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

Conditioned medium derived from the colon cancer cell lines was ineffective in solubilizing immobilized radiolabeled laminin. However, substantial degradation was observed in the presence of plasminogen and could be largely blocked by preincubation with polyclonal anti-urokinase antibody. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the solubilized products generated either by the conditioned medium or by authentic urokinase supplemented with plasminogen yielded identical results. Analysis of the spent medium for urokinase by an enzyme-linked immunosorbent assay method revealed a similar profile to that achieved with the laminin degradation assays for the six cell lines tested. However, Northern analysis of urokinase-specific mRNA indicated that protein levels could not be entirely predicted by steady-state levels of the transcript. In a previous study, undifferentiated colon cancer cell lines expressed larger amounts of the plasminogen activator into the conditioned medium compared with their well-differentiated counterparts. However, these earlier studies were performed using cells grown in defined medium which lacked epidermal growth factor (EGF). EGF has been reported to affect plasminogen activator levels. Consequently, to investigate the role of EGF in the modulation of urokinase protein/activity, cell types representative of well- and poorly differentiated colon cancer were examined for their sensitivity of expression to this growth factor. In the absence of EGF, primitive cell types secreted, on average, 5 times more urokinase than their well-differentiated counterparts. In response to EGF, however, well-differentiated cell lines exhibited 4- to 6-fold increases in these parameters while the primitive cell lines were refractory to the peptide. Consequently, the differences in urokinase protein expressed by the well- and poorly differentiated groups of cells were abolished by the presence of EGF. The expression of a well-differentiated phenotype by colon cancer cell types in vivo probably depends to some extent on laminin within a basement membrane. The data presented herein are consistent with the idea that depletion of this glycoprotein from a basement membrane by urokinase-dependent mechanisms may contribute to the undifferentiated phenotype seen with many of these malignancies.
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PMID:Examination of urokinase protein/transcript levels and their relationship with laminin degradation in cultured colon carcinoma. 291 54

Marked increases of plasminogen activator activity were observed in human colon cancer tissue, compared to corresponding normal tissues. This increase was attributable to urokinase-type activator (HPA52), with no increase evident in the level of the tissue-type plasminogen activator (HPA66). Human monocyte minactivin specifically inhibited HPA52 activity in cancer tissue homogenates and in colon cancer cell supernatants, an effect that was greatly enhanced by preincubation with plasminogen, indicating that the predominant form of HPA52 in tissue and the form that is secreted in vitro is the proenzyme. Inactivation of HPA52 by minactivin was shown to be dependent on proteolytic activation of HPA52 proenzyme. Utilization of HPA52 activity by tumors in vivo could therefore be dependent upon a protease, such as plasmin, to generate the extracellular proteolytic activity necessary to digest the intercellular matrix and permit invasion of normal tissue structures by colon cancer cells.
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PMID:Proenzyme to urokinase-type plasminogen activator in human colon cancer: in vitro inhibition by monocyte minactivin after proteolytic activation. 296 17

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 host reaction is an important factor in the biological behavior of cancers. In human colon adenocarcinoma, stromal cells and some cancer cells express the urokinase receptor (uPAR), a molecule involved in the regulation of extracellular proteolysis. The present study reveals the identity of uPAR-expressing cell types and the subcellular localization of this molecule by immunoelectron microscopy in colon cancer. uPAR-positive cells were most abundant at the invasive margin of colon cancer and were identified as macrophages, fibroblasts, neutrophilic and eosinophilic granulocytes, endothelial cells and cancer cells. Of these, the most numerous were macrophages with uPAR detected along the plasma membrane, in accordance with its function in plasminogen activation on the cell surface. Fibroblasts were labeled in the lumen of rough endoplasmic reticulum, indicating its intracellular synthesis. Some granulocytes and endothelial cells expressed immunoreactivity along the plasma membrane. uPAR-positive cancer cells were stained along the plasma membrane and in rough endoplasmic reticulum. These findings suggested that a variety of non-malignant host cells play an important role in the plasmin-mediated breakdown of the extracellular matrix at the invasive margin.
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PMID:Expression of urokinase receptor in various stromal-cell populations in human colon cancer: immunoelectron microscopical analysis. 755 16

