Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human colon adenocarcinomas and adjacent normal colon tissues were stained immunohistochemically with three different monoclonal antibodies and one preparation of polyclonal antibodies against each of the two plasminogen activators, uPA (urokinase type) and tPA (tissue type). The staining patterns seen with the respective sets of antibodies were identical. In all of 10 cases, staining for uPA in the normal colon tissue was confined to scattered fibroblastlike cells in the lamina propria. Other cells, including epithelial and endothelial cells, were uPA negative. All the tumor infiltrates contained many more uPA-positive cells than the normal tissues, but the staining was confined to fibroblastlike cells and endothelial cells in the tumor stroma, while no staining of the malignant epithelial cells was detected. Analysis for uPA by enzyme-linked immunosorbent assay (ELISA) in four cases showed an average uPA content of 0.15 ng uPA/mg protein in the normal colon tissues and 1.6 ng uPA/mg protein in the tumors. Tissue-type plasminogen activator immunoreactivity was confined to endothelial cells in both the normal colon tissue and in the colon carcinomas. These findings may indicate that colon cancer cells recruit stromal cells to produce uPA involved in degradation of the extracellular matrix during invasive growth.
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PMID:Localization of urokinase-type plasminogen activator in stromal cells in adenocarcinomas of the colon in humans. 170 28

The immunoperoxidase technique, using antibodies against human urinary urokinase (Mr 55,000), was used for the localization of this enzyme in histological preparations of human colon tumors and normal colon tissue. The localization of tissue (vascular) activator was also investigated using antibodies against enzyme purified from human malignant melanoma. Both the "indirect method" and the peroxidase-antiperoxidase technique were found to be useful. Urokinase-reactive material was found in all tissues examined (33 primary cancers, 11 metastases, and 8 adenomas). In the normal colon, urokinase was found only in some of the goblet cells of the mucosal epithelium. In colon cancer, diffuse specific staining was observed in the cytoplasm, but the most intense staining was localized at the edge of the cancer cells bordering the lumen of the glands. In some cases, intense supranuclear staining could be observed in a location corresponding to the Golgi apparatus. In a few instances, urokinase could be seen associated with fibroblasts near the advancing front of an invading tumor. Adenoma, a benign tumor but often a precursor of cancer, also showed the presence of urokinase. Most significant were the observations showing that, in regions of the mucosal glands where normal epithelial cells were abruptly replaced by cancer cells, the appearance of cytoplasmic urokinase showed strict and exclusive association with the malignant cells, and the same was the case in transitions from normal epithelium to adenoma. In contrast to urokinase, tissue plasminogen activator was not associated with cancer cells, but was consistently present in the stroma which separates the cancer glands and was localized in the endothelium of the blood vessels. This visual evidence was supported by results of extraction of plasminogen activators from tumors, and from the separated mucosal and submucosal layers of the normal colon of the same patients, which showed that urokinase is most abundant in the tumor tissue and least abundant in the submucosa, while tissue activator is most prevalent in the well-vascularized mucosa and submucosa and scarce in the usually poorly vascularized adenocarcinomas.
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PMID:Localization of plasminogen activators in human colon cancer by immunoperoxidase staining. 388 45

The plasminogen activator urokinase promotes tumor invasion by converting plasminogen into plasmin, which degrades several extracellular matrix components. Urokinase can bind to a specific cell surface receptor, which leads to accelerated plasmin production. While there is good evidence indicating a role for this binding site in tumor invasion/metastasis, there is little information concerning the regulation of urokinase receptor expression in invasive cancer. To address this question a series of colon cancer cell lines, which demonstrate either a high or low ability to invade an extracellular matrix-coated porous filter, was characterized for receptor expression at the transcriptional and post-transcriptional levels. The invasive cell lines possessed 10-fold more receptors than their non-invasive counterparts as shown by cross-linking experiments and by Western blotting. Northern blotting indicated that this disparity in receptor number could be largely accounted for by a different amount of steady-state mRNA encoding the binding site. However, neither gene amplification nor enhanced mRNA stability could account for the augmented receptor protein observed for the invasive colon cancer cell types. In contrast, nuclear run-on experiments with representative cell lines revealed that the 10-fold difference in receptor display between the invasive-competent and invasive-deficient cells could be largely accounted for by differences in transcription rates. Transcription of the u-PAR gene in the receptor-deficient GEO cells, but not in the receptor-rich RKO cells, could be augmented by protein kinase C stimulation. These findings provide a clear rationale for studies to determine if the urokinase receptor promoter in invasive colon cancer is activated in cis or in trans.
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PMID:Transcriptional activation of the urokinase receptor gene in invasive colon cancer. 807 48

Surveillance colonoscopy and biopsy are inaccurate methods of predicting the likelihood of ulcerative colitis patients to develop colon carcinoma. We examined uPA and PAI-1 as potential markers for assessing these patients and those with familial polyposis who are at risk of developing colon cancer. For comparison, biopsies of normal colon and Crohn's disease were evaluated. We examined 77 colonic mucosa specimens taken from patients undergoing elective resection for benign and malignant colonic disease. uPA and PAI-1 were measured using a monoclonal antibody-based ELISA kit (American Diagnostica, Greenwich, CT) and expressed as ng/mg extract protein. Intra- and interassay controls of uPA gave CV = 3-4% and CV = 8-9%, respectively, while those for PAI-1 were 6-7% and 10-11%, respectively. The Mann-Whitney test showed that both uPA and PAI-1 expression were significantly higher in colon cancer, chronic ulcerative colitis, and Crohn's disease than in normal colon. uPA in familial polyposis samples was similar to that of normal colon, while PAI-1 was much lower than in normal colon. Neither patient age nor sex appeared to influence the expression of these potential markers in any tissue. The pattern of uPA and PAI-1 expression in normal, benign and malignant colon suggests these proteins deserve further consideration as markers for assessing colon carcinoma risk.
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PMID:Expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in colon disease. 858 11

