Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solid tumors synthesize a number of extracellular matrix-degrading proteases that are important for tumor progression. Based on qualitative in situ hybridization studies in human cancer tissue, a range of components involved in proteolysis appear to be expressed by stromal cells rather than cancer cells. We have now used laser capture microdissection and real-time PCR to quantify the mRNA expression of components of matrix-degrading proteolytic systems in cancer and stromal areas of mouse mammary tumors genetically induced by the polyoma virus middle T (PyMT) antigen. We examined the mRNA levels of urokinase plasminogen activator, plasminogen activator inhibitor 1 and the matrix metalloproteases MMP-2, -3, -11, -13 and -14, and found that all these seven genes are predominantly expressed by stromal cells. Our results were qualitatively supported by in situ hybridization analysis of the expression of mRNAs for MMP-2, -3 and -13 in the PyMT tumors. Statistical analyses indicated that the quantitative expression patterns observed in cancer and stromal cells isolated from individual tumors from different PyMT mice are quite reproducible. The methodology described in this study provides excellent tools to study the possible interactions between cancer and stromal cells during the development of breast cancer, and the results suggest that stromal cells are involved in carcinogenesis and tumor progression, which may have important implications for the biology and therapy of cancer.
Carcinogenesis 2005 Jul
PMID:Extracellular protease mRNAs are predominantly expressed in the stromal areas of microdissected mouse breast carcinomas. 1576 Sep 18

Matrix metalloproteinase (MMP)-7 (matrilysin-1) plays significant roles in the growth, invasion, and metastasis of colorectal tumors, while (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol with chemopreventive properties, has been shown to be an inhibitor of MMP-2 and MMP-9. In the present study, HT-29 human colorectal cancer cells were treated with EGCG to examine its effects on pro-MMP-7 induction and production using RT-PCR and western blot analyses. Surprisingly, EGCG (10-100 microM) treatment increased both intracellular and extracellular pro-MMP-7 protein levels (2.6-8.4-fold and 1.9-6.4-fold, respectively) in dose- and time-dependent manner, with a significant upregulation of its mRNA expression. EGCG also activated extracellular signal-regulated protein kinase (ERK)1/2, c-JUN NH2-terminal kinase (JNK)1/2 and p38 mitogen-activated protein kinase (MAPK), as previously reported. In addition, the polyphenol triggered the phosphorylation of c-JUN (Ser63 and Ser73) and induced c-JUN/c-FOS, thereby increasing the DNA binding activity of activator protein-1 (AP-1), as shown by an AP-1 luciferase reporter assay. Pharmacological blockade of MAPK activities suggested that pro-MMP-7 expression was induced via JNK1/2 activation, but not in the case of ERK1/2 or p38 MAPK. N-Acetyl-L-cysteine, superoxide (O2-) dismutase and catalase attenuated the EGCG-induced pro-MMP-7 production, suggesting an involvement of oxidative stress in these events. Conversely, EGCG spontaneously generated O2- in a cell-free system that utilized a cytochrome C reduction method. Further, (-)-epicatechin-3-gallate (25 and 100 microM) and green tea polyphenols (33 and 132 microg/ml) induced pro-MMP-7 expression, whereas (-)-epicatechin and (-)-epigallocatechin (100 microM each) did not. Induction of pro-MMP-7 expression by EGCG was also shown in another human colorectal adenocarcinoma cell line, Caco-2. Our results suggest that some green tea catechins induce pro-MMP-7 production via O2- production and the activation of JNK1/2, c-JUN, c-FOS and AP-1 in HT-29 cells.
Carcinogenesis 2005 Sep
PMID:(-)-Epigallocatechin-3-gallate promotes pro-matrix metalloproteinase-7 production via activation of the JNK1/2 pathway in HT-29 human colorectal cancer cells. 1586 May 7