Recombinant human gamma 2 chain of laminin-5 was expressed in Escherichia coli, and used to generate specific polyclonal antibodies which were used to study the distribution of the protein in human cancers. A total of 72 biopsies of human cancers were stained, including 23 cases of colon adenocarcinomas, 16 ductal breast carcinomas, 9 malignant melanomas, 14 squamous cell carcinomas of the skin and cervix, and 10 sarcomas. As a control for the specificity of the antibodies, we performed in situ hybridization on adjacent sections of a number of the cases, and in all of these cases the localization of the gamma 2 chain protein and mRNA was identical. We found gamma 2 chain immunoreactivity in cancer cells in all cases of colon adenocarcinomas and squamous cell carcinomas but not in any of the sarcomas, supporting the view that the laminin-5 protein is specific for cells of epithelial origin. Notably, in all of the cases of colon adenocarcinomas, the positive staining was invariably associated with budding cancer cells located at the tip of invading malignant epithelium, whereas the cancer cells deeper in the tumors were most often negative. The staining was cytoplasmic in all cases and only in one case did we see additional extracellular immunoreactivity, indicating that this laminin isoform in cancer tissue is not laid down in the extracellular matrix but probably exerts its function at the cell surface or in its immediate vicinity. Using in situ hybridization to analyze the coexpression of laminin-5 and components of the plasminogen activation system, we found that the histological distribution of laminin-5-positive budding cancer cells at the invasion front in colon adenocarcinomas was identical to that of the receptor for urokinase-type plasminogen activator. These findings suggest that laminin-5 is a marker of invading cancer cells in at least some human malignancies, and that it therefore might represent a valuable marker for the invasive potential of these cancers. The colocalization of laminin-5 and urokinase-type plasminogen activator receptor in a subset of cancer cells in colon cancer also suggests that a controlled up-regulation of a number of gene products is a characteristic of budding colon cancer cells, and that these gene products serve functions crucial for the invasive phenotype of these cancer cells.
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PMID:Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. 766 91

Butyrate is a potent differentiating agent present in high concentrations in colonic lumen as a result of metabolic breakdown of dietary fibre and, as such, may directly influence colonic cancer progression. We have investigated the effects of butyrate on an enzyme system important in colonic tumour progression, the plasminogen-activating system, in a poorly differentiated colon cancer cell. Butyrate was found to induce a rapid and transient increase in plasminogen activator inhibitor type 1 (PAI-1) mRNA while concomitantly suppressing the constitutive production of both urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) mRNA transcripts. We have investigated the mechanisms involved in mediating these effects by run-on transcription and RNA stability analyses. Our data show that PAI-1 mRNA induction occurs through both regulation of the stability of the alternately spliced 3.3 kb PAI-1 mRNA transcript and induction of the 2.4 kb PAI-1 mRNA transcript. Studies using modulators of signal transduction pathways demonstrate that induction of PAI-1 mRNA synthesis is independent of protein kinase C but dependent on the activation of protein kinase A. Suppression of uPA mRNA by butyrate was found to occur by down-regulation of gene transcription through a process independent of de novo protein synthesis. The transcription rate of the uPAR gene was not modulated by butyrate, but rapid turnover of the uPAR gene by butyrate was dependent on ongoing protein synthesis. Our results demonstrate that butyrate can effect rapid changes in the expression of genes of the plasminogen-activating system through several different mechanisms in a gene-specific manner.
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PMID:Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells. 766 35

We examined the localization of urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitors (PAI-1 and PAI-2) and plasminogen (plg) in 26 cases of colon cancer by immunohistochemical staining. The u-PA antigen was detected in the cytoplasm of cancer cells (18/26) and stromal cells adjacent to cancer tissues (9/26). The localization of u-PA mRNA examined by in situ hybridization was consistent with that of u-PA antigen. The PAI-1 antigen was detected in fibroblasts and endothelial cells (22/26), while PAI-2 antigen was found in cancer cells (20/26). The plg antigen was seen in the extracellular matrix of the cancer stroma. The u-PA expression in cancer cells was significantly more frequently detected in cases with lymph node metastasis than in cases without metastasis. In either PAI-1- or PAI-2-expressing cases, lymph node metastasis seemed to be restrained. These findings indicate that cancer cells themselves produce u-PA, and suggest that u-PA converts plg into plasmin, which dissolves the extracellular matrix surrounding cancer cells, resulting in cancer invasion and metastasis. PAI-1 and PAI-2 may have inhibitory actions on cancer invasion and metastasis mediated by u-PA.
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PMID:Localization of urokinase-type plasminogen activator, plasminogen activator inhibitor-1, 2 and plasminogen in colon cancer. 773 9

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

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

The gene expression of two type IV collagen-degrading enzymes (72-kd and 92-kd type IV collagenases) was investigated in human colon adenocarcinomas by in situ hybridization. In all cases (18 out of 18), messenger RNA for the 72-kd type IV collagenase was present and located in numerous fibroblasts in the stroma surrounding the invasive cancer tissue. In normal-appearing colonic mucosa distant from the cancer tissue, either no expression or only very weak expression of this enzyme was detected. Also the 92-kd type IV collagenase was found in all samples investigated (10 out of 10), exclusively expressed by tissue macrophages. A very strong hybridization signal for messenger RNA for the 92-kd enzyme was found in a subpopulation of tissue macrophages surrounding invading malignant epithelium. In normal-appearing colon tissue, a markedly weaker hybridization signal was observed in macrophages contained in Peyer's patches. No hybridization signals for either of the two type IV collagenases were detected in cancer cells. Together with previous findings on expression of components of the plasminogen activation system, these results indicate that several nonepithelial cell types in the tumor stroma are involved in production of factors involved in extracellular proteolysis during colon cancer invasion.
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PMID:Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. 843 36


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