Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of suramin, a polysulfonated naphthylurea compound, on metastatic ability, proliferation, and production of plasminogen activators and plasminogen activator inhibitors were studied using the highly metastatic human renal cell carcinoma cell line, SN12C-PM6. After renal subscapular implantation of tumor cells in nude mice, suramin significantly inhibited metastasis of tumor cells to the lungs and liver. In vitro growth of tumour cells was inhibited by suramin in a dose-dependent manner, at relatively low doses (ID50 = 105 micrograms/ml). Plasminogen activator inhibitor type 2 (PAI-2) production by tumor cells was enhanced by suramin (100 micrograms/ml), whereas urokinase-type plasminogen activator (uPA) production was suppressed. Thus, the increase in PAI-2 and the decrease in uPA production correlated with the inhibitory effects on tumour growth and metastasis by suramin. Therefore suramin may be beneficial for the treatment of patients with an early stage of renal cancer with potential risk of metastasis.
Clin Exp Metastasis 1995 Mar
PMID:Effects of suramin on metastatic ability, proliferation, and production of urokinase-type plasminogen activator and plasminogen activator inhibitor type 2 in human renal cell carcinoma cell line SN12C-PM6. 788 14

In tumour development, proteases such as plasminogen activators (PAs) play a role in degradation of the extracellular matrix and other tissue barriers. Recently, we demonstrated that plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of cutaneous melanocytic tumour progression. In this study we investigated the expression and distribution of the various components of the PA system and the presence of PA enzyme activity in 45 freshly frozen primary uveal melanoma with known follow-up (14 spindle and 31 non-spindle type) and in metastases (n = 5). Tissue-type PA (t-PA) was found in endothelium of blood vessels and in tumour cells in almost all lesions, and was markedly present at the invasive front (towards the sclera and Bruch's membrane), but no correlation with tumour-related death could be established. Urokinase PA (u-PA) was expressed focally, by only five non-spindle cell melanomas but in all metastases. u-PA expression correlated with occurrence of metastasis. u-PA receptor (u-PAR) was present in one-third of all the tumours examined. Plasminogen activator inhibitors (PAI-1 and PAI-2) were found only focally in approximately 10 per cent of the lesions. Staining of t-PA, u-PA, and PAI was observed in all the metastases. We conclude that in uveal melanoma, u-PA expression may be associated with metastatic disease and accordingly with a poor prognosis. Further research on a larger group of tumours with known follow-up is needed to establish whether u-PA positivity is of additional prognostic value in uveal melanoma.
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PMID:Components of the plasminogen activation system in uveal melanoma--a clinico-pathological study. 789 Dec 28

Metalloproteinases, inhibitors of metalloproteinases, plasminogen activators, inhibitors of plasminogen activators and cathepsins are thought to be involved in invasion by tumor cells. Glioblastoma multiforme is highly malignant and extremely refractory to therapy. One reason is because of its highly invasive nature within the nervous system. However, it remains unclear how invasion/dissemination of glioblastoma multiforme proceeds. In this study, we attempted to determine which proteinases were responsible for the invasion activity of human glioma cell lines in vitro. Nine human glioma cell lines (NHG1, NHG2, IN157, IN301, IN500, U251, U343, T98G and CCF-STTG1) derived from patients with glioma were grown in culture and used. We compared the invasion activity of glioma cell lines in a Matrigel invasion assay system, and formulated the activity as invasion index (%). Among the nine cell lines, IN157, IN500 and U343 showed less than 10% invasion activity (low group); NHGI, IN301 and CCF-STTG1 showed 10-25% activity (intermediate group); NHG2, U251 and T98G showed more than 30% activity (high group). Addition of an inhibitor of metalloproteinases, TIMP-1, to the assay system was found to significantly inhibit invasion activity of T98G cells (P < 0.01). Northern blot analysis demonstrated expression of urokinase-type plasminogen activator (uPA), tissue-type PA (tPA) and PA inhibitor-1 (PAI-1) in some of the above cell lines. Cellular levels of PAs and their inhibitor mRNA, however, appeared not to be correlated with invasion activity in most glioma cell lines except for CCF-STTG1. Expression of 72 kDa type IV collagenase (MMP-2) was much lower in IN157, IN500 and U343 than other cell lines, whereas expression of TIMP-1 was much higher in IN500 than in other cell lines. Zymographic activity was found to be comparable to MMP-2 mRNA levels in all cell lines except for CCF-STTG1. Type IV collagenolytic activity was also comparable to invasion activity in nine cell lines. These observations suggest the role of type IV collagenase and its inhibitors in determining capacity for invasion by human gliomas. However, a comprehensive analysis both in vitro and in vivo is required to confirm the role for this enzyme in glioma cell invasiveness.
Clin Exp Metastasis 1994 Jul
PMID:Expression of 72 kDa type IV collagenase and invasion activity of human glioma cells. 803 4

