Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor progression, lung metastasis, and death occur in tumor-bearing BD IX syngeneic rats in a fashion similar to the course of patients with metastatic colon cancer. In an effort to establish a relevant model for monoclonal antibody (MoAb) therapy of tumors, we generated murine MoAb against DHD/TR, a dimethylhydrazine-induced rat colon carcinoma which has been adapted to cell culture. Murine MoAb 17B10 E4 (E4) reacts with the TR tumor and shows weak immunoperoxidase reactivity with normal rat tissues. Murine MoAb 5F7 D3 (D3) reacts with the tumor and a variety of normal rat epithelia. Both are IgG2a and mediate cytotoxicity by rat peripheral blood mononuclear cells. 18D5 F6 (F6) also reacts with the tumor and normal tissues but is an IgG2b and does not mediate cytotoxicity in the presence of rat effector cells. Iodinated E4 and D3 antibodies retained their immunoreactivity. E4 revealed 9.8 x 10(5) antigenic sites per TR cell, with an affinity constant of 9.35 x 10(7) M-1, while D3 demonstrated 2.5 x 10(6) antigenic sites and an affinity constant of 4.2 x 10(7) M-1. Immunoblotting showed that the antigens recognized by D3 and E4 are glycoproteins with molecular weights of 27,000 and 66,000, respectively. F6 failed to react with its antigen present in the blot. This rat colon carcinoma and the monoclonal antibodies described here may provide experimental data useful for implementing monoclonal antibodies in cancer therapy.
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PMID:Monoclonal antibodies to a rat colon carcinoma: model for monoclonal antibody therapy of solid tumors. 291 Apr 89

By the degradative effect on basement membrane collagen type IV, matrix metalloproteinases (MMPs) or gelatinases are important in the early invasion of malignant tumors. These enzymes may be released by the tumor cells themselves or may be derived from nearby fibroblasts that have been stimulated by the extracellular MMP inducer EMMPRIN. We studied the distribution of 92-kd gelatinase B (MMP-9) and of EMMPRIN in 33 benign and 41 malignant, paraffin-embedded pigment cell lesions using immunohistochemistry and monoclonal antibodies. In benign pigment cell lesions, EMMPRIN but not gelatinase B was expressed in cellular blue nevi whereas all other benign lesions, including common blue nevi, were negative. In malignant melanomas (MMs), both gelatinase B and EMMPRIN were variably expressed in the pure and invasive radial growth phase but not in the vertical growth phase. All lentigo maligna cases and all metastatic lesions were negative. Of MMs with thickness < 1.6 mm, 63% expressed gelatinase B and 70% expressed EMMPRIN, whereas in MMs with > 1.6 mm thickness, only 10% expressed gelatinase B and only 25% expressed EMMPRIN. We conclude that early invasion of MM is associated with de novo expression of gelatinase B and EMMPRIN by neoplastic melanocytes. Expression of EMMPRIN and MMP-9 may be partly responsible for the stromal changes observed in thin MM. Their absence in the vertical growth phase and in metastatic lesions suggests that other factors are involved in tissue degradation during later stages of tumor progression in MM. The lack of both gelatinase B and EMMPRIN in lentigo maligna may contribute to the indolent behavior of this type of pigment cell lesion.
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PMID:Expression of gelatinase B and the extracellular matrix metalloproteinase inducer EMMPRIN in benign and malignant pigment cell lesions of the skin. 928 14

