Matrix metalloproteinases: protective roles in cancer

Decock, Julie; Thirkettle, Sally; Wagstaff, Laura; Edwards, Dylan R.

doi:10.1111/j.1582-4934.2011.01302.x

Cited by 176 publications

(168 citation statements)

References 101 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…MMP-9 has the largest molecular mass of all the MMP family members and TIMP-1 is a specific inhibitor of MMP-9. They are involved in the degradation of the extracellular matrix (ECM) and play a role in the invasion and metastasis of tumor cells (3,4). Previous studies (36)(37)(38) have suggested that disruption to the ECM during tumor progression is due to an imbalance in the MMP/TIMP ratio.…”

Section: Discussionmentioning

confidence: 99%

“…The deregulation of the invasion process may cause a series of pregnancy-related diseases, such as hydatidiform mole and invasive mole; however, excessive invasion of trophocytes is significantly associated with the formation of placental choriocarcinoma (2). In this process, one critical step of choriocarcinoma invasion and metastasis is the degradation of the extracellular matrix (ECM), in which the MMP-9/TIMP-1 ratio plays a significant role (3,4).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

Zhang

et al. 2012

Oncology Letters

View full text Add to dashboard Cite

Abstract. Human choriocarcinoma is one of the most aggressive malignant tumors characterized by early hematogenous spread to lung and brain tissues, and may be a cause of death in patients. Choriocarcinoma may occur following pregnancy and during implantation; however, trophoblastic invasion in human pregnancy is tightly regulated. The transforming growth factor-beta 1 (TGF-β1) has been suggested to play a role in controlling this process. In this study, we investigated the impact of TGF-β1 on invasion, as well as its sites of action in the TGF-β1/Smad pathway using a JEG-3 choriocarcinoma cell line. Following the treatment of cells with different doses of TGF-β1, cell invasion was observed. We also detected the expression of TGF-β receptor type I (TβR I) and TGF-β receptor type II (TβR II), Smad4, matrix metalloprotease (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in JEG-3 cells. Our data demonstrated that TGF-β1 promoted the invasive capability of JEG-3 cells depending on the downregulation of TβR I, TβR II, Smad4 and the upregulation of MMP-9 and TIMP-1. These observations suggest that TGF-β1 may play a critical role in the initiation of the trophoblastic invasion process. IntroductionA successful human pregnancy requires embryonic trophocytes to invade into the womb and adhere to the endometrium; however, this kind of invasion is strictly regulated temporospatially (1). The deregulation of the invasion process may cause a series of pregnancy-related diseases, such as hydatidiform mole and invasive mole; however, excessive invasion of trophocytes is significantly associated with the formation of placental choriocarcinoma (2). In this process, one critical step of choriocarcinoma invasion and metastasis is the degradation of the extracellular matrix (ECM), in which the MMP-9/TIMP-1 ratio plays a significant role (3,4).The main treatment for choriocarcinoma is 5-fluorouracil, which has a very good therapeutic efficacy; however, it may also cause toxic reactions, side effects and drug resistance (5). Since conventional treatments including surgery and chemotherapy often fail, it is necessary to explore the metastasis mechanisms of proliferation and invasiveness, and find a new target for drug therapy.TGF-β belongs to a growth factor super-family which consists of a highly evolutionary conserved group of secreted cytokines (6). The TGF-β family consists of TGF-β, activins, bone morphogenetic proteins (BMPs), nodals, inhibins and antimullerian hormone (AMH). TGF-β1 is the prototypic family member and is secreted as an inactive latent precursor (7,8). It plays a significant role in the control of growth and development, including the regulation of cell proliferation and differentiation, the promotion of ECM formation and suppression of the immune response (9). TGF-β1 exerts its cellular effects through TβR I, TβR II and the Smad transcription factors, which have pivotal roles in intracellular signaling (7,10). Moreover, Smad4 is an essential factor in TGF-β signaling and is a frequently mutated tumor ...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

Zhang

et al. 2012

Oncology Letters

View full text Add to dashboard Cite

show abstract

“…Indeed, uPA-uPAR complex formation enhances pericellular proteolysis through the activation of plasminogen and, in turn, matrix metalloproteinases (MMP). However, recent experimental evidence indicates that some members of the MMP family behave as tumor-suppressor enzymes and may therefore be regarded as antitargets in cancer therapy (46). Moreover, small-molecule inhibitors of uPA binding to uPAR have been recently described (47,48).…”

