Matrix Metalloproteases and Tumor Invasion
http://www.100md.com
《新英格兰医药杂志》
Metastasis, the leading cause of death in patients with cancer, is a sequential process that allows cells to move from the primary tumor and grow elsewhere. The development of the metastatic program requires the establishment of a vibrant communication network between tumor cells and nontransformed cells in the host. A recent report by Boire et al.1 underscores this concept; it shows that matrix metalloproteases (MMPs) secreted by host fibroblasts promote tumor-cell invasion by activating a G-protein–coupled receptor — the protease-activated receptor 1 (PAR1). This work adds to the growing catalogue of highly specific roles played by MMPs during tumor invasion and provides fresh hope for antimetastatic therapies. The lack of specificity of MMPs can explain, at least in part, the toxic effects and the resounding failure of MMP inhibitors in clinical trials.2 The finding that MMPs target PAR1 opens a new avenue of investigation: the use of drugs to block MMP effectors.
Cells sense variations in the environment through interactions between receptors and their cognate ligands. Typically, extracellular ligands and cell-surface receptors are different molecular entities. The PARs, a family of four receptors, are a peculiar case: the receptor and a cryptic form of the ligand constitute one molecule. The activation of PARs is a two-step process. First, the tethered ligand is unmasked by proteolytic cleavage; then, an intramolecular rearrangement allows the ligand and the receptor moieties to interact.3 PARs can thus be considered sensors of some extracellular proteases. Until now, only certain members of the serine protease family were thought to activate PARs. Among them, thrombin (a serine protease that triggers coagulation) is considered the prototypical activator of PARs.3 Activated PARs couple to selected members of the G proteins, a family of intracellular effectors that regulate cell responses such as changes in cell shape and mobility.
Accumulating evidence has indicated a role for PAR1 in tumorigenesis and invasion. PAR1 was initially identified as an oncoprotein because of its ability to transform cells. It was subsequently found to mediate the migration of some tumor cells toward factors secreted by host fibroblasts. These studies culminated in the observation of a direct correlation between PAR1 expression and the degree of invasiveness of breast-tumor cells.4
Paradoxically, the activation of PAR1 by high concentrations of thrombin strongly inhibits tumor-cell migration and invasion induced by fibroblasts.5 Boire et al. have now resolved this paradox: they have shown that MMPs, but not serine proteases, are responsible for the proteolytic activation of PAR1 in this context.1 To do so, they tested specific inhibitors. The enzymatic mechanisms of metalloproteases and serine proteases are sufficiently different that compounds that inhibit one type of protease do not affect the other. Whereas inhibitors of serine proteases were without effect, MMP inhibitors efficiently blocked cell migration (Figure 1). Analysis of individual MMPs pointed to MMP1 as the main PAR1-activating metalloprotease secreted by fibroblasts.
Figure 1. Picking Apart PAR1.
Nontransformed host cells secrete matrix metalloproteases (MMPs) into the extracellular milieu (Panel A). A member of this family, MMP1, cleaves protease-activated receptor 1 (PAR1). The cleavage unmasks a tethered ligand that activates PAR1. Activated PAR1 couples to G proteins, which regulate cell responses leading to tumor invasion. In a recent study, Boire et al.1 showed that inhibitors of MMP1 abrogate PAR1 signaling by blocking its cleavage (Panel B). Alternatively, short peptides known as pepducins can block signaling by interfering with the interaction between PAR1 and G proteins. Boire et al. showed that both types of compounds block metastasis from breast-cancer xenografts in nude mice.
The profound difference between the effects of exogenous thrombin and endogenous MMPs provides an example of how fine-tuning of signal transduction is critical to the metastatic program. Because the activation of PAR1 is proteolytic and hence irreversible, the activated molecule is internalized quickly, ensuring the abrogation of PAR1 signaling. Thus, the firing of the receptor is transient and results in the limited generation of second messengers with half-lives that are, typically, also very limited. In contrast, the high concentrations of the second messenger achieved by intense and prolonged firing of PAR1 — as is achieved with high concentrations of thrombin — lead to inhibition of migration.
Various compounds that target PAR1 at various levels are available. Small-molecule inhibitors act by blocking the intramolecular interaction that activates PAR1. Cell-penetrating peptides, known as pepducins (and used by Boire et al. to block xenograft metastasis), alter the signal transferred from activated receptors to G proteins and may be useful in inhibiting metastasis in patients.