Invasive breast cancer varies widely in biologic aggressiveness, from fairly indolent tumors to rapidly disseminating carcinomas. Matrix metalloproteinases have enzymatic activity and assist in tumor invasion by degrading basement membranes and extracellular matrix. The extracellular matrix metalloproteinase inducer EMMPRIN is thought to stimulate fibroblasts to produce the zymogen pro-gelatinase A. The membrane type 1-matrix metalloproteinase (MT1-MMP) is thought to assist in tumor invasion and metastasis by activating pro-gelatinase A, which shows enhanced expression in various tumors. Overexpression of gelatinase A has shown to correlate with a malignant phenotype in many tumor forms. The aim of the study was to investigate the mRNA expression pattern of MT1-MMP, gelatinase A, and EMMPRIN in breast tumors. Formalin-fixed paraffin-embedded breast tissue samples from 18 patients operated on with breast-conserving surgery for invasive breast carcinoma <20 mm between 1977 and 1985 were analyzed using the mRNA in situ hybridization technique. Most of the patients were node-negative (15/18) and underwent postoperative irradiation to the breast (16/18). The median age at diagnosis was 52 years (21-83 years). At the time of the study 11 patients were alive, 4 without recurrence; 7 patients had been operated for ipsilateral breast tumor recurrences, and 2 had distant metastases. The median follow-up was 112 months (102-193 months). Seven patients died of disseminated breast cancer; their median follow-up was 43 months (22-116 months). (35)S-labeled antisense and sense mRNA probes transcribed from linearized plasmids containing cDNA for the matrix metalloproteinases gelatinase A and MT1-MMP and the glycoprotein EMMPRIN were hybridized to 5 microm paraffin-embedded tissue sections. Several invasive carcinomas were surrounded by normal tissue and carcinoma in situ lesions. Gelatinase A, MT1-MMP, and EMMPRIN mRNA expression were detected in all of the carcinomas. The gelatinase A mRNA expression was mainly localized to stromal cells at moderate to high levels surrounding the invading carcinoma cells but was also seen in single cells at low levels in in situ lesions and in some normal glandular cells. MT1-MMP and EMMPRIN were expressed in all of the carcinomas and were mainly localized to tumor cells; but they were also seen to some extent in single cells at low levels in in situ lesions and in normal glandular cells. No differences in levels of expression for gelatinase A, MT1-MMP, or EMMPRIN were seen in patients who survived compared to patients who died from metastatic disease. The co-expression of gelatinase A, MT1-MMP, and EMMPRIN mRNA in invasive breast carcinoma supports the theory that these proteins interact and are important for the invasive phenotype in breast carcinoma. Hence EMMPRIN may be a central factor for stimulation of gelatinase A activation. Specific inhibition for individual MMP members could in the future be target-specific events in breast tumor progression. Inhibition of EMMPRIN could be such a target.
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PMID:Gelatinase A, membrane type 1 matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer. 1065 69

Extracellular matrix metalloproteinase inducer (EMMPRIN) also called CD147, basigin or M6 in the human is a member of the immunoglobulin superfamily that is enriched on the surface of tumor cells and stimulates adjacent stromal cells to produce several matrix metalloproteinases (MMPs). In this study, we have demonstrated that coculturing of EMMPRIN-expressing human glioblastoma multiforme cells (U251) with brain-derived human fibroblasts not only stimulates production, but also activation of pro-gelatinase A (proMMP-2), an enzyme that is enriched in malignant gliomas and most likely crucial to tumor progression. Production of membrane types 1 and 2-MMPs (MT1-MMP and MT2-MMP), which are activators of proMMP-2, was also stimulated in these cocultures. Stimulation of MMP-2, MT1-MMP and MT2-MMP production was inhibited by anti-EMMPRIN monoclonal antibody in a dose-dependent manner. Thus, we have shown, for the first time, that EMMPRIN causes increased expression of MT1-MMP and MT2-MMP, as well as increased production and activation of MMP-2.
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PMID:Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. 1093 78

