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Pivot Concepts:
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Target Concepts:
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Query: EC:3.4.24.23 (
MMP
)
4,246
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The assessment of MMPs/TIMPs expression in various primary tumors has potential prognostic values. Considering the paucity of studies in secondary liver tumors, our aim was to study the expression of MMP2, MMP9, TIMP1, and
TIMP2
in secondary hepatic cancer, focusing on their variability in the malignant cells. The study group included 25 cases of liver metastases of colorectal cancer, diagnosed and surgically treated at "Sf. Spiridon" University Hospital of Iassy, Romania. Immunohistochemistry for MMP2, MMP9, TIMP1, and
TIMP2
has been performed, followed by the semi-quantitative assessment of the markers using a scoring system based on the positive tumoral cells percentage and the staining intensity. The expression of investigated markers revealed an increased staining variability. The scores showed that MMP2/
TIMP2
and MMP9/TIMP1 immunoreactivity was extremely heterogeneous within the analyzed group, with a dominant weak expression for MMP2 and MMP9, in contrast to strong
TIMP2
and TIMP1 expression. Ten different patterns of expression of the investigated markers have been identified. No major differences between the expression of MMP2 (14 positive cases) and MMP9 (16 positive cases) could be detected. Our results sustain the inverse correlation between
MMP
and the correspondent TIMP expression, supporting the hypothesis that MMPs/TIMPs balance has mainly an inhibitory effect on invasiveness. Our study demonstrated that tumoral cells are adapted to MMPs:TIMPs production in the liver microenvironment. The lack of significant differences between MMP2 and MMP9 expression shows that the activity of both MMPs is independent, without reciprocal influences.
...
PMID:High variability in MMP2/TIMP2 and MMP9/TIMP1 expression in secondary liver tumors. 2406 94
Evidence from biological and human studies strongly supports a role for
MMP
and TIMP genes as candidate genes for non-syndromic cleft lip with or without cleft palate (NSCL/P). We previously showed the association of promoter polymorphisms in MMP3 (rs3025058 and rs522616) and
TIMP2
(rs8179096) with NSCL/P. In this study, we examined the functional significance of these polymorphisms. A specific DNA-protein complex for MMP3 rs522616 A was detected, and this allele by itself showed greater promoter activity than the G allele. However, the effect of rs522616 was ultimately regulated by the rs3025058 allele on the background. For
TIMP2
rs8179096, the T allele showed a 2.5-fold increase in promoter activity when compared with allele C, whereas both C and T alleles were found to bind to nuclear factor kappa B. Our results provide new evidence that promoter polymorphisms in MMP3 and
TIMP2
are functional and may affect gene transcription with possible effects on craniofacial development leading to NSCL/P.
...
PMID:Functional Significance of MMP3 and TIMP2 Polymorphisms in Cleft Lip/Palate. 2479 19
MMP-14 and MMP-9 are two well-established cancer targets for which no specific clinically relevant inhibitor is available. Using a powerful combination of computational design and yeast surface display technology, we engineered such an inhibitor starting from a nonspecific
MMP
inhibitor, N-
TIMP2
. The engineered purified N-
TIMP2
variants showed enhanced specificity toward MMP-14 and MMP-9 relative to a panel of off-target MMPs.
MMP
-specific N-
TIMP2
sequence signatures were obtained that could be understood from the structural perspective of
MMP
/N-
TIMP2
interactions. Our MMP-9 inhibitor exhibited 1000-fold preference for MMP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions. Our results provide new insights regarding evolution of promiscuous proteins and optimization strategies for design of inhibitors with single-target specificities.
...
PMID:Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14. 2947 54
NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56
bright
CD16
dim/-
CD9
+
CD49
+
subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1,
TIMP2
, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or
MMP
inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.-Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9-
TIMP2
axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.
...
