Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolytic degradation of the extracellular matrix is essential to angiogenesis. Two families of proteases, the serine proteases of plasminogen activator/plasmin system and the matrix metalloproteinases (MMPs) are closely involved in these processes. The treatment of mice with a diet containing a new synthetic MMP inhibitor, OPB-3206: 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl] amino-1methoxy-3, 4-dihydrocarbostyril, abrogated the development of new vessels in a rat corneal assay, and in a mouse Matrigel assay. In an in vitro angiogenesis model, OPB-3206 inhibited the migration and the tube formation of bovine aortic endothelial cells at 10-100 times lower concentrations than those required to inhibit the growth of these cells. OPB-3206 as well as other MMP inhibitory drugs, batimastat/BB-94 and marimastat/BB-2516, also selectively inhibited tubular morphogenesis in vitro. OPB-3206 reduced the activities of interstitial collagenase and type IV collagenase, but the concentrations of 50% inhibition against these MMPs were much higher than those of BB-94 and BB-2516. However, this new compound also inhibited urokinase type plasminogen activator activity on fibrin zymogram, while BB-94 and BB-2516 did not. Furthermore, the addition of urokinase type plasminogen activator reduced the inhibitory effect of the tubular morphogenesis of vascular endothelial cells by OPB-3206. The treatment of mice with a diet containing this new compound also reduced the growth of implanted mammary carcinomas as well as the lung metastasis of colon carcinoma. The anti-angiogenic effect of OPB-3206 appeared to be associated with its inhibition of tumor growth and metastasis.
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PMID:A new synthetic matrix metalloproteinase inhibitor modulates both angiogenesis and urokinase type plasminogen activator activity. 1451 52

Membrane-type matrix metalloproteinases (MT-MMPs) have attracted strong attention, because four of them can activate a key player in the tumor scenario, proMMP-2/progelatinase A. In addition to this indirect effect on the cellular environment, these MT-MMPs degrade extracellular matrix proteins, and their overproduction is associated with tumor growth. We have solved the structure of the catalytic domain (cd) of MT3-MMP/MMP-16 in complex with the hydroxamic acid inhibitor batimastat. CdMT3-MMP exhibits a classical MMP-fold with similarity to MT1-MMP. Nevertheless, it also shows unique properties such as a modified MT-specific loop and a closed S1' specificity pocket, which might help to design specific inhibitors. Some MT-MMP-specific features, derived from the crystal structures of MT-1-MMP determined previously and MT3-MMP, and revealed in recent mutagenesis experiments, explain the impaired interaction of the MT-MMPs with TIMP-1. Docking experiments with proMMP-2 show some exposed loops including the MT-loop of cdMT3-MMP involved in the interaction with the proMMP-2 prodomain in the activation encounter complex. This model might help to understand the experimentally proven importance of the MT-loop for the activation of proMMP-2.
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PMID:Crystal structure of the catalytic domain of MMP-16/MT3-MMP: characterization of MT-MMP specific features. 1474 Dec 17

AMP-activated protein kinases (AMPKs) are a class of serine/threonine protein kinases that are activated by an increase in intracellular AMP concentration. They are a sensitive indicator of cellular energy status and have been found to promote tumor cell survival during nutrient starvation. We recently identified a novel AMPK catalytic subunit family member, ARK5, whose activation is directly regulated by Akt, which, in turn, has been reported to be a key player in tumor malignancy. In this study, we attempted to determine whether ARK5 is involved in tumor malignancy under regulation by Akt. Matrigel invasion assays demonstrated that both overexpressed and endogenous ARK5 showed strong activity dependent on Akt. In addition, ARK5 expression induced activation of matrix metalloproteinase 2 (MMP-2) and MMP-9 following new expression of membrane type 1 MMP (MT1-MMP), and the MT1-MMP expression induced by ARK5 was initiated by rapamycin-sensitive signaling. In nude mice, ARK5 expression was associated with a significant increase in tumor growth and significant suppression of necrosis in tumor tissue. Interestingly, only the ARK5-overexpressing PANC-1 cell line (P/ARK) tumor showed invasion and metastasis in nude mice, although Akt was activated in tumors derived from both P/ARK and its parental cell line. We report that a novel AMPK catalytic subunit family member, ARK5, plays a key role in tumor malignancy downstream of Akt.
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PMID:ARK5 is a tumor invasion-associated factor downstream of Akt signaling. 1506 Jan 71