Section: Discussionmentioning

confidence: 99%

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Rea

Lavecchia

Giovanni

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPAR) is able to bind vitronectin, via a direct binding site. Furthermore, uPAR interacts with other cell surface receptors, such as integrins, receptor tyrosine kinases, and chemotaxis receptors, triggering cell-signaling pathways that promote tumor progression. The ability of uPAR to coordinate binding and degradation of extracellular matrix (ECM) and cell signaling makes it an attractive therapeutic target in cancer. We used structure-based virtual screening (SB-VS) to search for small molecules targeting the uPAR-binding site for vitronectin. Forty-one compounds were identified and tested on uPAR-negative HEK-293 epithelial cells transfected with uPAR (uPAR-293 cells), using the parental cell line transfected with the empty vector (V-293 cells) as a control. Compounds 6 and 37 selectively inhibited uPAR-293 cell adhesion to vitronectin and the resulting changes in cell morphology and signal transduction, without exerting any effect on V-293 cells. Compounds 6 and 37 inhibited uPAR-293 cell binding to vitronectin with IC 50 values of 3.6 and 1.2 mmol/L, respectively. Compounds 6 and 37 targeted S88 and R91, key residues for uPAR binding to vitronectin but also for uPAR interaction with the fMLF family of chemotaxis receptors (fMLF-Rs). As a consequence, compounds 6 and 37 impaired uPAR-293 cell migration toward fetal calf serum (FCS), uPA, and fMLF, likely by inhibiting the interaction between uPAR and FPR1, the high affinity fMLF-R. Both compounds blocked in vitro ECM invasion of several cancer cell types, thus representing new promising leads for pharmaceuticals in cancer.

show abstract

“…Because the catalytic mechanism and catalytic domain fold are conserved among the MMP/ADAM (a disintegrin and metalloproteinase)/ ADAMTS (ADAM with thrombospondin motifs) superfamily members, the available small-molecule inhibitors (most frequently, active-site zinc-chelating hydroxamates) target multiple proteinases, resulting in off-target side effects (8,(12)(13)(14). This aspect is problematic, given that some MMPs (e.g., are always protumorigenic, whereas some other MMPs are antitumorigenic in certain cancer microenvironments (15,16). As a result, broad-spectrum hydroxamates failed in cancer clinical trials due to their low overall efficacy and side effects (13).…”

mentioning

confidence: 99%

Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries

Nam

Rodríguez

Remacle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

110

View full text Add to dashboard Cite

Proteases are frequent pharmacological targets, and their inhibitors are valuable drugs in multiple pathologies. The catalytic mechanism and the active-site fold, however, are largely conserved among the protease classes, making the development of the selective inhibitors exceedingly challenging. In our departure from the conventional strategies, we reviewed the structure of known camelid inhibitory antibodies, which block enzyme activities via their unusually long, convex-shaped paratopes. We synthesized the human Fab antibody library (over 1.25 × 10 9 individual variants) that carried the extended, 23-to 27-residue, complementarity-determining region (CDR)-H3 segments. As a proof of principle, we used the catalytic domain of matrix metalloproteinase-14 (MMP-14), a promalignant protease and a drug target in cancer, as bait. In our screens, we identified 20 binders, of which 14 performed as potent and selective inhibitors of MMP-14 rather than as broad-specificity antagonists. Specifically, Fab 3A2 bound to MMP-14 in the vicinity of the active pocket with a high 4.8 nM affinity and was similarly efficient (9.7 nM) in inhibiting the protease cleavage activity. We suggest that the convex paratope antibody libraries described here could be readily generalized to facilitate the design of the antibody inhibitors to many additional enzymes. family members control various physiological and pathological processes. Multiple diseases are associated with altered MMP expression and aberrant proteolysis, including cancer (1), wound healing (2), inflammatory diseases (3, 4), neurological pain (5, 6), and hypertension (7). There is consensus among researchers that the individual MMPs are promising drug targets in diversified pathologies and that inhibitor specificity is required for selective and successful MMP therapies (8-10).However, achieving target specificity and selectivity in small-molecule MMP inhibitors is remarkably challenging (11,12). Because the catalytic mechanism and catalytic domain fold are conserved among the MMP/ADAM (a disintegrin and metalloproteinase)/ ADAMTS (ADAM with thrombospondin motifs) superfamily members, the available small-molecule inhibitors (most frequently, active-site zinc-chelating hydroxamates) target multiple proteinases, resulting in off-target side effects (8,(12)(13)(14). This aspect is problematic, given that some MMPs (e.g., MMP-14) are always protumorigenic, whereas some other MMPs are antitumorigenic in certain cancer microenvironments (15, 16). As a result, broad-spectrum hydroxamates failed in cancer clinical trials due to their low overall efficacy and side effects (13). Alternatively, antibody-based MMP inhibitors are emerging as both research tools and potential therapeutic agents (10, 17-21) because of (i) high affinity and specificity due to the large antigen-antibody interaction area and multiple complementarity-determining regions (CDRs), (ii) long half-life and well-defined action mechanisms, (iii) low immunogenicity and toxicity, and (iv) multiple MMPs potentially targe...

show abstract

Matrix metalloproteinases: protective roles in cancer

Cited by 176 publications

References 101 publications

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

The impact of TGF-β1 on the mRNA expression of TβR I, TβR II, Smad4 and the invasiveness of the JEG-3 placental choriocarcinoma cell line

Discovery of New Small Molecules Targeting the Vitronectin-Binding Site of the Urokinase Receptor That Block Cancer Cell Invasion

Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries

Contact Info

Product

Resources

About