Elsevier

Biochimie

Volume 87, Issues 3–4, March–April 2005, Pages 361-368
Biochimie

EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair

https://doi.org/10.1016/j.biochi.2004.09.023Get rights and content

Abstract

Matrix metalloproteinases (MMPs) play a central role in normal tissue remodeling and disease, they regulate tumor microenvironment and their expression is increased in most human cancers. Targeting their activity remains a major challenge. Their production and activation is tightly regulated by complex mechanisms that include cytokines and growth factors, cell–matrix and cell–cell interactions. The observations of increased MMP level at the epithelio–stromal interface led to the identification of EMMPRIN/CD147, a membrane spanning molecule highly expressed in tumor cells, that stimulates MMPs production in neighboring fibroblasts. Later studies have shown that EMMPRIN can also induce MMP in the same population of cells. Elevated EMMPRIN level was detected in numerous malignant tumors and has been correlated with tumor progression in experimental and clinical conditions. The presence and modulation of EMMPRIN in normal tissues associated with increased MMP expression suggests that this EMMPRIN-mediated MMP induction could be a common mechanism in non-tumoral physiological and/or pathological situations. Targeting EMMPRIN in cancer and other pathological conditions such arthritis and ulceration appears a promising future therapeutic strategy, but requires a better understanding of its mode of action and regulation. Potential regulators that influence EMMPRIN level and its MMP inducing activity include growth factors, hormones, glycosylation and membrane shedding. This review will discuss the recent findings concerning these diverse regulatory mechanisms in various physiological and pathological situations.

Introduction

Basement membrane separates epithelia from the underlying connective tissue and participates in mediating and modulating epithelial–stromal interaction. Its disruption modifies epithelio–stromal interaction in a way that triggers stromal remodeling necessary for tumor growth, while in wound healing, this step represents the initiation of a repair process that aims to restore tissue homeostasis. Matrix metalloproteinases (MMPs) play a central role in these processes. Their production and activation is tightly regulated by complex mechanisms aimed at maintaining proper ECM turnover. These include paracrine factors such as cytokines, growth factors and hormones, but in diseased states such as cancer, there is often a high level of MMP activity at the tumor–stroma interface, suggesting the existence of an additional mechanism for focal MMP expression. The increased MMP activity in cancerous tissues was primarily thought to be due to tumor cell production of the enzymes needed for the invasion and metastatic spread. It was later realized that many of the MMPs present in the tumor tissue microenvironment are expressed by the stromal cells rather than by the tumor cells themselves. A search for an MMP inducing factors in tumor cell led to the identification of CD147/EMMPRIN [1], [2], a highly glycosylated cell surface transmembrane protein, associated with surface of tumor cell which stimulate MMP synthesis in neighboring fibroblasts. Depending on the cell system, EMMPRIN can stimulate production of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-3 (stromelysin 1) but has no effect on their physiological inhibitors TIMP-1 or TIMP-2, hence modifying the collagenolytic balance towards MMP production and activation [1], [2], [3], [4], [5]. The stimulation of the membrane type MMPs (MT-MMPs) as well as an increased activation of MMP-2 were also reported in some cases [6], [7], suggesting that different cell types may produce different MMPs in response to EMMPRIN [7], [8].

As EMMPRIN expression is often elevated on human tumor cells and was shown to increase tumor cell invasion, most studies so far focused on its role in cancer progression. However, EMMPRIN has a broader tissue distribution and was also shown to be expressed on activated T cells [9], on differentiated macrophage [10], on retinal pigment epithelium [11], in the endometrium [12] and in normal human keratinocytes [13]. The presence of EMMPRIN in non-tumoral tissues suggests a role in other physiological and/or pathological situations which may be associated with increased MMP expression. This review will focus on MMPs regulation through EMMPRIN in tumoral and non-tumoral tissue remodeling, as in both processes there is evidence that epithelial–stromal cell interaction leads to increase in MMP expression.

Section snippets

Biochemical properties of EMMPRIN

The cDNA for human EMMPRIN encodes a protein that belongs to the immunoglobulin (Ig) superfamily [14], and its sequence has been found to be identical to that of human basigin [15], leukocytes activation-associated M6 antigen [9] and hepatoma cell antigen Hab18G [16] for whom no function have been previously described. Homologues of EMMPRIN in other species have also been discovered, such as basigin or gp42 in mouse [15], OX47 in rat [17], [18] and 5A11, HT7 or neurothelin in chick [19], [20],

Characterization and regulation of EMMPRIN in cancer

The upregulation of MMPs such as MMP-1, MMP-2 and MMP-3 by tumor cell–fibroblast interactions has been demonstrated by several investigators and was shown to promote tumor progression [27], [28], [29], [30]. The tumor cell surface molecule responsible for inducing MMPs in neighboring normal fibroblasts was first designated tumor collagenase stimulating factor (TCSF) by the Biswas Laboratory, after isolation of a 58 kDa glycoprotein from the plasma membrane of cancer cells and the demonstration

Characterization and regulation of EMMPRIN in normal development and non-tumoral tissue remodeling

While the role of tumoral EMMPRIN in inducing fibroblasts to produce MMPs has now been extensively studied and its implication in tumor invasion and cancerogenesis has been convincingly illustrated, recently accumulated data also advocate a role for EMMPRIN in modulating MMPs expression during normal tissue remodeling and differentiation. Epithelial cells of various tissues were shown to contain high levels of EMMPRIN and, by analogy to the situation in cancer, it seems reasonable to assume

Conclusions and perspectives

In spite of the initial enthusiasm regarding the use of synthetic MMP inhibitors in cancer treatment, the results of several clinical assays were somewhat disappointing. Targeting EMMPRIN, which induces only a limited number of MMPs specifically increased during tumor–stromal interaction may represent an attractive new strategy of MMP inhibition. In this way, inhibiting EMMPRIN would inhibit MMPs even before they are produced, contrary to the synthetic inhibitors which aim at inhibiting their

Acknowledgements

We thank Ms. Elisabeth Savariau for the preparation of the artwork.

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