Matrix-directed regulation of pericellular proteolysis and tumor progression

https://doi.org/10.1016/S1044-579X(02)00026-3Get rights and content

Abstract

The microenvironment of cancer cells, composed of extracellular matrix (ECM) macromolecules, plays a pivotal function in tumor progression. ECM preexisting modules or cryptic sites revealed by partial enzymatic hydrolysis positively or negatively regulate matrix metalloproteinase (MMP) expression and activation, further influencing matrix invasion by cancer cells. Pericellular activation of gelatinase A (MMP-2) proceeds via the formation of a complex involving its inhibitor, TIMP-2, its activator(s), MT-MMPs and αvβ3 integrin forming a docking system. This proteinase has been invariably linked to cancer cell invasive potential and is often predictive of a poor survival. MMP-2 degrades most ECM macromolecules and appears to act as a main ‘decryptase’.

ECM modulation of MMP-2 activation pathway thus influences angiogenesis and tumor growth. For instance the noncollagenous domain of α3 chain of type IV collagen, through αvβ3 integrin binding, inhibits both MT1-MMP and αvβ3 integrin expression from melanoma cells and empedes cell migration and proliferation. At the opposite, a particular module in elastin (VGVAPG) with type VIII β turn conformation stimulates MT1-MMP and proMMP-2 activation through binding to S-gal elastin receptor, and increases the matrix invasive capacity of several cancer cell lines and endothelial cells. Endocytosis emerges as a main mechanism controlling MMP-2, and also other MMPs; it proceeds via the formation of a MMP-thrombospondin(s) complex further recognized by the LRP scavenger receptor.

ECM undergoes conspicuous variations with aging linked to alterations of tissue organization and post-translational modifications of matrix constituents that modify cell–matrix interactions and MMP-2 activation pathway.

Introduction

One of the main hallmarks of cancer progression resides in the capacity of cells to cross through several tissue boundaries. Degradation of the cell microenvironment, consisting in matrix macromolecules, has to be precisely controlled in space and time since either too little or too much degradation can empede such an invasive process.1 Thus, intuitively, the concept of pericellular and directional proteolysis comes to mind. To achieve such a vectorial tissue penetration, most often cancer cells use host cells by stimulating their proteinase machinery and further bind host proteinases.2., 3., 4. Requirement for certain stromal cells in tumor progression may therefore be in keeping with a long latency period, one feature of carcinogenesis.

The importance of stroma reaction in cancer is not limited to host cells; extracellular matrix (ECM) is no longer an inert scaffold but plays an active role in the control of tumor cells and tumor growth. ECM remodeling or limited proteolysis may reveal new cryptic sites that influence the proteolytic phenotype of the host or cancer cells; proteolytic degradation of ECM constituents may also release (and activate) ECM-bound cytokines and release matrix fragments which then modulate tumor cell growth and migration as well as angiogenesis.5 Conspicuous qualitative and quantitative modifications of ECM composition occur with aging and any cancer cell may sense differently such an aged microenvironment.6

Members of the matrix metalloproteinase (MMP) family7 have been associated with the invasive and metastatic behavior of virtually all types of cancers and most often the highest expression of those enzymes is recovered at the invasive front of tumor–stroma interface.8

MMPs belong to clan MB-family M-10 of metallopeptidases and share the same catalytic mechanism.9 The 24 members of that family characterized to date, are structurally organized in a modular fashion, each exosite imparting specific function.10 For instance, the carboxy-terminal hemopexin (PEX) domain may play a pivotal role in tissue inhibitor of metalloproteinases (TIMP) binding or can confer collagen triple helicase activity.7 Fibronectin domains (FN domains) adjacent to the catalytic center of gelatinases (MMP-2 and MMP-9) are main sites of substrate recognition.11 Several MMPs are membrane-associated proteases, either containing a transmembrane or a glycosylphosphatidylinositol-anchoring domain.12., 13., 14., 15. Those enzymes are ideally addressed for directing pericellular proteolysis and also participate in activation of other proMMPs.

Although MMPs were originally described as matrix-degrading enzymes, i.e. matrixins, it is now recognized that, in vitro or in cell systems, MMPs display a wide repertoire of potential substrates.5., 16. They can inactivate or activate cytokines and growth factors, degrade serpins, and hydrolyze cell receptors. Consequently, MMPs appear to play a crucial function in tumor growth by regulating both the growth environment of cancer cells and angiogenesis. Such an ECM modifying potential of cancer cells therefore constitutes a major determinant in tumor outgrowth and further dissemination of cancer cells; it needs to be emphasized that any compositional variation of ECM might influence either favorably or unfavorably tumor progression.

To illustrate the importance of ECM in directing MMP activity and to delineate how those partners can be interrelated in cancer, we will focus on one member of the MMP family, i.e. MMP-2 or gelatinase A. Overexpression of that enzyme, originally described as type IV collagenase, has been invariably correlated with an invasive phenotype in several cancer cell types and is often predictive of poor survival;3 MMP-2-deficient mice display lowered lung colonization following intravenous administration of cancer cells.17

Several matrix macromolecules were described as modulators of MMP-2 activity; here we mainly focus on the influence of three ECM constituents belonging to distinct tissue boundaries: type IV collagen as one of the main basement membrane components, elastin as the major constituent of the stromal elastic fiber system and one matricellular protein, namely thrombospondin(s).

Section snippets

Mechanisms involved in gelatinase A (MMP-2) activation

A TRE element as well as a PEA-3 site, which bind the Fos/Jun containing complex AP-1 and Ets family nuclear protooncogenes, respectively, are present in the promoters of most human MMP genes. AP-1 and PEA-3 sites, which act in a cooperative manner for gene transcription in response to several cytokines and growth factors, are absent in MMP-2 promoter.18 Although MMP-2 expression can be induced by agents like TGF-β or UVB/interleukin 819 in several cancer cell lines, it is now recognized that

Type IV collagen

Partial impairment or even entire loss of basement membrane around the invasive tumor in the stroma is one of the major characteristics of invasive carcinoma. Basement membrane is essentially composed of type IV collagen, laminin, entactin/nidogen, and proteoglycans.53 Type IV collagen is organized as a network of three α(IV) chains, each chain possessing distinct domains: a 7S domain at its N-terminus, a large central triple helical domain of about 1400 amino acids in α1(IV) chain and a

Concluding remarks

Disruption of the specialized microenvironment of cancer cells, composed of host cells and their insoluble ECM, can actively contribute to cancer spreading. Factors from cancer cells stimulate proteinase expression from the host leading to tumor angiogenesis; alternatively, cancer cells can bind and activate those host-produced enzymes, such as MMP-2, to effectively penetrate the tissue and ultimately metastasize. In the course of such a degradation and invasive process, the three-dimensional

Acknowledgements

This work was supported by ARERS (Région Champagne-Ardenne), the Ministère de la Recherche et de l’Enseignement Supérieur and the Centre National de la Recherche Scientifique (CNRS).

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