We investigated the ability of angiogenesis in PC9/F9 cells (from a highly metastatic human lung adenocarcinoma cell line) as compared with PC9 cells (from a low metastatic human lung adenocarcinoma cell line). In vivo tumor growth assay using BALB/c nude mice (7 mice/group), showed that the tumor volume of PC9/F9 cells on day 35 (230.7+/-31.3 mm(3)) was significantly larger than that of PC9 cells (90.9+/-24.7 mm(3)) (p<0.001). However, there was no significant difference between PC9/F9 cells and PC9 cells in an in vitro growth assay. In a dorsal air sac assay (DAS assay) using ICR mice (3 mice/group), PC9/F9 cells (4.7+/-1.2 vessels) showed stronger neovascurizationin in compared with PC9 cells (0.3+/-0.4 vessels) (p<0.05). In an enzyme linked immunosorbent assay (ELISA) and Western blotting analysis there were no significant differences between PC9/F9 cells and PC9 cells in the protein expression of vascular endothelial growth factor (VEGF). There was no significant difference between the gene expression levels of PC9/F9 cells and PC9 cells on cDNA array analysis. Matrix metalloproteinase-2 (MMP-2) activity in PC9/F9 cells was remarkably stronger than that of PC9 cells in Gelatin Zymography. From these results, we considered that of the increased metastasis of PC9/F9 cells might be induced by augmented angiogenesis. Furthermore, we speculated that the augmented angiogenesis of the highly metastatic PC9/F9 cell line might be induced by increased MMP-2 activity.
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PMID:The difference of angiogenesis in human lung adenocarcinoma cell lines with different metastatic potency. 1522 9

Type IV collagenase plays an important role in tumor invasion and metastasis through cleaving type IV collagen in the basement membrane and extracellular matrix. In this study a molecule-downsized immunoconjugate (Fab'-LDM) was constructed by linking lidamycin (LDM), a highly potent antitumor antibiotic, to the Fab' fragment of a monoclonal antibody directed against type IV collagenase and its antitumor effect was investigated. As assayed in 10% SDS-PAGE gel, the molecular weight of Fab'-LDM conjugate was 65 kD with a 1 : 1 molecular ratio of Fab' and LDM. The Fab'-LDM conjugate maintained most part of the immunoreactivity of Fab' fragment to both type IV collagense and mouse hepatoma 22 cells by ELISA. By MTT assay, Fab'-LDM conjugate showed more potent cytotoxicity to hepatoma 22 cells than that of LDM. Administered intravenously, Fab'-LDM conjugate proved to be more effective against the growth of subcutaneously transplanted hepatoma 22 in mice than free LDM in two experiment settings. In Experiment I, the drugs were given intravenously on day 1 and day 8. Fab'-LDM at the doses of 0.025 mg/kg, 0.05 mg/kg and 0.1 mg/kg inhibited tumor growth by 76.7%, 93.3% and 94.8%, while free LDM at 0.05 mg/kg inhibited tumor growth by 76.1%, respectively. In experiment II, the drugs were given intravenously on day 4 and day 11, Fab'-LDM at the doses of 0.025 mg/kg and 0.05 mg/kg inhibited tumor growth by 74.2%, 80.9%, while free LDM at 0.05 mg/kg inhibited tumor growth by 60.5%, respectively. In terms of survival time, Fab'-LDM was more effective than free LDM. The results suggest that the molecule-downsized immunoconjugate directed against type IV collagenase is of high efficacy in experimental cancer therapy.
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PMID:Antitumor effects of the molecule-downsized immunoconjugate composed of lidamycin and Fab' fragment of monoclonal antibody directed against type IV collagenase. 1538 78

