Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) play an important regulatory role in tissue morphogenesis, cell differentiation, tumor invasion and metastasis. Several authors have reported a direct correlation between the production of 72 kDa (MMP-2) and 92 kDa (MMP-9) type IV collagenases/gelatinases and the metastatic potential of cancer cells. Recently, we have identified the expression of both MMP-2 and MMP-9 in primary cultures of human giant cell tumor (GCT) of bone in vitro, and in tissue extracts in vivo. Interestingly, MMP-9 is not secreted by late-passaged GCT cells. It is possible that the production of MMP-9 is regulated by certain factor(s) secreted by the multinucleated giant cells in the primary culture. In order to test this hypothesis, the effect of primary-culture-conditioned medium on the expression of MMP-9 by late-passaged mononuclear stromal cells was examined. Adding conditioned medium from the primary GCT culture to the late-passaged stromal cells induced MMP-9, as evidenced by the presence of lytic bands at M(r) 92,000 and 72,000 on a gelatin zymogram. These enzyme activities were inhibited by EDTA, a well-known inhibitor of the MMPs. We confirmed these results by Western blotting using specific antibodies and RT-PCR for MMP-2 and MMP-9. Immunofluorescence studies with specific antibodies to MMP-9 further confirmed its expression by the passaged stromal cells cultured in the primary-culture-conditioned medium. The data indicate that MMP-2 and MMP-9 are produced by the mononuclear stromal cells when cultured in GCT primary-culture-conditioned medium. This suggests that multinucleated giant cells in primary cultures secrete a factor(s) that stimulates stromal cells to produce MMP-9, which, in turn, may contribute to the aggressive behavior of GCT.
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PMID:Regulation of MMP-9 (92 kDa type IV collagenase/gelatinase B) expression in stromal cells of human giant cell tumor of bone. 921 28

A new cell line MGM-1 was established from a primary tumor of the left temporal lobe with histological diagnosis of glioblastoma multiforme, removed from a 64-year-old Japanese male. The patient died of recurrence and unusual extracranial metastases of the tumor 7 months after the surgery. The cultured MGM-1 cells are spindle or polygonal in shape. After serial passages, glial fibrillary acidic protein became negative immunocytochemically in vitro. The modal chromosome number was 61-64. Doubling time and soft agar colony forming efficiency were 42.9h and 0.4%, respectively (at 25th passage). MGM-1 is a highly motile cell line in vitro and its serum-free conditioned medium is chemotactic and chemokinetic for other glioma cells. Secretion of gelatinases (probably MMP-2/72-kDa type i.v. collagenase) and MMP-9/92-kDa type i.v. collagenase) and urokinase-type plasminogen activator were also investigated. MGM-1 would therefore be useful for studying the mechanisms regulating glioma-cell motility and invasion. The MGM-1 cell line has been propagated continuously by serial passages (more than 100 passages) during the past 4 years.
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PMID:Establishment and characterization of a new human glioblastoma cell line (MGM-1) with highly motile phenotype. 923 71

The expression of matrix metalloproteinase-2 (MMP-2; 72 kDa type IV collagenase/gelatinase A) and MMP-9 (92 kDa type IV collagenase/gelatinase B) was immunohistochemically investigated in 79 T1 adenocarcinomas of the lung using non-commercial polyclonal anti-MMP-2 and -9 antibodies. Thirty-two (41%) and 22 (28%) among the 79 cases were positive in the tumor cells for MMP-2 and -9, respectively. The incidences of MMP-2 and -9 immunoreactivities were higher (64 and 45%, respectively) in poorly differentiated tumors than in well differentiated tumors (36 and 25%, respectively), and lower in bronchioloalveolar carcinoma (22 and 10%, respectively) compared with other subtypes of adenocarcinoma. The prognosis for patients with MMP-2 and/or -9 positive immunoreactivities was significantly poorer than for those with a MMP-negative tumor (P < 0.05). The degree of collagenization was divided into four grades, and tumors with a small to abundant amount of collagen (grade 2 and grade 3 fibrosis) had a higher incidence of immunoreactivity to both types of MMP. It is estimated that these expressions might be responsible for tumor invasion, metastasis, and for grade 2 and grade 3 fibrosis in T1 adenocarcinoma of the lung.
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PMID:Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung. 923 85

Clinicopathologic staging of colorectal cancers cannot always predict aggressiveness of prognosis for a particular patient. We have used activity assays for cysteine proteinases, cathepsins B, L and H (CB, CL and CH) and matrix metalloproteinases, MMP-2 and MMP-9, to identify several distinctive, reproducible proteolytic profiles in a large set of colorectal carcinomas. We observed that individual proteinases demonstrated specific and distinct levels of activity at different cancer stages, possible reflecting non-random steps in a proteolytic cascade related to tumor development. We also observed that individual colon cancers fell into relatively few categories when characterized for the combined expression of three proteinases: CB, CL and MMP-9. Four proteolytic profiles, designated "Early", "Middle", "Late", and "High", could be used to define almost 80% of the colorectal carcinomas analyzed. Such profiles, based on the expression of several proteinases in a given tumor, provided information independent of clinical stage and may identify crucial variations in tumor behavior.
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PMID:Characterizing human colorectal carcinomas by proteolytic profile. 923 13