The question whether urokinase is expressed in human colon cancer by the cancer cells themselves or by surrounding stromal elements such as fibroblasts, macrophages, and leukocytes, which transfer the activator to the receptors of the cancer cells, has been a controversial one. In the present study 12 cases of colorectal cancer were investigated by immunohistochemical methods using three monoclonal antibodies of different specificity against urokinase. Cytoplasmic staining of strongly varying intensity was observed in all cases, with the antigen expressed most strongly in the apical and the basal regions of the cancer cells. In some cases, staining was also found in stromal elements surrounding the cancer glands. That the activator was indeed the product of the cancer cells was demonstrated by in situ hybridization using a uPA-cDNA probe, which detected the presence of uPA-mRNA in both the basal and the apical regions of the cancer cells. A monoclonal antibody against the receptor for uPA showed similar localization. These findings indicate that the activator is expressed by the cancer cells and is not recruited by them from stromal elements.
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PMID:Demonstration of urokinase expression in cancer cells of colon adenocarcinomas by immunohistochemistry and in situ hybridization. 1051 94

The role of urokinase-type plasminogen activator receptor (uPAR) in human colon cancer metastasis has not been tested using an antisense approach. In our study, the HCT116 cells, with high metastatic potential were transfected with expression vectors containing a 3' or 5' uPAR cDNA fragment in an antisense (AS) orientation. Transfection of 4 clones was confirmed by DNA hybridization analysis. Receptor-bound endogenous uPA activities of the clones were reduced to 16-68% of controls. The extracellular matrix degradation by the 4 clones was decreased to 33-76%. Two of the clones, 3'-AS7 and 5'-AS, were evaluated in an in vivo assay system of experimental metastasis using athymic mice. Pulmonary metastases were found in 63-78% mice injected with the parent HCT116 or control cells. In mice injected intravenously with the antisense transfected clones, 3'-AS7 and 5'-AS, however, pulmonary metastases were found in only 19% and 9% respectively (p < 0.05). These results provide direct evidence that both 3' and 5'-AS uPAR can inhibit colon cancer invasion and metastasis and may offer the prospect of defining specific targets for gene therapy.
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PMID:Inhibition of colon cancer metastasis by a 3'- end antisense urokinase receptor mRNA in a nude mouse model. 1129 Oct 54

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.
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PMID:Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells. 1286 32

Recent epidemiological studies indicated risk reductions in ovarian cancer with consumption of acetaminophen or non-steroid anti-inflammatory drugs. Until now, there is not a systematic analysis, why these agents may reduce risk of ovarian cancer, as it has been performed to explain aspirin-reduction of colon cancer risk. This review tries to explain molecular mechanisms pertinent to acetaminophen- and NSAID-reduction of ovarian cancer. It is proposed that the major mechanism by these anti-inflammatory agents is a shared pathway dependent on the suppression of NF-kappaB activity, which may subsequently decrease transcription of growth factors, chemokines and proteases such as COX-2, VEGF, IL-8/CXCL8, MCP-1/CCL-2, MIP1alpha/CCL-3, tPA and uPA, which are shown to be elevated in ovarian carcinoma, and which play diverse roles such as inducing angiogenesis, invasion, autocrine growth loops and resistance to apoptosis. Besides these, specific mechanisms of action can be attributed to acetaminophen-reduction of ovarian cancer risk via I. Induction of specific reproductive atrophy due its sex-steroid resembling phenolic ring; II. Reduction of glutathione pools due to its NAPQI metabolite, which may play an important role for sterilizing pre-malignant ovarian lesions, since they are shown to lack proper levels of glutathione; III. Inhibition of tautomerization activity of MIF (macrophage migration inhibitory factor), which is shown to be released from ovarian cancer, and which is necessary for proper ovulation; IV. Inhibition of cytokine-induced and endothelia-origined cyclooxygenases. Except the chemosensitization studies, acetaminophen and NSAIDs should be investigated in animal models to test likely benefits in ovarian cancer, since most of their activity may origin from intervening with the cancer growth-stimulating inflammatory stimuli, rather than with the direct cellular toxicity.
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PMID:NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer. 1525 53

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

The interaction between the urokinase receptor (uPAR) and its ligand urokinase (uPA) mediates phenomena such as tissue remodelling, chemotaxis, tumour invasion, dissemination, proliferation, and angiogenesis. The broad-spectrum of biological processes that the uPA/uPAR interaction plays a role in has led researchers to speculate that this interaction may be a useful molecular target for therapeutic intervention in several pathological conditions, particularly in the prevention and inhibition of the dissemination of cancer cells. In syngeneic and xenograft murine tumour models, in which metastasis is driven by the uPA/uPAR interaction, inhibition of primary tumour growth, metastasis and angiogenesis has been shown with several proteins acting as uPAR antagonists. Immunohistochemistry, in conjunction with prognostic studies, has implicated the uPA/uPAR interaction in the dissemination of tumours, such as malignant melanoma, colon cancer, non-small cell lung cancer (NSCLC) and stomach cancer, as well as breast and ovarian carcinomas. A potential inhibitor of the uPA/uPAR interaction should result in a significant increase in the disease-free interval and survival time following resection of the primary tumour in a clinical Minimal Residual Disease (MRD) setting. Low molecular weight uPAR antagonists should be orally active, and have few side-effects, excellent bioavailability, favourable pharmacokinetic properties and a long half-life. Furthermore, these compounds should be able to inhibit the dissemination of cancer cells without the need for targeted drug and vector delivery.
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PMID:Urokinase receptor antagonists: novel agents for the treatment of cancer. 1599 80


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