Tumour invasion and matrix metalloproteinases

doi:10.1016/j.critrevonc.2003.10.008

Critical Reviews in Oncology/Hematology

Volume 49, Issue 3, March 2004, Pages 179-186

https://doi.org/10.1016/j.critrevonc.2003.10.008 Get rights and content

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes which play a major role in tumour invasion. They are mainly produced by host stromal cells in most carcinomas and their expression implies a close co-operation between tumour and stromal cells. Increasing data also demonstrate that, in association with a process of epithelial-to-mesenchymal transition, many MMPs can be expressed by tumour cell themselves.

Their most well-known role is the degradation of extra-cellular matrix macromolecules which in turn may regulate tumour invasion in some conditions. This ECM degradation generates some matrikins which are also implicated in tumour invasion and angiogenesis. Moreover, MMPs are also implicated in the degradation of cell adhesion molecules and release and activation of growth factors.

Introduction

Tumour invasion is greatly dependent on the permissive action of the microenvironment. One critical factor is the production of proteolytic enzymes involved in the degradation and remodelling of the extra-cellular matrix (ECM). Among these enzymes, matrix metalloproteinases (MMPs) represent a large family playing key roles in cell proliferation, angiogenesis, tumour invasion and metastasis. These enzymes principally degrade the ECM components, but have also other substrates such as cytokines, growth factor receptors, cell–cell and cell–matrix adhesion molecules which may also participate to the invasion process [1]. Moreover, the degradation of ECM macromolecules and cell adhesion molecules can release cryptic sites that in turn may function to modulate the cell behaviour.

Section snippets

The family of MMPs

MMPs are zinc-dependent endopeptidases, which are composed of at least a pro-domain, a catalytic domain and a highly conserved active site domain which contains the HEXGHXXGXXH motif (Table 1). This motif contains three histidine residues involved in the binding of zinc ligands necessary for MMP activity. MMPs also contain a PRCGVDP motif in the pro-domain that is responsible for maintaining latency in the zymogens. The production of active enzymes requires the proteolytic removal of the

The source of MMPs in tumours

Numerous tumour cell lines produce proteolytic enzymes involved in cell invasion in several in vitro migration/invasion assays by degrading various substrates such as type I collagen or Matrigel but are also implicated in vivo in tumour take and tumour invasion after subcutaneous injection in nude mice. These observations led to the hypothesis that tumour cells were largely implicated in the invasion process via secreted proteolytic enzymes. Indeed, the first observation using

The co-operation between tumour and stromal cells

Among the factors involved in the co-operation between tumour and host cells, extracellular matrix metalloproteinase inducer (EMMPRIN) is produced by tumour cells and is able to stimulate the expression of MMP-1, MMP-2 and MMP-3 by fibroblasts [25]. This factor is a transmembrane glycoprotein of 58 kDa identified as a member of the immunoglobulin superfamily. Immunohistochemical studies have demonstrated that EMMPRIN is localised in numerous tumours including bladder, skin, lung and breast

Role of the ECM degradation fragments in the regulation of MMPs and tumour invasion

An emerging concept in the field of tumour invasion is that proteolytic activity on ECM substrates uncovers or releases cryptic sites of ECM macromolecules that function to modulate a cellular response. Such sites have been referred as matricryptic sites or matrikins.

Among these ECM macromolecules, laminin 5 represents a factor able to stimulate tumour invasion. Thus, it has been shown that MMP-2 and MMP-14 selectively cleaves the γ2 chain of laminin 5, which in turn has chemotactic properties

MMPs and tumour cell phenotype

Although the principal source of MMPs is the stromal cells, in some circumstances, MMPs may be produced in vivo by tumour cells. MMP production by tumour cells themselves is often associated with the expression of other mesenchymal markers and the loss of many epithelial characteristics, a phenomenon referred as to an epithelial-to-mesenchymal transition (EMT) [69], [70], [71]. Indeed, these cells express intermediate filaments of vimentin and present a loss or a redistribution of cell adhesion

Conclusions

Tumour invasion is a complex process involving an interplay between different cell types present in the tumour environment. The enhanced production of MMP in the tumour environment either by stromal cells involved in the stroma reaction or by tumour cells undergoing an EMT appear as key events of tumour invasion. The detection of large amounts of MMPs in many cancers and their association with poor prognosis have emphasised their role as potential therapeutic targets. New therapeutic approaches

Myriam Polette is Assistant Professor of Cell Biology and she works in the INSERM Unit 514 in Reims, France.