Increased production of proteinases, such as matrix metalloproteinases (MMPs), is a characteristic feature of malignant tumors. Some human cancers and cell lines derived from them also express trypsinogen, but the function of the extrapancreatic trypsin has remained unclear. In this study we cloned and sequenced trypsinogen-2 cDNA from human COLO 205 colon carcinoma cells and characterized the ability of the enzyme to activate latent human type IV procollagenases (proMMP-2 and proMMP-9). As shown by cloning and N-terminal amino acid sequencing, the amino acid sequence of tumor-associated trypsin-2 is identical to that of pancreatic trypsin-2. We found that both pancreatic trypsin-2 and tumor cell-derived trypsin-2 are efficient activators of proMMP-9 and are capable of activating proMMP-9 at a molar ratio of 1:1000, the lowest reported so far. Human trypsin-2 was a more efficient activator than widely used bovine trypsin and converted the 92-kDa proMMP-9 to a single 77-kDa product that was not fragmented further. The single peptide bond cleaved by trypsin-2 in proMMP-9 was Arg87-Phe88. The generation of the 77-kDa species coincided with the increase in specific activity of MMP-9. In contrast, trypsin-2 only partially activated proMMP-2. Trypsin-2 cleaved the Arg99-Lys100 peptide bond of proMMP-2 generating 62-65-kDa MMP-2 species. Trypsin-2-induced proMMP-2 and -9 conversions were inhibited by tumor-associated trypsin inhibitor added either prior to or during activation indicating that proMMPs were not activated autocatalytically. Trypsin-2 also activated proMMPs associated with tissue inhibitor of matrix metalloproteinases, the complexes of which are thought to be the major MMP forms in vivo. The ability of human tumor cell-derived trypsin-2 to activate latent MMPs suggests a role for trypsin-2 in initiating the proteinase cascade that mediates tumor invasion and metastasis formation.
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PMID:Activation of type IV procollagenases by human tumor-associated trypsin-2. 926 Nov 9

Multiple myeloma is a very devastating cancer with a high capacity to destroy bone matrix. Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor invasion. In this study, we have investigated the involvement of interstitial collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9) in the biology of multiple myeloma. We show (1) that myeloma cells express MMP-9 and (2) that this expression is not subjected to regulation either by interleukin-6 (IL-6), the major myeloma cell growth factor, or by other cytokines involved in the multiple myeloma cytokine network. In the tumoral environment, we show that bone marrow stromal cells express MMP-1 and MMP-2. Whereas MMP-1 is positively regulated by IL-1beta, tumor necrosis factor-alpha, and Oncostatin M, MMP-2 is not modulated by any of these cytokines. To evaluate whether myeloma cells can modify the bone marrow stromal environment, we have examined these MMP activities in coculture. Interestingly, we have observed an upregulation of MMP-1 and a partial conversion of the proMMP-2 into its activated form. We conclude that the increase of MMP activity produced or induced by myeloma cells in these cocultures could favor bone resorption and tumor invasion. Inhibition of such activities could represent a new therapeutical approach in multiple myeloma.
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PMID:Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells. 926 85

Theaflavin and theaflavin digallate, which are components of black tea were examined by in vitro invasion assay with mouse Lewis lung carcinoma LL2-Lu3 cells, which are highly metastatic. The compounds inhibited invasion by the tumor cells. Gelatin zymography showed that the cells secreted matrix metalloproteinases (MMPs), probably including MMP-2 and MMP-9, which may be involved in tumor cell invasion and metastasis. Theaflavin and theaflavin digallate also inhibited MMPs from the culture medium of these tumor cells, as did (-)-epigallocatechin gallate. These results suggest that theaflavin, theaflavin digallate, and (-)-epigallocatechin gallate inhibit tumor cell invasion by inhibiting type IV collagenases of the LL2-Lu3 cells.
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PMID:Inhibition of collagenases from mouse lung carcinoma cells by green tea catechins and black tea theaflavins. 933 52

