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

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.

Figure 1. Major signaling pathways for cytokines and growth factors in synovial cells

Upon binding to its receptor, cytokines, such as IL-1β, and growth factors, such as basic fibroblast growth factor, stimulate several signaling pathways: NFkB, p38, JNK and MEK/ERK. These pathways target DNA sequences in the promoter of the MMP-1 gene, increasing transcription. P50/p65 proteins bind to the NFkB site and cFos/cJun proteins bind to the AP-1 site. TNFα and other growth factors, such as VEGF, activate similar pathways, and target these same sites in the MMP promoters [3,4].

Figure 2. Similarities between the activated fibroblasts in Rheumatoid Arthritis and the Carcinoma-Associated Fibroblasts in cancer

In both cell types, CXCR4, SDF-1, and MMP-1 are up-regulated compared to normal fibroblasts. Signaling through CXCR4 leads to activation of the ERK1/2 pathway, which is a component of the MAPK pathway, in CAFs and the MAPK pathway in activated fibroblasts. Both the MAPK and ERK1/2 pathways are known to stimulate MMP-1 and SDF-1 levels in other cell types [3,4,25].

Figure 3. MMP-1 has multiple functions within the tumor microenvironment

MMP-1 is secreted at high levels by melanoma cells, where it degrades collagen within the extracellular matrix surrounding the tumor cells to facilitate tumor cell invasion. MMP-1 also proteolytically activates PAR-1, expressed by multiple cell types within the microenvironment, to promote tumor progression. For example, MMP-1/PAR-1 signaling on endothelial cells induces pro-angiogenic gene expression, which may contribute to tumor metastasis, and autocrine MMP-1/PAR-1 signaling in melanoma cells induces pro-tumorigenic gene expression, which may contribute to several aspects of tumor progression, including proliferation, invasion and metastasis [34,36,48]. Both the collagenolytic and PAR-1 activating functions of MMP-1 also likely play a role in RA pathology.

Figure 4. Proposed steric hindrance model for inhibiting MMP-1

Overlapping degenerate DR-1 and AP-1 binding sites in promoter DNA. Numbers show distance from transcriptional start site in the rabbit MMP-1 gene [59]. In the model, IL-1β induces AP-1 proteins, which bind to their cognate element and increase transcription. However, if rosiglitzaone or LG268 is present, the liganded RXR:PPARγ dimer binds to the degenerate DR-1 site, and physically blocks AP-1 and transcriptional activation by IL-1β.