Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The transforming growth factor-beta (TGF-beta) has been identified as an important component of wound healing. Recent developments in molecular therapy offer exciting prospects for the modulation of wound healing, specifically those targeting TGF-beta. We investigated expression of angiogenic bFGF and VEGF, and collagenases MMP-2 and MMP-9 in tissue samples from chronic dermal wounds by immunohistochemistry. The effect of TGF-beta targeting using antisense oligonucleotides on the expression of these factors was analysed by ELISA in human keratinocytes. Immunohistochemical investigation demonstrated a decreased expression of bFGF and VEGF protein, and an increased expression of MMP-2 and MMP-9 in tissue samples from chronic dermal wounds compared to normal human skin. Antisense TGF-beta oligonucleotide treatment down-regulated collagenase secretion activity and up-regulated VEGF secretion in vitro. Therefore, TGF-beta antisense oligonucleotide technology may be a potential therapeutic option for the inhibition of proteolytic tissue destruction, and stimulation of angiogenesis in chronic wounds. Improving basic knowledge and pharmaceutical intervention in this area ultimately may help clinicians to identify and proactively intervene in an effort to prevent normal wounds from becoming chronic.
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PMID:Targeting TGF-beta in human keratinocytes and its potential role in wound healing. 1537 86

The constitutive activation of signal transducer and activator of transcription 3 (Stat3) is frequently detected in breast cancer tissues and cell lines. Stat3 has been classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumor formation in nude mice. Since Stat3 may play an important role in breast cancer, it is of interest to investigate the expression of phosphorylated Stat3, an activated form of Stat3, and its downstream mediators specifically in breast cancer, and to explore the possible mechanisms of Stat3 signaling pathway in oncogenesis of breast cancer. We analyzed Stat3 phosphorylation and expression of Stat3-regulated genes in breast cancer cell lines as well as invasive breast cancer tissues using tissue microarray slides. Our results showed that elevated levels of phosphorylation of Stat3 protein (Tyr705) were detected in 48 out of total 136 invasive breast tumors (35%) whereas normal breast tissues express much lower levels of Stat3 phosphorylation. The increased levels of Stat3 phosphorylation were associated with the metastasis in regional lymph nodes (P=0.042) and the expression of progesterone receptor (P=0.028) but not with distant metastasis, nor the expression of estrogen receptor. Our results also indicate that elevated levels of Stat3 phosphorylation were significantly associated with increased expression of potential downstream targets of Stat3 which include apoptosis inhibitors (Survivin, Mcl-1, HSP27, Adrenomedullin, and Bcl-xL), cell-cycle regulators (c-Fos, MEK5, and c-Myc), and inducer of tumor angiogenesis (VEGF, COX-2, MMP-2, MMP-10, and MMP-1) in invasive breast cancer tissues. Therefore, our findings suggest that constitutive Stat3 signaling may be one of the key upstream regulators to induce these downstream proteins, which may play important roles in Stat3-mediated oncogenesis in breast cancer.
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PMID:Evaluation of potential Stat3-regulated genes in human breast cancer. 1608 Oct 48

SCC-S2/GG2-1/NDED (approved gene symbol TNFAIP8) is a transcription factor NF-kappaB-inducible, antiapoptotic, and oncogenic molecule. In this study, we examined the role of SCC-S2 in invasion and experimental metastasis. We demonstrate that expression of SCC-S2 cDNA in MDA-MB 435 human breast cancer cells is associated with enhanced invasion in vitro and increased frequency of pulmonary colonization of tumor cells in athymic mice. Systemic treatment of athymic mice with a cationic liposomal formulation of SCC-S2 antisense oligo led to decreased incidence of pulmonary metastasis and inhibition of SCC-S2 expression in vivo. Antisense inhibition of endogenous SCC-S2 expression correlated with decreased expression of VEGF receptor-2 in tumor cells and human lung microvascular endothelial cells and loss of endothelial cell viability. In addition, downregulation of SCC-S2 expression in tumor cells was associated with decreased expression of known metastasis-related molecules MMP-1 and MMP-9. These results demonstrate a novel role for SCC-S2 in tumor progression, involving multiple effectors, and provide a basis for SCC-S2-targeted cancer gene therapy.
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PMID:Role of SCC-S2 in experimental metastasis and modulation of VEGFR-2, MMP-1, and MMP-9 expression. 1645 4

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), has been implicated in bladder cancer angiogenesis and invasion. However, the molecular basis of its role in invasion remains unclear. We investigated the expression of TP and 10 invasion-related genes in bladder cancers from 72 randomly selected patients by real-time two-step RT-PCR assay. We found that the expression levels of TP, MMP-9, uPA, and MMP-2 were significantly higher in invasive tumors than those in superficial tumors. Also, the expression level of TP significantly correlated with that of uPA, MMP-1, MMP-9, PAI-1 and VEGF. KK47/TP cells, bladder cancer cells that overexpress TP, had a higher expression of MMP-7 and MMP-9 than KK/CV cells that express lower level of TP in hypoxic condition. PC/TP cells, prostate cancer cells that overexpress TP, also had a higher expression of MMP-1 and MMP-7 than PC/CV cells that express no detectable TP. Taken together these data indicate that TP enhances the invasion of tumor cells through the induction of invasion-related genes.
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PMID:Molecular basis for the involvement of thymidine phosphorylase in cancer invasion. 1668 20

