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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isotopically labeled [( 3H]serine, [3H]proline, and [35S]sulfate) subendothelial cell basement membranes were used to determine the role of urokinase plasminogen activator (uPA) and its specific inhibitor plasminogen activator inhibitor 2 (PAI-2) in colon cancer cell extracellular matrix degradation. Recombinant PAI-2 irreversibly inhibited low and high molecular weight purified human uPA in addition to both colon cancer cell-associated and secreted uPA, particularly if pro-uPA had been preactivated. Two selected lines (COLO394 and LIM1215) preferentially degraded differently labeled matrices in a time- and plasminogen-dependent manner. This process was inhibitable by PAI-2 in the medium at levels which suggested that some degree of "shielding" of cell surface uPA from inhibitor occurred. The ability of PAI-2 to regulate the invasive phenotype of cells which express cell surface or receptor-bound uPA is discussed.
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PMID:Inhibition of cancer cell urokinase plasminogen activator by its specific inhibitor PAI-2 and subsequent effects on extracellular matrix degradation. 211 45

Activity of receptor-bound urokinase plasminogen activator (uPA) on the surface of colon cancer cells appears to be a function of the number of uPA receptors. The regulation of uPA therefore may determine the invasive phenotype. The effects of amiloride on the modulation of uPA mRNA and protein induced by phorbol ester (PMA) and cycloheximide (CHX) were studied in four colon cancer cell lines, HCT116, KM12SM, LIM1215 and LS123. Northern blot analyses showed that PMA induced uPA mRNA that peaked at 2-48 h in HCT116 cells. In all colon cancer cell lines tested, the expression of uPA mRNA by PMA was super-induced after the addition of the protein synthesis inhibitor CHX, suggesting that stimulation of uPA gene expression does not require de novo protein synthesis. uPA mRNA was also induced by CHX alone, indicating that there may be a labile protein which inhibits uPA mRNA processing. Amiloride profoundly inhibited uPA mRNA production at concentrations between 0.1-1 mM in the presence or absence of PMA or CHX. uPA protein levels on the colon cancer cell surface reflected PMA induction and amiloride inhibition of uPA mRNA levels. Transcriptional elongation experiments using isolated nuclei indicated that while the induction effects of PMA or CHX on uPA gene expression were mediated at the post-transcriptional level, amiloride acted at both transcription and post-transcription levels. The inhibitory effects of amiloride on uPA gene expression reported in this paper may offer the prospect of developing new therapeutic approaches to the prevention of invasion and metastasis by adenocarcinomas.
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PMID:Amiloride modulates urokinase gene expression at both transcription and post-transcription levels in human colon cancer cells. 775 Feb 7

Paraffin-wax embedded specimens from 30 cases of colonic adenocarcinoma were investigated for immunoreactivity for the receptor of urokinase-type plasminogen activator (uPAR). In all cases there was a strong signal, predominantly at the invasive foci. The positive cells were mainly tumour-infiltrating macrophages but neutrophils and eosinophils were also strongly stained. The neoplastic cells were positive in 19 of the samples with staining of occasional or a moderate number of cells. In uninvolved, normal-appearing mucosa adjacent to the malignant infiltrates, immunostaining of both macrophages and neutrophils was seen, but the labelling was less intense than that seen in the malignant lesions. Weak to moderate staining of normal intestinal epithelium was also seen at the luminal surface. Comparison between immunoreactivity and in situ hybridization showed a similar distribution of protein and mRNA with two exceptions: first, neutrophils (strongly immunoreactive for uPAR) were negative or only weakly positive for uPAR/mRNA; and second, many cancer cells at invasive foci showed prominent hybridization signals but no detectable uPAR immunoreactivity. Together with previous findings of urokinase plasminogen activator (uPA) protein and mRNA being expressed in tumour-infiltrating fibroblast-like cells at the invasive foci, these results support the view that the uPA pathway of plasminogen activation is involved in tissue degradation in colon cancer. The results also extend and consolidate an emerging picture of non-neoplastic tumour stromal cells producing molecules involved in the generation and regulation of extracellular proteolysis in cancer.
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PMID:Immunohistochemical detection of the receptor for urokinase plasminogen activator in human colon cancer. 818 5