Matrix metalloproteinase-2 (MMP-2; gelatinase A) is known to degrade a broad range of extracellular matrix components and chemokines, and has important roles in the processes of cell migration, invasion, and involution during development, as well as during tumor growth and metastasis and in inflammation and repair. To better elucidate the roles of this matrix metalloproteinase in the development and progression of experimental autoimmune encephalomyelitis, we used MMP-2-deficient (KO) mice. Surprisingly, we found that MMP-2 KO mice exhibited an earlier onset and more severe disease than did their wild-type (WT) counterparts. WT mice engrafted with MMP-2 KO bone marrow exhibited a similar earlier onset and more severe clinical disease score than WT mice engrafted with WT bone marrow. Lymphocytes derived from MMP-2 KO mice exhibited increased transmigration through endothelial cell monolayers as well as through collagen type IV and laminin-coated BD BIOCOAT inserts, which correlated with a 3-fold increase in expression of MMP-9 and was abrogated by inhibition of MMP activity. We demonstrated a correlation between expression levels of MMP-9 and MT1-MMP expression and suggest a signaling pathway involving tethering of MMP-2 to MT1-MMP as a modulator of MMP-9 expression. Last, we discuss other possible MMP-2-mediated mechanisms which may contribute to the observed phenotype.
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PMID:MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity. 1552 13

The matrix metalloproteinases (MMPs) are a family of proteolytic zinc-containing enzymes, which are responsible for the breakdown of the extracellular matrix components in pathological and physiological conditions. They are involved in basement membrane disruption, stroma and blood vessel penetration, metastasis and more recently there is evidence that they participate in tumor growth and angiogenic events. Matrix metalloproteinase 2 and 9 (MMP 2 and 9) belong to the gelatinases, a subgroup of MMPs, and have the capacity to degrade the triple helix type IV collagen of basal lamina of the basement membrane. With the present study, we tried to demonstrate the expression of MMP-9 immunohistochemically, comparatively in benign, premalignant and malignant lesions of the larynx. We studied 154 laryngeal lesions including 55 squamous cell carcinomas, 8 in situ carcinomas, 54 cases of dysplasia (of low and intermediate grade), 13 papillomas and 24 cases of keratosis. Overexpression of MMP 9 was observed in 74.4% and 50% in invasive and in situ squamous cell carcinomas respectively. In dysplastic cases, in papillomas and in keratoses the percentage of overexpression was 62.9%, 61.53% and 54.16% respectively and the expression of MMP-9 was significantly higher in invasive squamous cell carcinomas compared to dysplasias (p=0.000004). Also significantly higher was the expression of MMP-9 in dysplastic cases compared to papillomas (p=0.023). The MMP-9 expression was related neither to survival nor to the other available clinicopathological parameters (tumor size, grade, clinical stage, lymph node status and patient age). In conclusion, our study indicates that the expression of MMP-9 is up-regulated in a stepwise fashion, with two main steps, the first one, when a dysplastic lesion evolves and the next one, when the dysplasia progresses to invasive carcinoma.
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PMID:Expression of matrix metalloproteinase-9 (gelatinase B) in benign, premalignant and malignant laryngeal lesions. 1652 70

