Matrikines from basement membrane collagens: A new anti-cancer strategy

doi:10.1016/j.bbagen.2013.12.029

Biochimica et Biophysica Acta (BBA) - General Subjects

Volume 1840, Issue 8, August 2014, Pages 2589-2598

https://doi.org/10.1016/j.bbagen.2013.12.029 Get rights and content

Highlights

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Matrikines are endogenous angiogenesis inhibitors inducing endothelial cell apoptosis.
•
Matrikines inhibit tumor growth by down-regulating cell migratory properties.
•
In animal cancer models, matrikines increase the efficiency of conventional therapies.

Abstract

Background

Tumor microenvironment is a complex system composed of a largely altered extracellular matrix with different cell types that determine angiogenic responses and tumor progression. Upon the influence of hypoxia, tumor cells secrete cytokines that activate stromal cells to produce proteases and angiogenic factors. In addition to stromal ECM breakdown, proteases exert various pro- or anti-tumorigenic functions and participate in the release of various ECM fragments, named matrikines or matricryptins, capable to act as endogenous angiogenesis inhibitors and to limit tumor progression.

Scope of review

We will focus on the matrikines derived from the NC1 domains of the different constitutive chains of basement membrane-associated collagens and mainly collagen IV.

Major conclusions

The putative targets of the matrikine control are the proliferation and invasive properties of tumor or inflammatory cells, and the angiogenic and lymphangiogenic responses. Collagen-derived matrikines such as canstatin, tumstatin or tetrastatin for example, decrease tumor growth in various cancer models. Their anti-cancer activities comprise anti-proliferative effects on tumor or endothelial cells by induction of apoptosis or cell cycle blockade and the induction of a loss of their migratory phenotype. They were used in various preclinical therapeutic strategies: i) induction of their overexpression by cancer cells or by the host cells, ii) use of recombinant proteins or synthetic peptides or structural analogues designed from the structure of the active sequences, iii) used in combined therapies with conventional chemotherapy or radiotherapy.

General significance

Collagen-derived matrikines strongly inhibited tumor growth in many preclinical cancer models in mouse. They constitute a new family of anti-cancer agents able to limit cancer progression. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Introduction

Tumor microenvironment is a complex structure composed of a largely modified extracellular matrix (ECM) which closely interacts with various cell types to determine tumor angiogenesis and tumor progression. Cell–matrix interactions occurring in tumor progression and angiogenesis can be controlled by bioactive fragments revealed from ECM molecules by limited proteolysis or by cryptic site exposure. These fragments, named matrikines, are protein domains exerting a biological activity [1]. The term of matricryptin also defines a protein domain which exhibits a biological activity not carried by the native protein and unmasked by proteolysis [2]. Various matrikines have been described in the literature as endogenous inhibitors of angiogenesis [3]. In the present review, we will describe the anti-tumorigenic or anti-angiogenic matrikines derived from basement membrane-associated collagens, with a particular focus on matrikines derived from type IV and type XIX collagens.

Section snippets

Tumor microenvironment

During tumor progression, cancer cells create a local microenvironment characterized by a deregulated and disorganized ECM. Abnormal ECM affects cancer progression by directly promoting cell transformation and metastasis. ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation and thus lead to the generation of a tumorigenic microenvironment [4], [5]. In tumor areas, ECM consists in a surrounding basement membrane, produced by

Basement membrane collagens

Basement membranes are highly specialized ECM that represent a barrier between the epithelium and the underlying ECM. They consist of type IV collagen and associated collagens (collagens XV, XVIII and XIX), structural glycoproteins (laminin, entactin, …) and proteoglycans, as perlecan [24]. They provide mechanical support for the cell. Glomerular basement membrane has a more specific role of filtration. Basement membranes also serve as a reservoir of growth factors and cytokines, which, after

Matrikines derived from basement membrane collagens

These matrikines inhibit in vivo tumor growth through anti-angiogenic and/or anti-tumor activities at different levels. The first putative target is directly the cancer cells, with inhibition of their proliferation by induction of cell cycle blockade [43], [44], [45]. The inhibition can also be exerted on the migratory properties of cancer cells by inhibiting proteolytic cascades (MMPs, plasminogen activation system). The inhibition may occur through an alteration of protease location at the

Matrikine receptors and intracellular transduction

Matrikines derived from basement membrane collagens exert their anti-angiogenic or anti-tumor activities by binding to cell surface receptors, belonging to the integrin family, on tumor or endothelial cells (Table 2):