Source Information
From the Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, Barcelona.
References
Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 2005;120:303-313.
Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002;295:2387-2392.
Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258-264.
Even-Ram S, Uziely B, Cohen P, et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 1998;4:909-914.
Kamath L, Meydani A, Foss F, Kuliopulos A. Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells. Cancer Res 2001;61:5933-5940.(Joaquín Arribas, Ph.D.)
Cells sense variations in the environment through interactions between receptors and their cognate ligands. Typically, extracellular ligands and cell-surface receptors are different molecular entities. The PARs, a family of four receptors, are a peculiar case: the receptor and a cryptic form of the ligand constitute one molecule. The activation of PARs is a two-step process. First, the tethered ligand is unmasked by proteolytic cleavage; then, an intramolecular rearrangement allows the ligand and the receptor moieties to interact.3 PARs can thus be considered sensors of some extracellular proteases. Until now, only certain members of the serine protease family were thought to activate PARs. Among them, thrombin (a serine protease that triggers coagulation) is considered the prototypical activator of PARs.3 Activated PARs couple to selected members of the G proteins, a family of intracellular effectors that regulate cell responses such as changes in cell shape and mobility.
Accumulating evidence has indicated a role for PAR1 in tumorigenesis and invasion. PAR1 was initially identified as an oncoprotein because of its ability to transform cells. It was subsequently found to mediate the migration of some tumor cells toward factors secreted by host fibroblasts. These studies culminated in the observation of a direct correlation between PAR1 expression and the degree of invasiveness of breast-tumor cells.4
Paradoxically, the activation of PAR1 by high concentrations of thrombin strongly inhibits tumor-cell migration and invasion induced by fibroblasts.5 Boire et al. have now resolved this paradox: they have shown that MMPs, but not serine proteases, are responsible for the proteolytic activation of PAR1 in this context.1 To do so, they tested specific inhibitors. The enzymatic mechanisms of metalloproteases and serine proteases are sufficiently different that compounds that inhibit one type of protease do not affect the other. Whereas inhibitors of serine proteases were without effect, MMP inhibitors efficiently blocked cell migration (Figure 1). Analysis of individual MMPs pointed to MMP1 as the main PAR1-activating metalloprotease secreted by fibroblasts.
Figure 1. Picking Apart PAR1.
Nontransformed host cells secrete matrix metalloproteases (MMPs) into the extracellular milieu (Panel A). A member of this family, MMP1, cleaves protease-activated receptor 1 (PAR1). The cleavage unmasks a tethered ligand that activates PAR1. Activated PAR1 couples to G proteins, which regulate cell responses leading to tumor invasion. In a recent study, Boire et al.1 showed that inhibitors of MMP1 abrogate PAR1 signaling by blocking its cleavage (Panel B). Alternatively, short peptides known as pepducins can block signaling by interfering with the interaction between PAR1 and G proteins. Boire et al. showed that both types of compounds block metastasis from breast-cancer xenografts in nude mice.
The profound difference between the effects of exogenous thrombin and endogenous MMPs provides an example of how fine-tuning of signal transduction is critical to the metastatic program. Because the activation of PAR1 is proteolytic and hence irreversible, the activated molecule is internalized quickly, ensuring the abrogation of PAR1 signaling. Thus, the firing of the receptor is transient and results in the limited generation of second messengers with half-lives that are, typically, also very limited. In contrast, the high concentrations of the second messenger achieved by intense and prolonged firing of PAR1 — as is achieved with high concentrations of thrombin — lead to inhibition of migration.
Various compounds that target PAR1 at various levels are available. Small-molecule inhibitors act by blocking the intramolecular interaction that activates PAR1. Cell-penetrating peptides, known as pepducins (and used by Boire et al. to block xenograft metastasis), alter the signal transferred from activated receptors to G proteins and may be useful in inhibiting metastasis in patients.
Source Information
From the Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, Barcelona.
References
Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 2005;120:303-313.
Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 2002;295:2387-2392.
Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258-264.
Even-Ram S, Uziely B, Cohen P, et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 1998;4:909-914.
Kamath L, Meydani A, Foss F, Kuliopulos A. Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells. Cancer Res 2001;61:5933-5940.(Joaquín Arribas, Ph.D.)