Elsevier

Journal of Autoimmunity

Volume 33, Issues 3–4, November–December 2009, Pages 214-221
Journal of Autoimmunity

Matrix metalloproteinase and G protein coupled receptors: Co-conspirators in the pathogenesis of autoimmune disease and cancer

https://doi.org/10.1016/j.jaut.2009.09.011Get rights and content

Abstract

Similarities in the pathologies of autoimmune diseases and cancer have been noted for at least 30 years. Inflammatory cytokines and growth factors mediate cell proliferation, and proteinases, especially the collagenase, Matrix Metalloproteinase-1 (MMP-1), contribute to disease progression by remodeling the extracellular matrix and modulating the microenvironment. This review focuses on two cancers (melanoma and breast) and on the autoimmune disorder, rheumatoid arthritis (RA), and discusses the activated stromal cells found in these diseases. MMP-1 was originally thought to function only to degrade interstitial collagens, but recent studies have revealed novel roles for MMP-1 involving the G protein-coupled receptors: the chemokine receptor, CXCR-4, and Protease Activated Receptor-1 (PAR-1). Cooperativity between MMP-1 and CXCR4/SDF-1 signaling influences the behavior of activated fibroblasts in both RA and cancer. Further, MMP-1 is a vital part of an autocrine/paracrine MMP-1/PAR-1 signal transduction axis, a function that amplifies its potential to remodel the matrix and to modify cell behavior. Finally, new therapeutic agents directed at MMP-1 and G protein-coupled receptors are emerging. Even though these agents are more specific in their targets than past therapies, these targets are often shared between RA and cancer, underscoring fundamental similarities between autoimmune disorders and some cancers.

Section snippets

Matrix Metalloproteinase-1 (MMP-1), rheumatoid arthritis (RA), and cancer

MMPs are a family of zinc-dependent endopeptidases that function at neutral pH and that are responsible for the degradation of the extracellular matrix [2], [3], [4]. While low levels of these enzymes are essential for normal homeostasis, high levels are implicated in the pathology of several diseases. Although many MMPs are elevated in these conditions, MMP-1 has a particularly prominent role. Collagen (types I, II and III) is the body's most abundant protein, comprising 30% of all protein,

Regulation of MMP-1 gene expression

MMP expression is tightly regulated and occurs primarily at the level of transcription [2], [3], [4], [7]. In normal tissues, basal/constitutive expression is low, but is induced in response to growth factors and cytokines that activate signal transduction pathways (Fig. 1). The molecular mechanisms of transcriptional activation of several MMPs, including MMP-1, at the promoter are well characterized and comprise the Activator Protein-1 (AP-1) element in the proximal region of the promoter at

Carcinoma associated fibroblasts (CAFs), MMP-1 and CXCR4

While cancer research has traditionally focused on the tumor cells, host/tumor cell interactions in the tumor microenvironment are increasingly recognized as critical components of tumor development and progression [10], [11]. These interactions between the tumor and adjacent stromal cells result in the production of stromal factors, such as growth factors, chemokines, cytokines, proteases, and vascular-stimulating factors [12], [13], all of which can contribute to the growth of the primary

Endothelial cells, Protease Activated Receptor-1 (PAR-1) and MMP-1

The function of another G protein-coupled receptor, PAR-1, is directly linked to the enzymatic activity of MMP-1. Among all the MMPs, MMP-1 has the unique ability to cleave PAR-1 [34], with subsequent activation of signal transduction pathways and alterations in the expression of downstream genes. This unique ability to cleave PAR-1 gives MMP-1 a powerful role in controlling cell behavior.

As an example, we found that by silencing MMP-1 expression in a human melanoma cell line with shRNA

Therapeutic strategies that target MMP-1 and G protein-coupled receptors

RA and cancer share several therapeutic strategies, including the use of chemotherapeutic agents such as methotrexate, antibodies directed at cytokines/growth factors and their receptors, and/or small molecule inhibitors of signal transduction pathways ([3], [4], [49], [50], [51]; www.Cancer.org). In cancers, these treatments are often successful, but they may also eventually fail, resulting in relapse as tumors mutate and become resistant. Since stromal cells are recognized as critical

Concluding comments

As predicted by Sporn and Harris three decades ago, our knowledge of the precise molecular mechanisms that are driving non-malignant proliferative diseases (such as RA) and malignancies (such as breast cancer and melanoma) has grown enormously. This new information has re-enforced the original concept that these two seemingly disparate categories of diseases share many common properties, and the analogy between the reactive stroma in the tumor microenvironment and the pannus of RA has become

Acknowledgement

Supported by grants NIH-AR-25699 and NIH-CA-77267 to C.E.B., and by T32-CA-009658 to S.M.E., T32-AI-07363 to J.S.B., and T32-AR-07576 to A.C.S. and P.S.B.

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