Chemokines have been found to alter tumor growth and metastasis. We have described previously that a particular chemokine receptor, CXCR4, was predominantly expressed on various glioma cell lines and in resected glioblastoma specimens. Herein, we have tested the ligand of CXCR4, stromal cell derived factor-1alpha (SDF-1alpha, CXCL12), on the response of human glioma cells. We found that SDF-1alpha increased the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9. The SDF-1alpha enhanced MT2-MMP expression was blocked by a CXCR4 antagonist, AMD3100. Functional invasion assays showed that SDF-1alpha stimulated glioma cells to invade through matrigel-coated chambers and this effect was inhibited in glioma cells by the stable downregulation of MT2-MMP expression using small interfering RNA (siRNA). In vivo and at asymptomatic stages following intracerebral implant of cells, mice harboring MT2-MMP siRNA downregulated clones had smaller and less invasive tumors compared with mice implanted with non-specific siRNA control cells. Analyses at symptomatic stages demonstrate that mice with MT2-MMP siRNA clones survive longer than mice harboring control cells. These results highlight MT2-MMP as an effector of CXCR4 signaling in glioma cells, and they reveal the novel role of MT2-MMP in modulating tumor activity.
Carcinogenesis 2005 Dec
PMID:The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. 1603 74

An immortalized human prostate stromal cell line (PS30) was previously established using recombinant retrovirus encoding human papillomavirus 16 gene products. In this study, we further characterize this stromal cell line for its potential use in a stromal-epithelial coculture model for prostate cancer prevention. Using reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry, we examined expression of androgen receptor (AR), vitamin D receptor (VDR), prostate-specific antigen (PSA), transforming growth factor-beta (TGF-beta), and insulin-like growth factors (IGF) families and their receptors, metalloproteinases (MMP) MMP-2 and MMP-9, as well as the cells' ability to respond to the synthetic androgen R1881. The PS30 stromal cells do not express PSA, confirming their stromal origin. They are positive for both AR messenger ribonucleic acid (mRNA) and protein; however, they do not respond to growth stimulation by the synthetic androgen R1881. The PS30 cells express mRNA for VDR, TGF-betas, IGFs and their receptors, as well as the MMPs. Moreover, they produce significant amounts of TGF-beta1, TGF-beta2, IGFBP-3, and MMP-2 proteins. Our observations confirm the use of PS30 for the study of stromal-epithelial interactions in the modulation of prostate carcinogenesis.
 ...
PMID:Characteristics of a human prostate stromal cell line related to its use in a stromal-epithelial coculture model for the study of cancer chemoprevention. 1615 46

Fibronectin (FN) was found to be up-regulated in human oesophageal squamous cell carcinoma (ESCC) by cDNA microarray analysis in our laboratory. In order to elucidate the chronology of FN expression at various stages of oesophageal carcinogenesis, RT-PCR, immunohistochemistry and Western blot analysis were carried out on ESCC tissue samples with different pathological characteristics. FN was mainly localized in the interstitial tissues, and its up-regulation in ESCC was significantly associated with the depth of invasion by carcinoma (R = 0.803, p < 0.01). To investigate its relationship with the Erk pathway further, pRaf-1 and pErk-1/2 expression were also analysed in ESCC. Activation of Erk1/2 and Raf was identified in 63.3% and 60.3% of the tumour specimens, respectively, whereas normal mucosal epithelial tissues were negative. Moreover, a close association was observed between pErk-1/2 expression and the differentiation grade (R = -0.421, p = 0.002): pErk-1/2 signal was greater in poorly differentiated tissues than in well and moderately differentiated tissues. Co-expression of FN and pErk-1/2 was found at the invasive front of tumour nests by double immunofluorescence staining and there was a statistical correlation between the expression of FN and pErk-1/2 (p < 0.05). In the cell line EC9706, plasma FN was able to phosphorylate Raf and further activate Erk, but it did not alter MMP-2 protein expression or activity, indicating that MMP-2 may not be the downstream target gene of the Erk pathway. All the above data suggest that the up-regulation of FN contributes to the later stage of oesophageal carcinogenesis, and that activation of the Erk pathway may be involved in the roles of FN in ESCC.
 ...
PMID:Up-regulation of fibronectin in oesophageal squamous cell carcinoma is associated with activation of the Erk pathway. 1615 61