The malignant potential of solid tumors is related to the ability to invade adjacent tissue and to metastasize. These properties of cancer cells depend on the synthesis of proteolytic enzymes which are able to digest adjacent connective tissue and basement membranes. We hypothesized that all elements of the plasminogen activation system might be overexpressed in malignant human breast tumors, functioning as an essential element in tumor invasion and metastasis. As determined by histopathological methods, the malignant tumors showed statistically significantly higher expression of urokinase plasminogen activator (uPA), type-1 plasminogen activator inhibitor (PAI-1), and especially urokinase plasminogen activator receptor (uPAR) than benign tissues. All those elements were present in higher amounts in the cancer cells than in the cells of benign or normal breast tissues. High exhibition of tissue plasminogen activator (tPA) found in cancer seems to be random and not related to the malignant or benign state, since benign and malignant tumors show overexpression of tissue plasminogen activator with similar frequency. When the tumors express high amounts of uPA, they express a high amount of uPAR in 50% of cases and PAI-1 in 57.3% of cases. When urokinase is expressed in low amount, the receptor is low in 28.6% and inhibitor in 21.4% of malignant breast tumors. This statistically significant consensus, 78.6% in the case of urokinase and its receptor and 78.6% in case of urokinase and its inhibitor, suggests that these activities may be the result of a unique mechanism of control, activated in the last steps of malignant transformation.
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PMID:Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers. 822 86

Degradation of the extracellular matrix and other tissue barriers by proteases like plasminogen activators (PAs) is a prerequisite for neoplastic growth and metastasis. Recently, we reported that highly metastatic behavior of human melanoma cells in nude mice correlates with urokinase-type PA (u-PA) expression and activity and with PA inhibitor type 1 and 2 (PAI-1, PAI-2) expression. Here we report on the occurrence of components of the PA system in the various stages of human melanoma tumor progression in situ. We studied the protein distribution on freshly frozen lesions of common nevocellular nevi (n = 25), dysplastic (= atypical) nevi (n = 16), early primary melanomas (n = 8), advanced primary melanomas (n = 11), and melanoma metastases (n = 17). Tissue-type PA was present in endothelial cells in all lesions, whereas in metastases it could be detected in tumor cells in a minority of the lesions. u-PA, its receptor, PAI-1, and PAI-2 could not be detected in benign and in early stages but appeared frequently in advanced primary melanoma and melanoma metastasis lesions. u-PA was detected in stromal cells and in tumor cells at the invasive front, the u-PA receptor and PAI-2 in tumor cells, and PAI-1 in the extracellular matrix surrounding tumor cells. Localization of the corresponding messenger RNAs and enzyme activities revealed a similar distribution. We conclude that plasminogen activation is a late event in melanoma tumor progression.
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PMID:Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression. 829 13

We investigated the effects of purified human urinary trypsin inhibitor (UTI) and fragments derived from UTI by proteolysis on the invasive potential of ovarian cancer cells (HOC-I) and gestational choriocarcinoma cells (SMT-ccl) using an in vitro reconstituted basement membrane invasion assay. These cells express cell-associated plasmin and functional uPA receptors that are partially occupied by ligands. SMT-ccl cells, which express threefold higher levels of cell-associated plasmin activity than HOC-I cells, showed approximately twofold increase in their invasive potential. For the invasion assay, HOC-I cells were primed with exogenous plasminogen, but SMT-ccl cells were not. Human leukocyte elastase (HLE)-digested UTI (22 kDa fragment; UTI-22) inhibited plasmin practically with the same strength as native UTI. Trypsin-digested UTI (20 kDa fragment; UTI-20), however, did not inhibit plasmin significantly. Treatment of cells with UTI or UTI-22 reduced the incidence of tumor cell invasive capacity, whereas the inhibitory effect of UTI-20 was not remarkable. The inhibitory effect on tumor cell invasion was dose-dependent and non-toxic; moreover, it was not mediated by inhibition of the tumor cell chemotactic response or of cell attachment to matrigel. These results indicate that inhibition of the proteolytic enzyme plasmin specifically reduced the invasive capacity of tumor cells in vitro.
Clin Exp Metastasis 1994 Mar
PMID:Urinary trypsin inhibitor (UTI) and fragments derived from UTI by limited proteolysis efficiently inhibit tumor cell invasion. 830 25

