MMPs are associated with multiple human cancers; hence they were early considered as drug targets to treat cancer. The first drug development programs based on the notion of blocking MMP-mediated angiogenesis and metastasis were started about 25 years ago and led to a number of small-molecule metalloproteinase inhibitor (MPI) drugs in phase III clinical trials. The effects of MPIs in these trials turned out to be disappointing as they failed to increase the survival rate of cancer patients. Possible reasons for the failure of MPIs have been extensively discussed previously (Coussens et al., 2002
). Indeed, the clinical studies were suboptimally designed with respect to the stage of cancer, so the question remains whether MPIs might have proven more effective when used in earlier stages of the disease.
Part of the rationale to use MPIs as anticancer drugs was to block interstitial migration of metastatic cancer cells. However, recent analyses have shown that cancer cells can switch to an amoeboid-like protease-independent migration mode by forming actin-rich protrusions and “squeezing” through the ECM (Wolf et al., 2007
). This would render MPIs impotent to inhibit the migratory behavior of metastatic tumor cells. Whether this alternative migration mode is actually relevant for cancer cell migration under in vivo conditions in the presence of a naturally crosslinked collagen matrix currently remains questionable. Mounting evidence supports a dominant role of MMP-14 in the migration and invasion of metastatic tumor cells; hence MMP-14 remains a promising therapeutic target (Sabeh et al., 2009
). This would support the use of MPIs that specifically inhibit MMP-14 as anti-invasive drugs.
The cytostatic potential attributed to MPIs is certainly in keeping with the numerous studies describing MMP-mediated regulation of cell growth signals, such as the activation of TGF-β by MMP-2, -9, and -14 (Dallas et al., 2002
; Mu et al., 2002
), the proteolytic release of soluble EGFR ligands, or the degradation of E-cadherin by MMP-3 or -9 (Cowden Dahl et al., 2008
; Radisky et al., 2005
). Moreover, MMPs interfere with apoptosis induction, especially after chemotherapy, by cleaving Fas ligand from the surface of cancer cells as shown for MMP-7 (Mitsiades et al., 2001
). In the clinical trials, MPIs were administered to patients with advanced cancer, which was most likely too late to exert any beneficial effect on survival.
Interfering with the tumor vasculature is regarded as one of the most promising strategies to inhibit tumor growth and has motivated the development of drugs like Bevacizumab (Avastin, anti-VEGF monoclonal antibody), which has been FDA approved for the treatment of metastatic cancers in combination with chemotherapy. Many studies also support a dominant role of MMP-9 in the angiogenic switch by regulating the bio-availability of VEGF tumors (e.g., Bergers et al., 2000
), suggesting a beneficial effect of MPI on tumor angiogenesis. However, in other cancer models, MMP-9 generates ECM fragments like tumstatin, a potent suppressor of tumor vasculature formation, resulting in increased tumor growth in MMP-9-deficient mice (Hamano et al., 2003
). This illustrates that one MMP can have opposing effects in different tumor types and highlights that the use of MPIs has to be carefully considered and evaluated for each specific kind of cancer.
Most of the initial studies utilized cancer cell lines that over-express certain members of the MMP family (reviewed in Egeblad and Werb, 2002
). These studies may not recapitulate the situation in vivo, where the major source of MMPs is nonmalignant stromal cells. In fact, the cellular source of each MMP is of high significance, as the activity of the released enzyme varies substantially between cell types. This should be taken into account when assessing the expression patterns of MMPs in cancer types that should be considered for treatments with MPIs.
Certainly, the complexity of the mode of action of MMPs has expanded considerably from proteinases that simply degrade the ECM, to specific modulators of angiogenesis as well as fine-tuners of cell signaling pathways and the inflammatory response (). One of the major, recent advances in MMP research is the discovery of specific regulatory effects of MMPs on the stromal cells in the tumor microenvironment. MMPs affect adipocyte function, which is especially likely to be implicated in adipose-rich tumor sites such as breast. They also regulate the course of the inflammatory reaction in multiple ways and facilitate the recruitment of inflammatory cells by altering the function of chemokines and the bioavailability of important proinflammatory cytokines. Regarding the link between inflammation and cancer (Lin and Karin, 2007
), the interference with MMP-mediated immunoregulatory functions could prove beneficial for cancer patients. For example, given that TNF-α contributes to progression of several sorts of cancer (Balkwill, 2009
), inhibiting TNF-α activation using MPIs might dampen the inflammatory milieu at the tumor microenvironment.
Modulation of the Tumor Microenvironment by MMPs
Effects of MMPs on myeloid cells may well be implicated in the generation of the premetastatic niche. In fact, MMP-2, -3, and -9 have already been shown to contribute to the establishment of metastasis-prone sites at tumor-distant organs (Erler et al., 2009
; Huang et al., 2009
; Kaplan et al., 2005
). These insights argue for the use of MPIs at early stages of malignant disease, prior to the full initiation of tumor-associated inflammation and before the soil has been primed for metastasis in distant organs.
The tumor-suppressing functions of these MMPs is probably another reason for the failure of broad-spectrum MPIs as anticancer drugs (Lopez-Otin and Matrisian, 2007
). The inflammation-suppressing function of MMPs accounts for increased incidence of cancer development in MMP-8
knockout mice (Balbin et al., 2003
) and for the link between MMP-8 loss-of-function mutations and melanoma in humans (Palavalli et al., 2009
). Also, MMP-12 delivered by macrophages can suppress the growth of lung metastases, which appears to involve regulation of the tumor vasculature (Houghton et al., 2006a
). Apart from that, some MMPs carry out biological functions other than proteolytic, mediated by specific binding to certain target molecules, for instance via their hemopexin domain. Small-molecule MMP inhibitors as used in clinical trials are certainly ineffective to interfere with a nonproteolytic role of MMPs.
One of the major tasks for the future is the development of active site-directed inhibitors or antibodies that are specific for single MMPs and show little or no cross-reaction with other MMPs (Cuniasse et al., 2005
). For example, a monoclonal antibody raised against the catalytic domain of MMP-14 successfully inhibits the migration and invasion of endothelial cells in collagen and fibrin gels (Galvez et al., 2001
). Antibodies could also target functional noncatalytic domains of MMPs. Moreover, MMP activity can be exploited to activate cytotoxic agents such as anthrax toxin to target the tumor vasculature (Liu et al., 2008b
). These agents need to be validated for specificity using MMP-deficient animals and rigorously tested in experimental cancer models. New activity-based imaging probes specific for MMPs will facilitate monitoring the effect of MPIs on the function of MMPs in vivo. The combination of these probes with minimal invasive imaging techniques will soon allow the improved endpoint assessment for the efficacy of these compounds in inhibiting the target function in vivo. Imaging activity of specific MMPs in vivo will further advance our understanding of the time frame of MMP function during the progression of certain tumors. Like the development of tailor-made therapies and medications based on individual oncogenic pathway signatures in human cancers (Bild et al., 2006
), expression patterns of MMPs in cancer patients could facilitate a fully rational decision about when and in what combination MPIs and anti-cancer drugs should be used in the future.