Chronic exposure to the chloracetanilide herbicide alachlor has been shown to cause olfactory mucosal neoplasms. Genomic analysis of olfactory mucosa from rats given alachlor (126 mg/kg/d) for from 1 day to 18 mo suggested that matrix metalloproteinases MMP-2 and MMP-9 were upregulated in the month following initiation of treatment. The present studies were designed to confirm this latter finding and to explore the potential role of MMPs in alachlor-induced olfactory carcinogenesis. Zymographic analysis of olfactory mucosal extracts confirmed that MMP-2 activity is higher in the olfactory mucosa of alachlor-treated rats. Therefore, rats were fed alachlor (126 mg/kg/d in the diet for 1 year) either with or without the MMP-2/MMP-9 inhibitor Ro 28-2653 (100 mg/kg daily by gavage for the first 2 months of alachlor treatment). The number of olfactory mucosal neoplasms was reduced by 25% after 1 year of alachlor treatment in rats that received both alachlor and Ro 28-2653. The morphology of alachlor-induced olfactory tumors was similar whether or not Ro 28-2653 had been given; the MMP inhibitor itself had no impact on olfactory mucosal histology. These data confirm that olfactory mucosal MMP-2 activity is increased following short-term alachlor exposure and show that administration of an MMP-2/9 inhibitor reduced the incidence of olfactory neoplasms in alachlor-treated rats, thereby implicating MMP-2 activity as a mediator of alachlor-induced carcinogenicity.
 ...
PMID:Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653. 1617 23

Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) is a key enzyme involved in degradation of extracellular matrix (ECM) and various surface-associated proteins that control cell growth, differentiation and survival, plays crucial roles in molecular carcinogenesis, tumor cell growth, invasion, and angiogenesis. We tested the inhibitory effect of antisense MT1-MMP on the ability of metastatic human ovarian carcinoma cell line SW626 in proliferation and invasion. RT-PCR was used to amplify MT1-MMP cDNA fragments with two different restriction sites at its 5'-end. Antisense MT1-MMP cloned in eukaryotic expression vector pMMP14as was transfected into SW626 cells. MT1-MMP protein expression, activities of MMP-2 and MMP-9, changes of cell proliferation, and cell invasion ability were detected by Western blot, optimized gelatin zymography, MTT assay and matrigel in vitro invasion assay, respectively. After 48 h transfection, decreased expression of endogenous MT1-MMP protein was detected in pMMP14as-transfected SW626 cells and showed significantly lower proliferation level when compared with control cells. The activation of proMMP-2 was inhibited markedly, and the mean percentage of invasive cells was 63.30+/-5.80% in pMMP14as-transfected cells, which was less than that (97.60+/-7.50%) in control cells (P<0.05). Both cell proliferation and invasion in SW626 cells were inhibited effectively by antisense MT1-MMP transfection, suggesting that MT1-MMP may be a proper target molecule for anti-invasion therapy for human ovarian cancers.
 ...
PMID:Down-regulation of MT1-MMP expression suppresses tumor cell invasion in metastatic human SW626 ovarian cancer cells. 1639 76