References (74)

S.D. Shapiro
Matrix metalloproteinases degradation of extracellular matrix: biological consequences
Curr. Opin. Cell Biol.
(1998)
H. Nagase et al.
Matrix metalloproteinases
J. Biol. Chem.
(1999)
S. Hernandez-Barrantes et al.
Regulation of membrane-type matrix metalloproteinases
Sem. Cancer Biol.
(2002)
V. Knauper et al.
Cellular mechanisms for human procollagenase (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase A (MMP-2) are able to generate active enzyme
J. Biol. Chem.
(1996)
Y.E. Liu et al.
Preparation and characterization of recombinant tissue inhibitor of metalloproteinase-4 (TIMP-4)
J. Biol. Chem.
(1997)
S. Zucker et al.
Tumorigenic potential of extracellular matrix metalloproteinase inducer
Am. J. Pathol.
(2001)
E. Petitclerc et al.
New functions for noncollagenous domains of human collagen IV. Novel integrin ligands inhibiting angiogenesis and tumor growth in vivo
J. Biol. Chem.
(2000)
C. Martinella-Catusse et al.
Down regulation of MT1-MMP by the alpha-3 chain of type IV collagen inhibits bronchial tumor cell line invasion
Lab. Invest
(2001)
J.C. Monboisse et al.
The α3 chain of type IV collagen prevents activation of human polymorphonclear leucocytes
J. Biol. Chem.
(1994)
A.G. Marneros et al.
The role of collagen derived proteolytic fragments in angiogenesis
Matrix Biol.
(2001)

Z.Y. Dong et al.

Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma

Cell

(1997)

S. Hirohashi

Inactivation of the E-cadherin-mediated cell adhesion system in human cancers

Am. J. Pathol.

(1998)

B. Nawrocki-Raby et al.

E-Cadherin mediates MMP downregulation in highly invasive bronchial tumor cells

Am. J. Pathol.

(2003)

M. Seiki

Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion

Cancer Lett.

(2003)

J.A. Dumin et al.

Pro-collagenase 1 (matrix metalloproteinase-1) binds to the α2β1 integrin upon release from keratinocytes migrating on type I collagen

J. Biol. Chem.

(2001)

P.C. Brooks et al.

Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin αvβ3

Cell

(1996)

J.M. Whitelock et al.

The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase

J. Biol. Chem.

(1996)

J.L. Fowlkes et al.

Matrix metalloproteinases as insulin-like growth factor binding protein-degrading proteinases

Prog. Growth factor Res.

(1995)

B. Bertaux et al.

Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases

J. Invest. Dermatol.

(1991)

A.F. Chambers et al.

Changing views of the role of matrix metalloproteinases in metastasis

J. Natl. Cancer Inst.

(1997)

N. Johansson et al.

Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck

Am. J. Pathol.

(1997)

B.S. Nielsen et al.

Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ to invasive lesion ductal carcinoma

Cancer Res.

(2001)

T.H. Vu et al.

Matrix metalloproteinases: effectors of development and normal physiology

Genes Dev.

(2000)

P. Mignatti et al.

Plasminogen activators and matrix metalloproteinases in angiogenesis

Enzyme Protein

(1996)

H. Nagase

Activation mechanisms of matrix metalloproteinases

Biol. Chem. Hoppe Seyler

(1997)

H. Kolkenbrock et al.

Generation and activity of ternary gelatinase B/TIMP-1/LMW-stromelysin 1 complex

Biol. Chem. Hoppe Seyler

(1995)

S.H. Barsky et al.

Type IV collagenase immunoreactivity in invasive breast carcinoma

Lancet

(1993)

P. Basset et al.

A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas

Nature

(1990)

K. Nabeshima et al.

Matrix metalloproteinases in tumor invasion: role for cell migration

Pathol. Annual

(2002)

J.A. Uria et al.