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arresten exerted its effects through α1β1 integrin liganding [55].
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canstatin bound to αVβ3 and αVβ5 integrins on endothelial or tumor cells [63], [66].
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tumstatin bound to α3β1 and αvβ3 integrins on a site distinct of the RGD binding site and induced a conformational change of the

Matrikine generation

Tumstatin was produced in vivo by cleavage of collagen IV by MMP-2 and MMP-9, as demonstrated by using MMP-2 and MMP-9-null mice [88]. The serum concentration of circulating tumstatin in mice was determined by ELISA and found to be between 300 and 360 ng/mL [88]. In addition, COL4A3 null mice, deficient in tumstatin, showed an increased pathological angiogenesis and accelerated tumor growth which could be reversed by exogenous tumstatin administration at physiological concentrations [88]. In our

Basement membrane-associated collagen chains as biomarkers

The expression of various basement membrane-associated collagens is modulated during tumor invasion. The destruction of the basement membrane is the first step in epithelial cancer invasion and metastasis. The alteration of α1(IV) and α2(IV) chain expression was correlated with tumor differentiation degree and preceded the loss of the other α(IV) chains in various cancer types [96], [97].

Tumor sections from patients with lung carcinoma showed tumstatin expression around some cancer clusters [98]

Preclinical therapeutic strategies

Matrikines have been tested in animal cancer models under different experimental protocols:

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matrikine in vivo overexpression, using constructions with viral vectors or plasmid DNA electrotransfer
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use of recombinant proteins
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use of synthetic peptides reproducing the active sequences or structural analogues.

Clinical trials

To increase survival in cancer, many clinical trials with MMP inhibitors have been developed, but unsuccessfully because of the complexity of the multiple roles of these proteases [22]. Anti-cancer therapeutic strategies using matrikines gave efficient results in preclinical cancer models in mouse, even though, in some cases, matrikine-treated tumors might escape to growth suppression [125]. Nevertheless, their application to human appears more difficult and only a few examples of clinical

Conclusions

Experimental studies in vitro and in various preclinical cancer models in mice highlight the strong potential of matrikines for anti-cancer agents design and development. Their ability to inhibit the proliferative and invasive properties of cancer cells and their anti-angiogenic activities are opening new opportunities to limit tumor progression. In addition, their endogenous origin contributes to a better tolerance, limiting side effects. The characterization of active minimal sequences will

Acknowledgements

This work was supported by funds from the Centre National de la Recherche Scientifique (UMR 7369), University of Reims Champagne Ardenne, the Region Champagne-Ardenne and the FEDER (Contract State-Region 2007–2013), the Ligue contre le Cancer

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^☆: This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

View full text

Matrikines from basement membrane collagens: A new anti-cancer strategy☆

Highlights

Abstract

Background

Scope of review

Major conclusions

General significance

Introduction

Section snippets

Tumor microenvironment

Basement membrane collagens

Matrikines derived from basement membrane collagens

Matrikine receptors and intracellular transduction

Matrikine generation

Basement membrane-associated collagen chains as biomarkers

Preclinical therapeutic strategies

Clinical trials

Conclusions

Acknowledgements

Am. J. Pathol.

Cell

Dev. Cell

Semin. Cancer Biol.

Biochem. Pharmacol.

Biochim. Biophys. Acta

Semin. Cell Dev. Biol.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Matrix Biol.

Cell

Exp. Cell Res.

J. Biol. Chem.

Methods Enzymol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Am. J. Pathol.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Blood

Blood

Cancer Cell

Biochem. Biophys. Res. Commun.

Clin. Chim. Acta

Anal. Biochem.

Hum. Pathol.

Régulation de l'activité cellulaire par la matrice extracellulaire: le concept de matrikine

J. Soc. Biol.

Endogenous inhibitors of angiogenesis

Cancer Res.

The extracellular matrix: a dynamic niche in cancer progression

J. Cell Biol.

The Matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices

Mol. Cell. Proteomics

Fibroblasts in cancer

Nat. Rev. Cancer

Matrix metalloproteinases and tumor metastasis

Cancer Metastasis Rev.

Cell surface remodeling by plasmin: a new function for an old enzyme

J. Biomed. Biotechnol.

Acid-mediated tumor proteolysis: contribution of cysteine cathepsins

Neoplasia

Tumour microenvironment — opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy

Nat. Rev. Cancer

Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer

Cancer Metastasis Rev.

The other side of MMPs: protective roles in tumor progression

Cancer Metastasis Rev.