We investigated the serum concentration of total metalloproteinase-9 (tMPP-9), active MMP-9 (aMMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a group of 41 patients with SLE and 20 healthy controls. Serum levels of tMMP-9 and TIMP-1 were assessed by an enzyme-linked immunosorbent assay (ELISA) and aMMP-9 by fluorometric assay. The tMMP-9 level was lower in SLE patients (mean 262 ng/mL) than in healthy volunteers (mean 325 ng/mL) (P = .048). Similarly, aMMP-9 level was lower in SLE patients (mean 121 ng/mL) than in control group (mean 169 ng/mL) (P = .0355) and lower in active SLE (mean 54 ng/mL) than in inactive disease (mean 99 ng/mL) (P = .033). TIMP-1 level was also lower in SLE patients (mean 181 ng/mL) than in control group (mean 233 ng/mL) (P = .004). In SLE patients, a positive correlation was found between tMMP-9 and aMMP-9 (rho = 0.568; P = .001). We also found a positive correlation of tMMP-9 and TIMP-1 with VEGF concentrations (rho = 0.450, P = .005 and rho = 0.387; P = .018, resp). tMMP-9, aMMP-9, and TIMP-1 serum levels are lower in SLE patients than in healthy control group.
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PMID:Circulating total and active metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in patients with systemic lupus erythomatosus. 1686 98

Previous work has shown the importance of tumour-stroma interactions for prostate cancer development at the primary site. The aim of the present study was to find out whether evidence can be found for a tumour-stroma cross- talk also between metastatic prostate cancer cell lines and non-prostatic stromal fibroblasts which are encountered by metastatic cells at most sites. We addressed this issue in cell culture systems using 3 metastatic human prostate cancer cell lines (LnCaP, PC-3 and DU-145) on the one hand, and a human fibroblast line (HFF, human foreskin fibroblasts) on the other. We incubated fibroblasts with tumour cell- and tumour cells with fibroblast-conditioned media and evaluated several parameters important for the establishment of metastases such as cell proliferation, migration and expression of matrix degrading proteases. We also determined in the conditioned media the concentrations of several growth factors and cytokines which might be responsible for the observed effects. We found that media conditioned by all 3 metastatic prostate cancer cell lines stimulated fibroblast proliferation which corresponds to fibrous stroma induction in vivo. DU-145 cell conditioned media induced in fibroblasts expression of mmp-1 mRNA known to be important for tumour invasion. ELISA assays revealed that tumour cells secrete bFGF, PDGF and TNFalpha known to stimulate fibroblast proliferation and/or MMP-1 expression. Cultivation of DU-145 carcinoma cells in fibroblast conditioned medium resulted in an enhanced proliferation and anchorage-independent growth of this cell line in soft agar. Fibroblast conditioned medium also increased migration of PC-3 cells in the wound assay and slightly augmented mmp-1 expression. KGF (able to stimulate proliferation of normal and neoplastic prostate epithelial cells) was secreted by fibroblasts at higher concentrations than by all 3 tumour cell lines. In addition, fibroblasts secreted TNFalpha, bFGF, PDGF, HGF and also VEGF, the most important factor for tumour vascularization. Our results provide evidence that tumour-stroma interactions do not only exist at the primary site but also between metastatic prostate cancer cell lines and their fibroblastic microenvironment. These interactions, which are mediated through secreted factors, affect several steps of the metastatic cascade including proliferation, anchorage-independent growth, migration and the secretion of matrix-degrading proteases.
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PMID:Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts. 1701 25

To isolate and culture adipose stromal cells (ASCs), and study the effect of cytokines secreted by ASCs on endothelial cells, human adipose tissue was digested with collagenase type I solution and ASCs were derived by culture. The cells surface phenotype was examined by flow cytometry. ELISA was used to detect the secretion of VEGF, HGF, SDF-1 alpha and RT-PCR was employed to detect the expression of their mRNA. Then the ASC medium was utilized to culture human umbilical vein endothelial cells ECV304. Cells were counted by hemacytometer to determine the proliferation and Annexin V/ PI was employed for the examination of the apoptosis rate of ECV304. ASCs were derived by culture and expressed CD34, CD105 while they did not express CD31 or CD45. ASCs secreted cytokines such as VEGF, HGF and SDF-1 alpha so the ASC medium could stimulate proliferation and counteract apoptosis of endothelial cells (P < 0.05). Bcl-2 mRNA was also found to be up-regulated in the endothelial cells. It is concluded that ASCs can secrete cytokines and has significant effect on the proliferation of endothelial cells and apoptosis.
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PMID:Effect of cytokines secreted by human adipose stromal cells on endothelial cells. 1712 Jul 30

