MMP9: A Tough Target for Targeted Therapy for Cancer

Abstract

Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.

Keywords: cancer-related inflammation; epithelial–mesenchymal transmission; extracellular matrix; matrix metalloproteinase 9; targeted therapy.

Figure 1

A schematic representation of the MMP9 gene and protein organization. The exons are indicated by the numbered grey rectangles. The 5′-untranslated and 3′-untranslated regions (UTR) are indicated by white boxes. The 5′-flanking region includes relative positions of key transcription factor binding sites. The domain structure of the MMP9 protein starts from a signal peptide (lilac square), followed by a propeptide (blue rectangle). An O-glycosylated (OG) domain (red rectangle) is located between a catalytic domain and a hemopexin (PEX) domain (green rectangle); it comprises a zinc-binding active-site motif (Zn) and tree fibronectin-like (Fn II-like) repeats.

Figure 2

Schematic representation of the signaling pathways involved in MMP9 expression. The various extracellular signals, including proinflammatory cytokines (TNF-α, IL-8, and IL-1β) and growth factors (TGF-β, PDGF, and bFGF), can bind to their receptors and activate downstream signaling cascades involved in the activation of transcription factors (NF-κB, SP1, and AP1), which can than bind to specific sequences of the MMP9 gene promoter to trigger transcription. Transcription factors activate transcription in cooperation with additional transcriptional cofactors (CBP/p300, GRIP1, and CARM1). A secreted MMP9 protein degrades extracellular matrix proteins (collagens and elastin), cytokines (IL-1β, IL-8, and TNF-α), chemokines (CXCLs), and other matrix metalloproteases (MMPs). MMP9 by interactions with cellular receptors (CD44, E-cadherin, and α/β integrins) is able to proteolyze cell surface proteins. MMP9 activity in the extracellular matrix (ECM) can be regulated by its natural inhibitor TIMP-1. INFγ was found to inhibit the expression of MMP9 by STAT-1α-dependent sequestration of a PCAF cofactor. In this way, MMP9 regulates tissue remodeling, cell–cell and cell–ECM interactions, and activation of extracellular signal molecules, which promote cell migration, proliferation, angiogenesis, EMT, and ECM remodeling.

Figure 3

Alternative mechanisms for targeting MMP9 lead to enhanced specificity. Starting from the nonspecific small MMP9 inhibitors that chelate zinc ions (e.g., marimastat, ilomastat, and batimastat), through inhibitors targeting other than catalytic domain (N-(4-fluorophenyl)-4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-ylthio) butanamide; JNJ0966) and ending with function blocking antibodies (REGA 3G12, andecaliximab), which in addition to blocking the activation of MMP9 also inhibit MMP9 activity and substrate binding. The yellow arrow symbolizes increasing specificity of MMP9 inhibitors.