb)

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DATABASES

CancerNet:

brain tumours

breast cancers

colon cancer

gastric cancer

Kaposi's sarcoma

liver cancer

non-small-cell lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

skin cancer

small-cell lung cancers

bladder cancer

 LocusLink:

aggrecan

BCL-XL

CCL7

CD44

c-JUN

c-MET

collagen type IV

CXCL1

CXCL12

CXCL4

CXCL7

CXCL8

CXCR4

decorin

E-cadherin

EGFR

emmprin

endostatin

ETS

FAS

FASL

FGF receptor 1

FGFs

fibronectin

HB-EGF

HER2

HER4

IL-2Rα

αv integrin

αvβ3 integrin

keratan

laminin-5

LEF-1

MMP-1

Mmp-2

MMP-2

MMP3

Mmp-7

MMP-7

Mmp-9

MMP-9

Mmp-11

MMP-11

MMP-12

MMP-13

Mmp-14

MMP-14

MMP-15

MMP-20

MMP23

MMP24

MMP-28

nidogen

p53

PECAM-1

perlecan

RECK

serpins

syndecans

tenascin

TGF-α

TGF-β

thrombospondin-1

thrombospondin-2

Timp-1

TIMP-1

Timp-2

TIMP-2

TIMP-3

TIMP-4

VE-cadherin

VEGF

versican

vitronectin

α2-macroglobulin

β-catenin

 OMIM:

neuroblastoma

FURTHER INFORMATION

Agouron Pfizer Press Release

Bayer Pharmaceutical Division Press Release

British Biotech Press Release

CancerNet, search for clinical trials

ClinicalTrials.gov, search for clinical trials

International Society for Fibrinolysis and Proteolysis

Glossary

EXTRACELLULAR MATRIX

All secreted molecules that are immobilized outside cells, see Box 1.

CLINICAL TRIALS

Phase I: the first testing of a new drug in humans. A small group of people is tested to determine drug safety, safe dosage range and side effects. Phase II: the drug is tested on a larger group of patients to see if it is effective and to further evaluate its safety. Phase III: conducted on a large group of patients to confirm the effectiveness, monitor side effects and compare the drug to commonly used treatments.

ZYMOGEN

An enzyme that is secreted by cells as an inactive precursor. Activation of the enzymes occurs as one or more peptide bonds in the zymogen are cleaved.

INTRACELLULAR FURIN-LIKE SERINE PROTEINASES

A family of intracellular proteinases, including furin, that are localized in the trans-Golgi network, where they have an important role in the intracellular processing of secreted proteins.

SCAVENGER RECEPTORS

A broad class of receptors that 'scavenge' cellular debris: the ligands are endocytosed and subsequently degraded. Scavenger receptors also have other activities, such as adhesion.

CRYPTIC SITE

Part of a protein that is normally hidden within the three-dimensional structure. The cryptic site might be exposed following conformational changes in the protein — for example, as a result of proteolytic cleavage.

ADAM

(A disintegrin and metalloproteinase). A family of transmembrane proteinases with metalloproteinase, disintegrin (integrin-binding), cysteine-rich and epidermal growth factor (EGF)-like domains. ADAMs participate in cell-surface proteolysis and cleave substrates such as tumour necrosis factor-α and Notch.

XENOGRAFT

Transplantation of tissue or cells from one species to another. In cancer research, most xenografts are human cancer-cell lines or human tumours that have been transplanted to immune-deficient rodents.

K14-HPV16 MOUSE MODEL OF SQUAMOUS-CELL CARCINOMA

A transgenic mouse strain that expresses the human papillomavirus type 16 (HPV16) early-region genes, including the E6/E7 oncogenes, under the control of the human keratin-14 promoter (K14) in basal keratinocytes. Invasive squamous carcinomas of the epidermis develop through characteristic stages.

RIP-TAg MOUSE MODEL OF ISLET-CELL CARCINOMA

A transgenic mouse strain that expresses the simian virus T antigen (TAg) under the rat insulin II promoter (RIP) in the pancreatic islet β-cells. Carcinomas develop in the pancreatic islets cells and progress through characteristic stages.

PLASMINOGEN

The precursor of plasmin, a trypsin-like serine proteinase that cleaves fibrin in blood clots.

ANGIOSTATIN

A proteolytic fragment of plasminogen and an inhibitor of angiogenesis.

ENDOSTATIN

A proteolytic fragment of the non-collagenous domain of collagen type XVIII and an inhibitor of angiogenesis.

UROKINASE-TYPE PLASMINOGEN-ACTIVATOR RECEPTOR

(uPAR). A cell-surface receptor for urokinase-type plasminogen activator (uPA), a serine proteinase that catalyses the formation of plasmin from plasminogen.

METASTASIS ASSAYS

In spontaneous metastasis assays, the tumour cells are inoculated either subcutaneously or orthotopically in animals, and spontaneous metastases from this primary site to distant locations are monitored. In experimental metastasis assays, tumour cells are injected into the bloodstream (for example, intravenously for lung metastasis, into the left heart ventricle for bone metastases and into the portal vein for liver metastases), thereby circumventing the first steps in the metastatic process.

MATRIGEL

The extracellular matrix secreted by the Engelbrecht–Holm–Swarm mouse sarcoma cell line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and so resembles the basement membrane.

HYALURONAN

A high molecular weight glycosaminoglycan. It is widely distributed both in the extracellular matrix and at the cell surface.

INVADOPODIA

Specialized membrane protrusions (also known as an invasive pseudopodia) where active extracellular matrix degradation takes place.

INTRAVASATION

Passage from tissue into blood or lymph vessel.

EXTRAVASATION

Passage from blood or lymph vessel into tissue.

CHEMOKINES

A family of chemotactic proteins that are divided into C, CC, CXC and CX3C chemokines, depending on the number and spacing of conserved cysteine residues in the amino-terminal part of the protein. Chemokines are involved in inflammatory-cell recruitment and act through G-protein-coupled receptors.

RIBOZYMES

RNA molecules that function like enzymes and exert a catalytic activity. Ribozymes can be designed to cleave specific mRNAs and thereby inhibit protein synthesis.

COCCIDIOSTAT

A drug used to treat coccidiosis, an intestinal disease that is caused by a protozoan.

ANTHRAX TOXIN

Anthrax toxin is a three-part toxin that is secreted by the bacterium Bacillus anthracis and consists of protective antigen (PA), oedema factor (EF) and lethal factor (LF). PA is cleaved by furin-like proteinases at the cell surface, and cleaved PAs form a complex with EF and LF. The complex is endocytosed, and LF and EF are translocated to the cytosol where they act cytotoxically. The requirement for proteolysis of PA has been exploited by replacing the furin-like cleavage site with a sequence recognized by MMPs, in a recombinant anthrax toxin derivative.

ADAMTS

(A disintegrin and metalloproteinase with thrombospondin type 1 motifs). A family of soluble proteinases, closely related to the ADAMs, that contains domains with high homology to thrombospondin.

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Egeblad, M., Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2, 161–174 (2002). https://doi.org/10.1038/nrc745

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