EMMPRIN (extracellular matrix metalloproteinase inducer), also called CD147, basigin or M6 in the human, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). In our study, we investigated expression of EMMPRIN in human normal brain and gliomas, since mouse basigin and chicken HT7, the species homologues of human EMMPRIN, are associated with neuronal interactions and normal blood-brain barrier function, respectively. EMMPRIN expression was detected in all samples of non-neoplastic brain and glioma tissues examined. However, expression levels of EMMPRIN mRNA and protein were significantly higher in gliomas than in non-neoplastic brain. Moreover, levels of mRNA expression and immunohistochemical staining correlated with tumor progression in gliomas: They were highest in the most malignant form of glioma, glioblastoma multiforme, followed by anaplastic astrocytoma and then low-grade astrocytoma. Also, immunolocalization revealed quite different distributions in non-neoplastic brain and glioma: EMMPRIN was demonstrated only in vascular endothelium in non-neoplastic regions of the brain, whereas it was present in tumor cells but not in proliferating blood vessels in malignant gliomas. These data indicate that an MMP inducer molecule EMMPRIN is differently expressed in human normal brain and gliomas and could be associated with astrocytoma progression. Possible mechanisms whereby glioma cell EMMPRIN could influence tumor progression will be discussed.
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PMID:Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas. 1096 35

Matrix metalloproteinases-2 (MMP-2, gelatinase A) has been regarded as a crucial enzyme for tumor progression, invasion, and metastasis by its capability to degrade the basement membrane components, and its activation process is critical for tumor development. Recently, EMMPRIN/CD147, which is a member of immunoglobulin superfamily, has been reported to be highly expressed in tumor cells and induce production of MMPs from fibroblasts adjacent to the tumor cells. In this study, we demonstrated that production of pro- and active forms of MMP-2 by human dermal fibroblasts was enhanced by the direct cell-cell contact with co-cultured HEp-2 cells derived from a human laryngeal epidermoid carcinoma. The results from immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that HEp-2 cells express a higher level of EMMPRIN but only a low level of MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP), whereas fibroblasts express a higher level of MMP-2 and MT1-MMP and a low level of EMMPRIN. In a mixed co-culture with direct cell-cell contacts, co-cultured HEp-2 cells stimulated the pro- and active MMP-2 production from fibroblasts, but not in a separated co-culture through polycarbonate membrane. Production of pro/active MMP-2 and MT1-MMP (activator of pro-MMP-2) in fibroblasts was induced by the addition of membrane fractions prepared from HEp-2 cells to the fibroblast culture, and the induction was suppressed by the EMMPRIN depletion after immunoprecipitation, signifying the participation of EMMPRIN for the induction and activation of MMP-2. Our results suggest an importance of the direct cell-cell interaction involving EMMPRIN rather than humoral factors such as cytokines for pro-MMP-2 production and activation followed by tumor progression, invasion, and metastasis in laryngeal cancer.
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PMID:Direct cell-cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts: involvement of EMMPRIN and MT1-MMP. 1472 63

Ets transcription factors play a central role in invasion and metastasis through regulation of synthesis of proteolytic enzymes and angiogenic molecules. The objective of this study was to investigate the role of PEA3 in tumor progression of ovarian and breast carcinoma metastatic to effusions, and to evaluate the expression of Ets-2 and Erg in ovarian carcinoma. Ovarian (83 malignant effusions, 102 corresponding solid lesions) and breast (33 malignant effusions, 40 corresponding solid lesions) carcinomas were evaluated for expression of PEA3 using mRNA in situ Hybridization (ISH). Expression of Ets-2 and Erg mRNA was analyzed in 50 ovarian carcinoma effusions using the same method. PEA3 mRNA expression was comparable at all sites in ovarian carcinoma (44 out of 83; 53% of effusions, 48 out of 102; 47% of solid tumors). PEA3 mRNA expression in effusions correlated with mRNA expression of the previously studied alphav (P = 0.022), alpha6 (P < 0.001) and beta1 (P < 0.001) integrin subunits, the matrix metalloproteinase (MMP) inducer EMMPRIN (P = 0.015) and interleukin-8 (IL-8) (P = 0.033). Erg and Ets-2 mRNA was expressed in 15 out of 50 (30%) and 18 out of 50 (36%) effusions, respectively, and co-localized with PEA3 (P = 0.017 for Erg, P = 0.004 for Ets-2). In breast carcinoma, PEA3 expression was seen in 19/40 (48%) of solid lesions, with a significant upregulation in corresponding effusions compared to primary tumors (24 out of 33; 73%, P = 0.038). PEA3 mRNA expression in effusions obtained prior to the institution of chemotherapy predicted significantly shorter overall survival in univariate analysis (24 vs 37 months, P = 0.03), with a similar trend for Erg (13 vs 30 months, P = 0.1). In conclusion, PEA3 is expressed at all anatomic sites in serous ovarian cancer and co-localizes with Erg, Ets-2 and several metastasis-associated molecules. PEA3 mRNA expression is a novel marker for tumor progression to malignant effusion in breast carcinoma, and predicts poor outcome in effusions sampled prior to therapeutic intervention in ovarian carcinoma. These findings support a biological role for Ets transcription factors in these malignancies and suggests that they may be targets for therapeutic intervention.
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PMID:The clinical role of the PEA3 transcription factor in ovarian and breast carcinoma in effusions. 1538 69