Regulation of collagenase-3 in human breast carcinomas is mediated by stroma-epithelial cell interactions

Cancer Res.

(1997)

M. Polette et al.

Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy

Virchows Arch.

(1994)

K.J. Heppner et al.

Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response

Am. J. Pathol.

(1996)

A. Okada et al.

Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon

Proc. Natl. Acad. Sci. U.S.A.

(1995)

B. Nawrocki et al.

Expression of matrix metalloproteinases and their inhibitors in human bronchopulomonarty carcinomas: quantificative and morphological aspects

Int. J. Cancer

(1997)

C. Bisson et al.

Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells

Int. J. Cancer

(2003)

C. Gilles et al.

Implication of collagen type I induced membrane type-1 matrix metalloproteinase expression in matrix metalloproteinase-2 activation in the metastastic progression of breast carcinoma

Lab. Invest.

(1997)

H.S. Azzam et al.

Collagen-induced activation of the Mr 72,000 type IV collagenase in normal and malignant human fibroblastoid cells

Cancer Res.

(1992)

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Myriam Polette is Assistant Professor of Cell Biology and she works in the INSERM Unit 514 in Reims, France.

Béatrice Nawrocki-Raby is searcher in INSERM Unit 514 in Reims, France.

Christine Clavel is Professor of Cell Biology and she works in INSERM Unit 514 in Reims, France.

Christine Gilles is a research associate from the “Fond National de la Recherche Scientifique” (F.N.R.S., Belgium).

Philippe Birembaut is Professor of Histology and he works in INSERM Unit 514 in Reims, France.

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Tumour invasion and matrix metalloproteinases

Abstract

Introduction

Section snippets

The family of MMPs

The source of MMPs in tumours

The co-operation between tumour and stromal cells

Role of the ECM degradation fragments in the regulation of MMPs and tumour invasion

MMPs and tumour cell phenotype

Conclusions

Curr. Opin. Cell Biol.

J. Biol. Chem.

Sem. Cancer Biol.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

Lab. Invest

J. Biol. Chem.

Matrix Biol.

Cell

Am. J. Pathol.

Am. J. Pathol.

Cancer Lett.

J. Biol. Chem.

Cell

J. Biol. Chem.

Prog. Growth factor Res.

J. Invest. Dermatol.

Changing views of the role of matrix metalloproteinases in metastasis

J. Natl. Cancer Inst.

Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck

Am. J. Pathol.

Collagenase-3 expression in breast myofibroblasts as a molecular marker of transition of ductal carcinoma in situ to invasive lesion ductal carcinoma

Cancer Res.

Matrix metalloproteinases: effectors of development and normal physiology

Genes Dev.

Plasminogen activators and matrix metalloproteinases in angiogenesis

Enzyme Protein

Activation mechanisms of matrix metalloproteinases

Biol. Chem. Hoppe Seyler

Generation and activity of ternary gelatinase B/TIMP-1/LMW-stromelysin 1 complex

Biol. Chem. Hoppe Seyler

Type IV collagenase immunoreactivity in invasive breast carcinoma

Lancet

A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas

Nature

Matrix metalloproteinases in tumor invasion: role for cell migration

Pathol. Annual

Regulation of collagenase-3 in human breast carcinomas is mediated by stroma-epithelial cell interactions

Cancer Res.

Gelatinase A expression and localization in human breast cancers. An in situ hybridization study and immunohistochemical detection using confocal microscopy

Virchows Arch.

Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response

Am. J. Pathol.

Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon

Proc. Natl. Acad. Sci. U.S.A.

Expression of matrix metalloproteinases and their inhibitors in human bronchopulomonarty carcinomas: quantificative and morphological aspects

Int. J. Cancer

Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells

Int. J. Cancer

Implication of collagen type I induced membrane type-1 matrix metalloproteinase expression in matrix metalloproteinase-2 activation in the metastastic progression of breast carcinoma

Lab. Invest.

Collagen-induced activation of the Mr 72,000 type IV collagenase in normal and malignant human fibroblastoid cells

Cancer Res.