Review
Missing the target: matrix metalloproteinase antitargets in inflammation and cancer

https://doi.org/10.1016/j.tips.2013.02.004 Get rights and content

Matrix metalloproteinases (MMPs) are reputed to cause the inflammatory tissue destruction characterizing chronic inflammatory diseases and to degrade basement membrane collagen, thereby facilitating cancer cell metastasis. However, following the disappointing MMP drug cancer trials, recent studies using mouse models of disease coupled with high-throughput methods for substrate discovery have revealed surprising and unexpected new biological roles of MMPs in inflammatory diseases and cancer in vivo. Thus, MMPs modify signaling pathways and regulate the activity of whole families of cytokines of the immune response by precise proteolytic processing. By cleaving and inactivating cytokine-binding proteins and protease inhibitors, cytokine activities are unmasked and activities of diverse proteases are increased in an interconnected protease web. With new substrates come new roles, and 10 of 24 murine MMPs have antitumorigenic and anti-inflammatory roles making them drug antitargets; that is, their beneficial actions should not be inhibited. Here, we examine whether the discovery that MMPs are drug antitargets for one disease might pave the way for their use for other indications or whether this is a serious threat to the development of MMP inhibitors.

Section snippets

MMPs as inflammation and cancer drug targets

MMPs were identified as cancer drug targets (see Glossary) more than 30 years ago. At this time, MMP1, MMP2, and MMP3 were the only MMPs known and the therapeutic strategy was focused on inhibiting the degradation of the extracellular matrix (ECM) proteins that facilitate metastasis and angiogenesis 1, 2. The first anticancer MMP inhibitors were peptidomimetics that were not orally available (e.g., Batimastat, BB94; Ilomastat, GM-6001) and these were followed by improved second-generation

MMPs as drug antitargets

Human studies ultimately are the most relevant test of the efficacy of blocking a drug target. From the failure of broad-spectrum MMP inhibitors in cancer clinical trials, we have learned that: (i) in tumors, MMPs are produced by both the cancer cells and the surrounding stromal cells, and infiltrate inflammatory and immune cells; (ii) the role of MMPs differs according to the stage of cancer; and (iii) some MMPs are antitargets. Drug antitargets are molecules with essential normal roles in

Intertwining of cancer with inflammation

Cancer and inflammation are intertwined [27]. Thus, as the tumor inflammatory component increases tumorigenicity or metastasis, anti-inflammatory roles for MMPs potentially are also antitumorigenic and antimetastatic. Therefore, it is unsurprising that many MMPs can also interfere with cancer progression (Table 1). Since the first review of unexpected anticancer roles for MMPs [2], other examples of anticancer mechanisms have been reported. Some of these observations are strictly model

Sifting through MMP roles in vivo to uncover beneficial and detrimental activities

To reveal the protease substrate repertoire and hence the biological role for a MMP in a specific disease or particular organ, or to shed light on the temporal aspects of the role, one approach is to study the substrate degradome of the MMP. Theoretical activities inferred from cell culture (2D or 3D) or in vitro experiments can differ greatly in the more complex in vivo milieu in which all proteins and mediators are present at relevant concentrations [37]. With the recent advent of

Think inside the box

Multiple MMPs have been described as both targets and antitargets – so are MMPs friends or foes? Is our current view of the roles of MMPs becoming blurrier or clearer? Erwin Schrödinger designed a thought experiment – a paradox – using everyday objects to illustrate his view of quantum mechanics. The scenario comprises a cat inside a closed box in which a sealed poison vial is enclosed and can break at any time. An observer can never be sure whether the cat is dead or alive. This example was

Protease web alterations

In addition to the beneficial activities of MMPs that optimally need to be spared in treatment, in recent years new added complexity has become apparent arising from the complicated interconnectivity of protease networks that form a larger protease web embedded in each proteome [2]. Proteases do not act alone in vivo; they activate protease zymogens, as well as inactivating proteases and their inhibitors. By zymogen activation or by inactivating protease inhibitors, such as MMP cleavage of

Proteolytic signatures

How, then, to deal with the intertwined activity of the protease web in vivo interwoven in a melee of substrates, inhibitors, signaling molecules, and cell receptors? Collectively, a ‘proteolytic signature’ can be established to describe the cleaved proteins present in a tissue or cell. Proteomically, this is now possible using N-terminomics techniques such as TAILS and combined fractional diagonal chromatography (COFRADIC) whereby all N termini, both original protein and neo-termini generated

Taking Schrödinger's cat out of the box

There is no doubt that MMPs play crucial roles in various human pathologies, both beneficial and detrimental, but what are the options to address the Schrodinger's cat paradox in the context of MMPs? The failure of MMP inhibitors in Phase III of cancer clinical trials has led to a reevaluation of the diverse biological roles of MMPs. Where is the balance between the target and antitarget properties of MMPs and what are the issues we need to address for the design of effective inhibitors in the

Design of more selective inhibitors

Several groups have developed highly selective small-molecule MMP inhibitors to single MMPs (e.g., MMP12) 42, 52, 53. However, biologicals generally offer the best approach for ultraselective inhibition to date. A promising monoclonal antibody targeted at only the active form of MMP14 was demonstrated to inhibit angiogenesis and slow tumor progression and metastasis in several animal models including orthotopic, subcutaneous, and xenograft murine models 54, 55. However, the precise role of

Target the substrates of MMPs

Proteomic analyses have revealed myriad novel substrates of MMPs. Most of these proteins are involved in inflammatory and immune processes and are not classic components of the ECM. As a strategy to avoid blocking beneficial MMP antitarget activities, drugs targeting the MMP substrate might be a more effective way specifically to treat disease by blocking the responsible substrate activity or masking cleavage sites and thereby sparing MMP antitarget activities. One example could be to target

Concluding remarks

MMPs are clearly established as major players in diverse biological functions and thus remain of immense interest in understanding many homeostatic and pathological processes. Hence, MMPs remain potential drug targets. However, the variety of their substrates and physiological activities means that they can function both as drug targets and as antitargets, which hampers drug development. There are several important remaining questions. Can an MMP be targeted for one disease in which it is known

Glossary

Anti-target
a molecule or protein with essential or host protective roles in the normal state of a cell or tissue function. Inhibition of its activity results in clinically unwanted side effects and initiation or worsening of disease.
Degradomics
all system-wide genomics, proteomics, and systems biology techniques that study the structural and functional roles of the proteases, inactive homologs, and protease inhibitors that are present in an organism.
Target
a molecule or protein that unambiguously

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