PMID:Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer. 2976 80
The cytokine IL-17A is associated with the progression of various cancers, but little is known about the molecular cross-talk between IL-17A and other tumor-promoting factors. Previous studies have shown that the IL-17A-mediated invasion of breast cancer cells can be inhibited by selective antagonists of the matrix metalloproteinase 9 (MMP-9), suggesting that the cross-talk between IL-17A and MMP-9 may promote cancer invasiveness and metastasis. Here, we present a novel strategy for developing cancer therapeutics, based on the simultaneous binding and inhibition of both IL-17A and MMP-9. To this end, we use a bi-specific heterodimeric fusion protein, comprising a natural inhibitor of MMPs (N-
TIMP2
) fused with an engineered extracellular domain (V3) of the IL-17A receptor. We show that, as compared with the mono-specific inhibitors of IL-17A (V3) and MMP-9 (N-
TIMP2
), the engineered bi-specific fusion protein inhibits both MMP-9 activation and IL-17A-induced cytokine secretion from fibroblasts and exhibits a synergistic inhibition of both the migration and invasion of breast cancer cells. Our findings demonstrate, for the first time, that dual targeting of inflammatory (IL-17A) and extracellular matrix remodeling (
MMP
) pathways can potentially be used as a novel therapeutic approach against cancer. Moreover, the platform developed here for generating the bi-specific IL-17A/MMP-9 inhibitor can be utilized for generating bi-specific inhibitors for other cytokines and MMPs.
...
PMID:A bi-specific inhibitor targeting IL-17A and MMP-9 reduces invasion and motility in MDA-MB-231 cells. 2998 76
Introduction:
All organs of human body are a conglomerate of various cell types with multidirectional interplay between the different cells and the surrounding microenvironment, leading to a stable tissue formation, homeostasis, and function. To develop a functional smooth muscle tissue, we need to simulate and create a multicellular microenvironment. The multilineage adipose-derived stem cells (ADSCs), which can be easily harvested in large numbers, may provide an alternative cell source for the replacement of smooth muscle cells (SMCs) in cell-based detrusor bioengineering therapeutic approaches. The aim of this study was to investigate whether predifferentiated smooth muscle-like ADSC (pADSC) can support SMCs to generate stable smooth muscle tissue through remodeling of extracellular matrix (ECM) and factor secretion.
Methods:
Rat SMC and pADSC were mono- and cocultured in the cell ratios 1:1, 1:2, 1:3, and 1:5 (SMC-pADSC) and grown for up to 2 weeks
in vitro
. The expression of the SMC-specific markers alpha-smooth muscle actin, calponin, myosin heavy chain 11 (MyH11), and smoothelin was assessed, and cell proliferation and contractility were analyzed. Proteomic analysis of the secretome (cell-cell contact was compared with a noncontact transwell 1:1 coculture) and the cell pellets was performed, with the focus on ECM deposition and remodeling, integrin expression and growth factor secretion.
Results:
SMC and pADSC were strongly positive for all smooth muscle markers. After 1 and 2 weeks of culture, the 1:1 cell ratio developed a significantly higher number of smooth muscle organoids and improved contractility. These organoids were highly structured, consisting of an SMC core surrounded by a pADSC layer. The deposition of various EMC proteins, such as collagens 1a1, 1a2, 2a1, 3a1, 5a2, 6a2, 12a1, and fibrillin 1, was significantly increased. A decreased matrix metalloproteinase 3 (MMP3), MMP9 and MMP13 secretion, as well as increased tissue inhibitors of metalloproteinase 1 (TIMP1) and
TIMP2
secretion were found in the contact coculture compared with the monoculture controls.
Conclusion:
SMC-pADSC 1:1 cocultures exhibit an improved cell proliferation, contractility, and organoid formation compared with all other ratios and monoculture, while retaining a stable phenotype that is comparable with the SMC monoculture. These effects are mediated by increased ECM deposition and tight ECM remodeling by the secreted
MMP
and TIMP. Impact statement Harvesting smooth muscle cells (SMCs) from diseased bladders represents a significant limitation for clinical translation of bladder Tissue Engineering. Our results suggest that autologous predifferentiated smooth muscle-like adipose-derived stem cell can substitute SMCs, and may be used in combination with SMCs to generate contractile detrusor muscle tissue for patients suffering from end-stage bladder diseases. We demonstrate a beneficial effect when using these cells in a 1:1 ratio with improved deposition of extracellular matrix (ECM) molecules and superior remodeling of the ECM by matrix metalloproteinases and decreased tissue inhibitors of metalloproteinase activity.
...
PMID:Predifferentiated Smooth Muscle-Like Adipose-Derived Stem Cells for Bladder Engineering. 3209 75
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