Angiocidin, a protein over-expressed in many different solid tumors and tumor capillary endothelial cells inhibits angiogenesis and tumor growth [Zhou, J., et al., 2004. Cloning and characterization of angiocidin, a tumor cell binding protein for thrombospondin-1. J Cell Biochem. 92, 125-146]. Since several splice variants of angiocidin have distinct biochemical functions in membrane transport and protein degradation, we sought to evaluate the function of endogenously expressed angiocidin in human umbilical vein endothelial (HUVE) cells using siRNA. We observed a 90% reduction of the target mRNA levels after 24 h. Endogenous angiocidin protein expression was reduced by 80% after three days, as evaluated by Western blot analysis. We also found that anti-angiocidin siRNA down-regulated 90% of the protein expression of matrix metalloproteinase 2 (MMP-2) and 50% of its gelatinolytic activity. Reduction of endogenous angiocidin completely inhibited endothelial cord formation on Matrigel. Cells expressing low levels of angiocidin grew more slowly, were less invasive and less adhesive than control cells. Consistent with the reported function of one of the angiocidin analogues S5a, we found that the expression of polyubiquitinated proteins was higher in anti-angiocidin siRNA-treated cells as compared to normal and control siRNA-treated cells. These results suggest that endogenous angiocidin and its homologues promote endothelial cell invasion, adhesion, and angiogenesis through mechanisms involving polyubiquitin-dependent protein degradation and MMP-2 expression.
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PMID:Reduction of angiocidin expression in human umbilical vein endothelial cells via siRNA silencing inhibits angiogenesis. 1690 4

Matrix metalloproteinase-2 (MMP-2) has been used as a target for cancer immunotherapy. The activation of immunization by breaking immune tolerance to self-MMP-2 may be one of the promising approaches for the treatment of MMP-2-positive tumors. In this study, we constructed the xenogeneic tumor cell vaccine c-MMP-2 by transfecting CT26 and LLC cells with chicken MMP-2 cDNA constructs. MMP-2-specific autoantibodies in sera and tumor cells were found in mice immunized with c-MMP-2. Protection against tumor growth was evaluated in respect of the relative contributions of autoantibodies, CD4+, and CD8+ T cells. Treatment with this vaccine (c-MMP-2) also prolonged the survival time of mice bearing cancer. The specific cytotoxic T-cell responses suggested that the treatment increased CD8+ T-cell activity. The antitumor activity of c-MMP-2 was abrogated by in vivo depletion of CD4+ and CD8+ T-lymphocytes and improved by adoptive transfer of CD4+ and CD8+ T-lymphocytes from the mice treated with c-MMP-2. An alternative DNA vaccination strategy for cancer therapy was identified in this study by eliciting humoral and cellular immunoresponse with a crossreacting transfectant.
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PMID:Humoral and cellular immunity induced by tumor cell vaccine based on the chicken xenogeneic homologous matrix metalloproteinase-2. 1712 9

Single-domain antibodies are attractive as tumor-targeting vehicles because of their much smaller size than intact antibody molecules. Lidamycin is a macromolecular antitumor antibiotic, which consists of a labile enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). An enediyne-energized fusion protein VH-LDP-AE composed of single-domain antibody directed against type IV collagenase and lidamycin was prepared by a novel two-step method including DNA recombination and molecular reconstitution. VH-LDP-AE demonstrated extremely potent cytotoxicity to cancer cells and marked antiangiogenic activity in vitro. In the mouse hepatoma 22 model, drugs were administered intravenously as a single dose on day 1 with maximal tolerated doses. VH-LDP-AE (0.25 mg/kg) suppressed the tumor growth by 95.9%, whereas lidamycin (0.05 mg/kg) and mitomycin (1 mg/kg) by 79.6 and 51.1%, respectively. In the HT-1080 xenograft model in nude mice, drugs were given intravenously as a single dose on day 4 after tumor implantation. VH-LDP-AE at 0.25 mg/kg suppressed tumor growth by 76% (P<0.05) compared with that of lidamycin at 0.05 mg/kg (53%) on day 18. No obvious toxic effects were observed in all groups during treatments. The results showed that energized fusion protein VH-LDP-AE was more effective than lidamycin and mitomycin. These properties, together with its much smaller size than conventional antibody-based agents, suggested that VH-LDP-AE would be a promising candidate for cancer-targeting therapy. In addition, the two-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs for a variety of cancers.
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PMID:An enediyne-energized single-domain antibody-containing fusion protein shows potent antitumor activity. 1715 99


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