Tumor spread may be favored by a reduced production and/or an enhanced degradation of extracellular matrix components (collagen, fibronectin, laminin). Most tumor cell behavior, from growth to spread, may be regulated by cytokines, the exact roles of which, however, are not yet fully understood. We here evaluate the effects of some cytokines (epidermal growth factor, transforming growth factor-beta 1, interleukin-1 alpha, and interleukin-1 beta) on both cell growth and the production of the aminoterminal peptide of type III procollagen, the urokinase plasminogen activator, and the plasminogen activator inhibitor-1 in neoplastic cell lines originating in the pancreas and colon. Cells were stimulated daily with the above cytokines and the aminoterminal peptide of type III procollagen, urokinase plasminogen activator, and plasminogen activator inhibitor-1 were measured in the conditioned media. Epidermal growth factor stimulated cell growth of both cell lines. Transforming growth factor-beta 1 counteracted cell proliferation and stimulated type III procollagen and plasminogen activator inhibitor-1 production only in the colon cancer cell line. Interleukin-1 alpha slightly stimulated cell growth, but inhibited plasminogen activator inhibitor-1 production in both cell lines; interleukin-1 beta did not affect cell growth, but stimulated plasminogen activator inhibitor-1 production by the colon cancer cell line. Our findings suggest that transforming growth factor-beta 1 and interleukin-1 beta may have an antidiffusive effect. These results confirm that cytokine-producing cells have a potential role in stimulating or counteracting tumor growth and spread and also confirm the pivotal role of host-tumor interactions in determining the outcome of a particular neoplasia.
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PMID:Cytokines may influence tumor growth and spread. An in vitro study in two human cancer cell lines. 900 14

To study the temporal expression of motile structures and protease activity during colon cancer cell invasion by heregulin-beta1 (HRG) and prostaglandin E2 (PGE2), we have developed a three-dimensional spatial model system. HRG and PGE2 each induced the formation of well-organized, three-dimensional structures with empty spaces in the center and stimulated the expression of urokinase plasminogen activator (uPA) with differential localization of membrane-bound uPA at the focal adhesion points and leading edges of the motile cells. A specific cyclooxygenase-2 inhibitor blocked the formation of three-dimensional luminal glandular structures induced by HRG but did not block those induced by PGE2. A specific antagonist of uPA receptor completely blocked the formation of these luminal glandular structures induced by PGE2 and HRG. These findings suggest that HRG-mediated increased invasiveness of colon cancer cells is augmented at least in part by induction of PGE2 and uPA, and this augmentation may involve the formation of three-dimensional invasive structures via the uPA pathway. In addition, the three-dimensional model system presented here may have a wider application to screen the effects of therapeutic compounds and biomolecules on different spatial aspects of colonic biology, including cell growth, motility, invasion, survival, and apoptosis.
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PMID:A three-dimensional and temporo-spatial model to study invasiveness of cancer cells by heregulin and prostaglandin E2. 1119 3

High intakes of dietary fiber or resistant starches have been associated with a lower incidence of colon cancers. Because short-chain fatty acids (SCFA) such as butyrate are produced in the colonic lumen by the bacterial fermentation of dietary fibers and resistant starches, we hypothesized that SCFA may inhibit the development of invasive human colon cancers. To test this hypothesis, primary human invasive colonocytes were isolated from fresh surgical specimens and treated with 0.01 mol/L acetate, propionate or butyrate; cell invasion, cell adhesion, F-actin polymerization, urokinase plasminogen activator (uPA), tissue inhibitor matrix metalloproteinase (TIMP)-1, TIMP-2 and mutant p53, Bcl-2, Bax, p21 and proliferating cell nuclear antigen (PCNA) protein expression levels were examined. Although each of the SCFA tested significantly reduced primary cell invasion, butyrate was the most potent, inhibiting primary invasive human colon cancer invasion by 54% (P < 0.0001). The effects of SCFA on primary cell invasion appeared to be independent of cell adhesion and F-actin polymerization but dependent on the inhibition of uPA (P < 0.05) and the stimulation of TIMP-1 and TIMP-2 activities (P < 0.05). Protein expression levels of mutant p53, p21, Bax, Bcl-2 and PCNA were significantly altered by each of the SCFA tested (P < 0.05). These data indicate that SCFA inhibit invasive human colon cancer by modulating proteolytic uPA and antiproteolytic TIMP-1 and TIMP-2 activities, but their mechanisms of action on tumor suppression, apoptosis and growth arrest may differ.
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PMID:Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, mutant p53, Bcl-2, Bax, p21 and PCNA protein expression in an in vitro cell culture model. 1169 45

Pericellular proteolysis plays a crucial role in tumor cell invasion. The controlled degradation of the extracellular matrix by tumor cell-associated proteases allows tumor cells to invade surrounding tissues and gain access to the circulation. One of the main protease systems involved in tumor cell invasion and metastasis is the plasminogen/plasmin system (PPS). The components of the PPS include the urokinase plasminogen activator (uPA), its cell surface receptor urokinase plasminogen activator receptor (uPAR), and its naturally occurring inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Increases in tumor and serum levels of uPA, uPAR, and PAI-1 are associated with a worse prognosis in patients with colon cancer. Use of these proteins as either tumor or serum markers may allow more accurate determination of the prognosis in colon cancer patients. Furthermore, these proteins appear to be attractive as targets for the biologic therapy of colon cancer.
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PMID:Plasmin/plasminogen system in colorectal cancer. 1196 42

Expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) strongly correlates with a malignant tumour cell phenotype. In the multistep process of metastasis, uPA binding to uPAR influences different cellular functions. In the present study, a highly metastatic colon cancer cell line, HCT116 was transfected with an expression vector containing a 5' uPAR cDNA fragment in an antisense orientation. This construct was most effective in reducing uPAR cell surface expression as confirmed by flow cytometry analysis. Antisense transfection of HCT116 cells had no effect on proliferation but the following effects were observed: (1) a 1.3-fold decreased adhesion; (2) a two-fold decreased Erk MAP kinase activity; (3) a 2.7-fold decrease in Src kinase activity; (4) a 1.5- and two-fold decrease in uPA cell surface expression and secretion; (5) abrogation of promatrix metalloproteinase-9 secretion; and (6) a complete suppression of plasminogen-dependent matrix degradation. Using proteomic analysis, we demonstrate loss of approximately 200 proteins and quantitative differences in the expression of 141 other proteins in an antisense-clone compared to wild-type and mock-transfected control. Such changes in protein expression with the down-regulation of uPAR may be an important contributor in colon cancer progression and metastasis and may not only provide a basis to develop a proteomic data bank of uPAR-mediated signaling molecules but may also lead to the development of therapeutic approaches for the cure and better management of colon cancer.
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PMID:Proteomic profiling of proteins associated with urokinase plasminogen activator receptor in a colon cancer cell line using an antisense approach. 1262 82

Cathepsin B and pro-urokinase plasminogen activator (pro-uPA) localize to the caveolae of HCT 116 human colorectal carcinoma cells, an association mediated by active K-RAS. In this study, we established a stable HCT 116 cell line with a gene encoding antisense caveolin-1 (AS-cav-1) to examine the effects of caveolin-1, the main structural protein of caveolae, on the expression and localization of cathepsin B and pro-uPA, and their cell-surface receptors p11 and uPA receptor (uPAR), respectively. AS-cav-1 HCT 116 cells secreted less procathepsin B than control (empty vector) cells as measured by immunoblotting and pepsin activation of the proenzyme. Expression and secretion of pro-uPA was also downregulated in AS-cav-1 HCT 116 cells. Localization of cathepsin B and pro-uPA to caveolae was reduced in AS-cav-1 HCT 116 cells, and these cells expressed less total and caveolae-associated p11 and uPAR compared with control cells. Previous studies have shown that uPAR forms a complex with caveolin-1 and beta1-integrin, and we here show that downregulation of caveolin-1 also suppressed the localization of beta1-integrin to caveolae of these cells. Finally, downregulation of caveolin-1 in HCT 116 cells inhibited degradation of the extracellular matrix protein collagen IV and the invasion of these cells through Matrigel. Based on these results, we hypothesize that caveolin-1 affects the expression and localization of cathepsin B and pro-uPA, and their receptors, thereby mediating cell-surface proteolytic events associated with invasion of colon cancer cells.
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PMID:Caveolin-1 mediates the expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell-surface receptors in human colorectal carcinoma cells. 1576 46

Patients undergoing resection of hepatic metastases of colorectal cancer have a high risk of extrahepatic recurrence, most likely caused by early tumor cell dissemination or the manipulation of liver tumors during surgical resection. Using immunocytochemistry, we studied 47 patients for cytokeratin (CK)-positive (+) cells in: a) bone marrow (BM) samples to determine whether tumor cell dissemination had already occurred before surgery; and b) blood samples directly taken from the hepatic vein before and during surgery of liver metastases. In addition, normal and malignant liver tissues were evaluated for markers known to be involved in tumor progression and metastasis [urokinase plasminogen activator (uPA), Her-2/neu, epidermal growth factor receptor (EGF-R)] using sandwich enzyme immunoassays. CK+ cells were detected in the BM of 26/47 patients (55%), in blood samples of 14/47 patients (30%) before surgery and 11/47 patients (23%) during surgery with a median detection rate of 1 (range, 1-14) CK+ cell per 4x10(6) MNC. No CK+ cells were found in 15/47 patients (32%) in any sample studied. Tumor tissue was obtained from 32/47 patients and normal liver tissue from 24/32 patients. While no differences were found for EGF-R and Her-2/neu, a 9-fold higher expression of uPA could be demonstrated in tumor tissue of 20/32 patients (63%) compared to normal liver tissue. When all obtained results were correlated with clinical outcome, neither the detection of CK+ cells nor the expression pattern in the tumor tissue, or the combination of both, was predictive for extrahepatic recurrence or overall survival after a mean observation time of 43 months (range, 26-54 months). Although uPa is overexpressed in liver metastases of colorectal cancer, and dissemination of CK+ cells during surgery of these metastases is a frequent event in colon cancer, these findings do not predict extrahepatic recurrence. Further characterization of single cells, especially those spread during surgery, will help to identify those patients with an increased risk of later relapse.
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PMID:Tumor cell dissemination in colon cancer does not predict extrahepatic recurrence in patients undergoing surgery for hepatic metastases. 1639 68


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