Malignant transformation is associated with alterations in both cell-cell and cell-matrix interactions. The E2 and C5 clones, derived from the human colon adenocarcinoma LoVo cell line, show, respectively, low and high metastatic capacity as experimental xenografts in vivo. In this study, we have assessed the adhesion and spreading of E2 and C5 cells on basement membrane laminin, expression of the laminin receptor integrins alpha 6 beta 1 and alpha 6 beta 4 and expression of gelatinolytic and plasminogen-dependent activities. On days 5 and 7 after subcutaneous grafting to immunosuppressed newborn rats, well-differentiated E2 tumors displayed a polarized expression of these integrin subunits, with the exception of the beta 1 subunit which remained pericellular. In contrast, C5 tumors were unorganized and the three integrin subunits remained nonpolarized and pericellular. Flow cytometry results showed that the expression of alpha 6 beta 1 and alpha 1 beta 4 integrins was weaker in the highly metastatic C5 clone than in the E2 clone whereas laminin expression was not significantly different. Under-expression and pericellular localization of these integrin receptors in C5 cells as compared to E2 cells may explain the difference in their binding and spreading capacity on laminin, organization of peritumoral basement membrane and maintenance of a differentiated phenotype. Whereas similar levels of gelatinolytic and plasminogen activator activities have been detected in the culture supernatant of the two clones, histozymograms showed that plasminogen-dependent caseinolysis appeared earlier in sections of C5 and parental tumors than in those of E2 xenografts. These results suggest that enhanced aggressiveness of C5 tumors in vivo may be linked to both an impairment of basement membrane setting due to integrin underexpression and distribution and of proteolytic activities modulated by tumor/host interactions.
Invasion Metastasis 1995
PMID:Expression of the alpha 6, beta 1 and beta 4 integrin subunits, basement membrane organization and proteolytic capacities in low and high metastatic human colon carcinoma xenografts. 862 Dec 66

We have investigated the localization of urokinase-type plasminogen activator (u-PA), type-1 plasminogen-activator inhibitor (PAI-1), u-PA receptor (u-PAR) and alpha(2)-macroglobulin- receptor/low-density-lipoprotein-receptor-related protein (alpha(2)MR/LRP) in human breast tumors by immunohistochemical methods. Frozen sections of 133 primary breast carcinomas, 6 ductal carcinomas in situ and 33 lymph-node metastases were stained with monoclonal antibodies. Formalin-fixed sections of 15 primary tumors and 2 lymph-node metastases were stained with polyclonal antibodies. In primary tumors, u-PA and PAI-1 immunoreactivities were intense in macrophages and mast cells, and moderate in benign and malignant epithelial cells as well as in myofibroblasts and endothelial cells. A sub-group of poorly differentiated tumors showed particularly strong staining of stromal fibroblasts. u-PA immunoreactivity was also present in lymphocytes. alpha(2)MR/LRP and u-PAR immunoreactivities were intense in macrophages, but apart from these cells, alpha(2)MR/LRP was found only in fibroblasts, and u-PAR only in tumor cells located peripherally in tumor-cell clusters and glands and some myofibroblasts in the adjacent stroma. Lymph-node metastases showed staining for u-PA and PAI-1 both of cancer cells and of stromal fibroblasts, also staining for u-PA of lymphocytes. Similarly to some of the poorly differentiated primary tumors, approximately half of the metastases showed very strong staining of stromal fibroblasts, and extracts of these metastases had higher u-PA and PAI-1 levels, as determined by ELISA, than extracts of metastases without this staining pattern. alpha(2)MR/LRP was present only in fibroblasts and u-PAR only in some tumor cells. The presence of u-PA, PAI-1, alpha(2)MR/LRP and u-PAR was controlled biochemically by immunoblotting analyses, ligand-blotting analyses, and direct and reverse zymography. The spatial distribution and the variation in concentration of the various components of the plasminogen-activation system point to a complex, multifunctional role for the 4 proteins in and/or during the development and spread of breast cancer.
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PMID:Immunohistochemical localization of urokinase-type plasminogen activator, type-1 plasminogen-activator inhibitor, urokinase receptor and alpha(2)-macroglobulin receptor in human breast carcinomas. 863 58

Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.
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PMID:Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. 875 32

The induction of expression of the components of the proteolytic plasminogen activation system in cutaneous melanocytic tumour progression has previously been reported. Plasminogen activators, their inhibitors, and the receptor for urokinase were present only in advanced primary melanomas and melanoma metastases. The present study reports on the presence of tetranectin and plasmin/ plasminogen, two proteins connected with plasminogen activation, in cutaneous melanocytic lesions. The distribution of tetranectin and plasminogen was studied by immunohistochemistry in 105 freshly frozen melanocytic lesions of common naevocellular naevi (n = 24), atypical naevi (n = 14), early (n = 12) and advanced (n = 20) primary melanomas, and melanoma metastases (n = 35). Both tetranectin and plasminogen were detected in a variety of tissue components. In all stages of melanocytic tumour progression, tetranectin was found in endothelium, perivascular dendritic cells, and leukocytes. Plasminogen was present in endothelium and in the basal layer of the normal skin. Tetranectin and plasminogen staining of fibroblastic cells at the invasive front and of extracellular matrix was, however, restricted to malignant lesions. Co-localization of tetranectin and plasminogen was found in 50 per cent of the early primary melanomas and in more than 75 per cent of the advanced melanomas and melanoma metastases. These results suggest a coordinated role for tetranectin and plasminogen at the invasive front of melanomas. Tetranectin-bound plasminogen may facilitate the migration of tumour cells.
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PMID:Tetranectin and plasmin/plasminogen are similarly distributed at the invasive front of cutaneous melanoma lesions. 877 80


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