Matrix metalloprotease-9 (MMP-9; 92-kd type IV collagenase, gelatinase B) is regarded as important for degradation of the basement membrane and extracellular matrix during cancer invasion and other tissue-remodeling events. Expression of MMP-9 was analyzed in 22 cases of human ductal breast cancer by immunohistochemistry and in 8 of these cases also by in situ hybridization. For immunohistochemistry we used affinity-purified polyclonal antibodies as well as a MMP-9-specific monoclonal antibody (clone 6-6B). Three different stromal cell types with a positive MMP-9 immunoreaction were identified morphologically: neutrophils and macrophage-like cells in all cases and vascular cells in 16 of 22 cases. Double immunofluorescence with antibodies to CD68 conclusively demonstrated MMP-9 expression in macrophages. To identify the positive vascular cells, we employed antibodies to von Willebrand factor and PAL-E for identification of endothelial cells, high molecular weight melanoma-associated antigen for pericytes, and alpha-smooth muscle actin for vascular smooth muscle cells. Using conventional and confocal double immunofluorescence microscopy, colocalization of MMP-9 was seen with high molecular weight melanoma-associated antigen, the pericyte marker, whereas little or no coexpression was seen with alpha-smooth muscle actin. Virtually no coexpression was seen with the endothelial cell markers PAL-E and von Willebrand factor. In situ hybridization showed that MMP-9 mRNA colocalized with MMP-9 immunoreactivity in macrophages and vascular structures, whereas no MMP-9 mRNA was detected in neutrophils. No MMP-9 immunostaining or in situ hybridization signal was detected in cancer cells in any of the cases. Based on these results, it is concluded that MMP-9 in human breast cancer is located in tumor-infiltrating stromal cells, including neutrophils, macrophages, and vascular pericytes, and that the latter two cell types also produce this metalloprotease. We suggest that the MMP-9 produced in pericytes may play a role in extracellular matrix degradation during tumor angiogenesis.
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PMID:Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. 935 69

We investigated the effects of epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha on migration, invasion and matrix metalloproteinase (MMP) expression of uterine cervical-carcinoma SKG-IIIb cells, and whether these growth factors affect pyrimidine-nucleoside-phosphorylase (PyNPase) activity and 5'-deoxy-5-fluorouridine (5'-dFUrd) sensitivity of tumor cells. Tumor-cell migration along a gradient of substratum-bound fibronectin and invasion into reconstituted basement membrane were stimulated by 0.1 to 100 ng/ml of EGF and TGF-alpha in a concentration-dependent manner. The zymography of tumor-conditioned medium showed that the treatment of tumor cells with EGF and TGF-alpha resulted in an increase of the 92-kDa type-IV collagenase (MMP-9), which was confirmed by immunoblot analysis. These growth factors also up-regulated the expression of PyNPase activity of tumor cells and consequently enhanced the anti-proliferative action of 5'-dFUrd, a cytostatic that is biotransformed to 5-fluorouracil (5-FUra) by PyNPase. However, EGF and TGF-alpha did not have significant effects on the 5-FUra sensitivity of tumor cells. These results suggest that EGF and TGF-alpha, tumor environmental factors, simultaneously up-regulate the potential of uterine cervical-carcinoma cells to invade extracellular matrices and their PyNPase activity, which are subsequently associated with the specific action of 5'-dFUrd selectively killing tumor cells of gynecological origin with high invasive and metastatic potential.
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PMID:Stimulatory effects of EGF and TGF-alpha on invasive activity and 5'-deoxy-5-fluorouridine sensitivity in uterine cervical-carcinoma SKG-IIIb cells. 937 37

Treatment of mouse Lewis lung carcinoma with razoxane or dacarbazine was protracted for 10 transplant generations. While the capacity of the treated tumors to grow locally in immuno-competent or in immuno-depressed hosts was retained and not significantly modified, the metastatic phenotype was eliminated when the treated tumor cells were transplanted into immuno-competent hosts. The reduction in metastatic potential was slightly less pronounced, in terms of both number and volume of metastases, when the treated tumor cells were transplanted into immuno-depressed hosts. These properties were retained after 3 transplant generations without treatment. Northern blotting and zymography of primary-tumor crude extracts revealed that treatment with either razoxane or dacarbazine for one generation approximately doubled the expression of MMP-2 and MMP-9, while lacking any effect on that of 1.0 and of 3.5 kb TIMP-2. When the treatment was maintained for 10 generations, the expression of MMP-2 and MMP-9 for both drugs showed up-regulation of approximately 10- and 2-fold respectively. TIMP-2 mRNA of 1.0 kb doubled its expression, while that of 3.5 kb registered just above the control. Dacarbazine doubled the expression of uPA after 10 generations, while razoxane boosted it approximately 3-fold after either 1 or 10 generations. The permanent loss of metastatic phenotype induced in Lewis lung carcinoma by dacarbazine and razoxane is thus attributable to biological mechanisms independent of down-regulation of expression and/or activation of the 2 gelatinases.
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PMID:Suppression of metastatic potential and up-regulation of gelatinases and uPA in LLC by protracted in vivo treatment with dacarbazine or razoxane. 937 40


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