Repetitive exposure of the skin to UV radiation induces various harmful changes, such as thickening, wrinkle formation, inflammation and carcinogenesis. A variety of natural compounds and synthetic compounds have been studied to determine whether they can prevent UV-induced harmful effects. In this study, we investigated the effect of a novel compound, Melanocin A, which was isolated from Eupenicillium shearii F80695, on UV-induced premature skin aging. First, we studied the effect of Melanocin A on UV-induced matrix metalloproteinase (MMP)-9 expression in an immortalized human keratinocyte cell line, HaCaT, in vitro. Acute UV irradiation induced MMP-9 expression at both the mRNA and protein levels and Melanocin A suppressed this expression in a dose-dependent manner. We then investigated the effect of Melanocin A on UV-induced skin changes in hairless mice in vivo. Chronic exposure of hairless mouse dorsal skin to UV increased skin thickness and induced wrinkle formation and the gelatinase activities of MMP-2 and MMP-9. Moreover, Melanocin A significantly suppressed UV-induced morphologic skin changes and MMP-2 and MMP-9 expression. Taken together, these results show that Melanocin A can prevent the harmful effects of UV that lead to skin aging. Therefore, we suggest that Melanocin A should be viewed as a potential therapeutic agent for preventing and/or treating premature skin aging.
 ...
PMID:Prevention of UV radiation-induced premature skin aging in hairless mice by the novel compound Melanocin A. 1661 15

Matrix metalloproteinases (MMP) are important regulators of tumor progression and angiogenesis. MMPs generate both proangiogenic and antiangiogenic fragments, such as vascular endothelial growth factor and endostatin. The in vivo activation of MMPs and endostatin generation occur mainly in the extracellular environment by interactions of different cell types. Therefore, these processes are necessary to study in the extracellular space in vivo. Sex steroids play a dominant role in breast carcinogenesis, by largely unknown mechanisms. In the present study, we used in vivo microdialysis to directly quantify MMP-2 and MMP-9 activity and sample endostatin from both stroma (murine) and tumor (human) cells in vivo in solid MCF-7 tumors in nude mice. We found that tamoxifen in combination with estradiol increased tumor MMP-2/MMP-9 in vivo activity, endostatin levels, and decreased tumor vascularization compared with estradiol treatment only. The stroma-derived endostatin was three to five times higher than cancer cell-generated endostatin. After inhibition of MMP-2/MMP-9, endostatin levels decreased, providing evidence that these proteases are highly involved in the generation of endostatin. Our results support the previously reported concept that MMPs may serve as negative regulators of angiogenesis. The regulation of endostatin generation by modulation of MMP-2/MMP-9 activities suggests a previously unrecognized mechanism of estradiol and tamoxifen, which may have implications for the pathogenesis of breast cancer.
 ...
PMID:Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo. 1665 33

Trypsin is involved in colorectal carcinogenesis and promotes proliferation, invasion, and metastasis. Although a well-known pancreatic digestive enzyme, trypsin has also been found in other tissues and various cancers, most importantly of the colorectum. Moreover, colorectal cancers with trypsin expression have a poor prognosis and shorter disease-free survival. Biological understanding of how trypsin causes cancer progression is emerging. It seems to act both directly and indirectly through a 'proteinase-antiproteinase-system', and by activation of other proteinase cascades. Invasion of the basal membrane by cancer cells may be promoted directly by trypsin digestion of type I collagen. Trypsin activates, and is co-expressed with matrix metalloproteinases (MMPs), which are known to facilitate invasion and metastasis. MMP-2, MMP-7, and MMP-9 are co-expressed together with trypsin and seem to be of particular importance in proliferation, progression, and invasion. MMPs may play a role in both conversion from adenoma to carcinoma, and in the initiation of invasion and metastasis. Co-segregation of trypsin and MMPs within the tumour environment is important for the activation of MMPs, and may explain the deleterious effect of trypsin on prognosis in colorectal cancer. Trypsin and proteinase-activated receptor 2 (PAR-2) act together in an autocrine loop that promotes proliferation, invasion, and metastasis through various mechanisms, of which prostaglandin synthesis is important. Stimulated by trypsin, both MMP and PAR-2 may activate the mitogenic MAPK-ERK pathway through activation of the epidermal growth factor receptor. Experimental trypsin inhibition is feasible but not very effective, and trypsin as a target for clinical therapy is unlikely to be successful owing to its universal distribution. However, as the pathways of trypsin and co-activated protein cascades emerge, biological understanding of colorectal carcinogenesis will be further illuminated and may pave the way for prognosticators, predictors, and novel targets of therapy.
 ...
PMID:Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis. 1669 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>