Matrix metalloproteinases (MMPs) play a central role in normal tissue remodeling and disease, they regulate tumor microenvironment and their expression is increased in most human cancers. Targeting their activity remains a major challenge. Their production and activation is tightly regulated by complex mechanisms that include cytokines and growth factors, cell-matrix and cell-cell interactions. The observations of increased MMP level at the epithelio-stromal interface led to the identification of EMMPRIN/CD147, a membrane spanning molecule highly expressed in tumor cells, that stimulates MMPs production in neighboring fibroblasts. Later studies have shown that EMMPRIN can also induce MMP in the same population of cells. Elevated EMMPRIN level was detected in numerous malignant tumors and has been correlated with tumor progression in experimental and clinical conditions. The presence and modulation of EMMPRIN in normal tissues associated with increased MMP expression suggests that this EMMPRIN-mediated MMP induction could be a common mechanism in non-tumoral physiological and/or pathological situations. Targeting EMMPRIN in cancer and other pathological conditions such arthritis and ulceration appears a promising future therapeutic strategy, but requires a better understanding of its mode of action and regulation. Potential regulators that influence EMMPRIN level and its MMP inducing activity include growth factors, hormones, glycosylation and membrane shedding. This review will discuss the recent findings concerning these diverse regulatory mechanisms in various physiological and pathological situations.
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PMID:EMMPRIN/CD147, an MMP modulator in cancer, development and tissue repair. 1578 23

Basigin/CD147, also named extracelluar matrix metalloproteinase inducer (EMMPRIN), has been implicated in playing very important roles in several aspects of tumor progression. In this study, we examined the inhibitory effects of antisense RNA of CD147 on invasion and angiogenesis of human glioblastoma U251 cells in vitro. The U251 cell line was transfected by a plasmid containing antisense CD147 cDNA. Gelatin zymography was used to determine the effect on reducing secretions of MMP-2 and MMP-9 of the transfected cells. Boyden chamber was employed to test the invasion of U251 cells in vitro. We found that downregulation of CD147 resulted in reducing secretions of MMP-2, MMP-9, and VEGF. Moreover, the invasion of stable antisense transfectants was inhibited. Wound-induced migration assay also showed decreased migration in stable antisense transfectants compare to parental- and empty vector-transfected cells. Taken together, these results provide evidence that invasion of human glioblastoma cells can be inhibited by antisense RNA of CD147. Basigin/CD147 may be used as a potential target of drugs for anti-invasion and metastasis of human glioblastoma cells.
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PMID:Inhibition of basigin expression in glioblastoma cell line via antisense RNA reduces tumor cell invasion and angiogenesis. 1597 Jun 88

Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappaB pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappaB activity exhibited enhanced invasiveness. Inhibition of the NF-kappaB pathway by TNF-alpha neutralizing Abs, an NF-kappaB inhibitor, RNAi to RelA, or overexpression of IkappaB inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappaB binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappaB-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappaB, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells.
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PMID:Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. 1600 23


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