Calcineurin inhibitors (tacrolimus) and steroids continue to be an important component of hepatocyte transplantation protocols, despite reports of hepatotoxicity and inhibitory effects of steroids on cell proliferation. The aim of the study was to investigate whether isolated human hepatocytes were more vulnerable to the toxicity of these agents and also to investigate their effects on hepatocyte VEGF secretion, a vascular permeability factor suggested to be involved in the cell engraftment process. Human hepatocytes were isolated from donor livers/segments rejected or unused for orthotopic liver transplantation using a collagenase perfusion technique. Hepatocytes were plated for cell function tests and to determine VEGF production. Tacrolimus (0-50 ng/ml) and methylprednisolone (0-500 ng/ml) were added to the culture media and cells incubated for 24 h. Cell metabolic activity was assessed using the MTT assay, cell number using the SRB assay, and cell attachment from hepatocyte total protein content and protein synthesis using [14C]leucine incorporation. VEGF in culture supernatants was measured by ELISA. Tacrolimus and methylprednisolone had no statistically significant inhibitory effects on metabolic activity or protein synthesis compared to controls at all concentrations of the agents tested when added after plating. There were also no significant effects on cell attachment when tacrolimus or methylprednisolone was added at the time of cell plating. There were no differences in the responses obtained when either fresh or cryopreserved hepatocytes were used. The amount of VEGF secreted by untreated hepatocytes was highly variable (0-1400 pg/10(6) cells/24 h). VEGF levels in the culture supernatant from hepatocytes isolated from < or = 20-year-old donors (687 +/- 59 pg/10(6) cells/24 h) was significantly greater than from older donors (61 +/- 7 pg/10(6) cells/24 h; p = 0.003). Tacrolimus and methylprednisolone did not significantly affect VEGF secretion by hepatocytes. Tacrolimus and methylprednisolone did not have detrimental effects on the metabolic function of human hepatocytes, cell attachment, or VEGF secretion after cell isolation.
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PMID:The effects of immunosuppressive agents on the function of human hepatocytes in vitro. 1726 48

A new 3D porous and biostable collagen scaffold has been developed to improve the biocompatibility of implantable glucose sensors by minimizing tissue reactions while stimulating angiogenesis around the sensors. The novel collagen scaffold was crosslinked using nordihydroguaiaretic acid (NDGA) to enhance biostability. NDGA-treated collagen scaffolds were stable without physical deformation in the subcutaneous tissue of rats for 4 weeks. In contrast, glutaraldehyde (GA)-treated collagen scaffolds were extremely damaged following implantation. Both types of scaffolds (NDGA- and GA-crosslinked) were stable in vitro in the presence of collagenase with 70% retention of original weight after 4 weeks of incubation. The response current (i.e. sensitivity) of sensors with porous scaffolds was not significantly changed when compared with control sensors (no scaffold), while the response time (T(95%)) was slightly delayed after a glucose concentration increase from 5 to 15 mM. Above this range, the sensors coated with scaffolds had only a slightly lower sensitivity than the control sensors. These results indicate that we have developed a stable NDGA-crosslinked collagen scaffold for biosensors, and that the scaffold does not impair the function of our sensor. We plan to use this scaffold to enhance the function and lifetime of the implantable biosensors by providing a controlled local environment around the sensors with the help of various drugs and growth factors (dexamethasone, VEGF, PDGF).
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PMID:A novel porous collagen scaffold around an implantable biosensor for improving biocompatibility. I. In vitro/in vivo stability of the scaffold and in vitro sensitivity of the glucose sensor with scaffold. 1808 51

Tumor-stroma interactions are of great importance not only for the development and progression of primary prostate carcinoma but probably also for the establishment of metastasis. Fibroblasts are an important stromal cell type encountered by metastatic tumor cells at different sites. In previous investigations, we had found that media conditioned by three metastatic prostate cancer cell lines (LNCaP, PC-3, and DU-145) induced cultured nonprostatic fibroblasts to proliferate or to express matrix-metalloproteinase-1 considered important for tumor invasion. Fibroblast-conditioned media in turn stimulate proliferation of DU-145 cells and migration of PC-3 cells. Both tumor cells and fibroblasts secrete VEGF suggesting that not only metastatic but also stromal cells at metastatic sites contribute to the vascularization of metastasis necessary for continuous growth. In order to better understand the reciprocal tumor-stroma cross-talk in molecular terms we used the mRNA extracted from stimulated and unstimulated neoplastic and fibroblastic stromal cells for cDNA array hybridization using Affymetrix chips. The three prostate cell lines influenced the fibroblasts nearly in the same manner. In particular proteins involved in cell adhesion, cell-cell contact, and cell cycle regulation were downregulated in stimulated fibroblasts. In contrast, fibroblasts affected every prostate cancer cell line in different ways, which may be because of the different origin of the metastatic prostate cancer cell lines.
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PMID:Tumor-stroma interactions of metastatic prostate cancer cell lines: analyses using microarrays. 1822 Feb 34


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