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)

Nude mice have been subcutaneously inoculated with human tumorigenic fibrosarcoma cells (HT-1080) producing urokinase-type plasminogen activator (u-PA) or with human tumorigenic melanoma cells (G-361) producing tissue-type plasminogen activator (t-PA). Human u-PA (hu-PA) and t-PA (ht-PA) were found in the plasma and in the tumors of mice injected with HT-1080 or G-361 cells, respectively. Metastases containing ht-PA were observed in different organs of mice transplanted with G-361 cells, while mice injected with HT-1080 cells did not develop metastases. These data would suggest a relationship between the metastatic potential of G-361 cells and t-PA. The parallel increase of the levels of endogenous murine PAs (m-PA) activities might play a crucial role in the early stages of tumor growth and metastasis, since the biological effects of the PAs produced by the transplanted tumor cells can not be dissociated from those of the PAs induced in the host.
Invasion Metastasis 1995
PMID:Plasminogen activators in nude mice xenotransplanted with human tumorigenic cells. 767 29

A metastatic human melanoma cell line that produces urokinase-type plasminogen activator was stably transfected with cDNA encoding human plasminogen activator inhibitor 2 (PAI-2). Transfected clones expressed PAI-2 at levels two to nine times higher than both the parental cell line and mock transfectants, as detected by ELISA of cell lysates and conditioned medium. The clone with the highest PAI-2 expression exhibited complete inhibition of soluble and cell-surface-bound plasminogen activator activity. The level of PAI-2 overexpression in these clonal cell lines correlated positively with the inhibition of their ability to degrade extracellular matrix in vitro. Parental, mock-transfected, and PAI-2-transfected cell lines produced rapidly growing tumors when injected s.c. into the skin of mice with severe combined immunodeficiency. The tumors producing the highest levels of PAI-2 were surrounded by a dense tumor capsule. Both parental cells and mock-transfected cells invariably metastasized from s.c. tumors to lymph nodes and lungs of mice. PAI-2-transfected cell lines produced significantly less or no metastases. Taken together, these data indicate a critical role for plasminogen activator activity in melanoma invasion and metastasis.
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PMID:Overexpression of plasminogen activator inhibitor 2 in human melanoma cells inhibits spontaneous metastasis in scid/scid mice. 781 18

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

The present study extends our investigations into the metastatic heterogeneity among four clonal cell lines (S2-007:H, S2-013:M1, S2-020:M2, and S2-028:L) from a human pancreatic cancer cell line (SUIT-2), and extends our discussion the positive correlation between metastatic potential and the type I collagenase activity of the cells, focusing on their interaction with extracellular matrix. Ability to attach to the reconstituted basement membrane (Matrigel) was higher for clone H than clone L during an observation period of 30-60 min, whereas clones M1 and M2 were found to be intermediate in ability. In densitometric and radioactive studies, clone L exhibited the lowest collagenolytic activity against mouse and human type IV collagen, while clone H exhibited the highest activity in the densitometric study and clone M1 was the highest in the radioactive study. The production of urinary-type plasminogen activator was highest in clone L and lowest in clone H. On the other hand, tissue-type plasminogen activator was highest in clone M2 and low in both clones H and L. Clone M2 exhibited the highest chemotactic activity toward diluted Matrigel, whereas clone L had the lowest activity. On the whole, these clones showed heterogenous interactions with an extracellular matrix. It is suggested that the attachment activity to basement membrane and the type IV collagenolytic activity of the cells may be positively correlated with their metastatic potential, whereas the production of urinary-type plasminogen activator was negatively correlated, but confirmation of these findings awaits further study.
Clin Exp Metastasis 1994 May
PMID:Heterogeneities of attachment, chemotaxis, and protease production among clones with different metastatic potentials from a human pancreatic cancer cell line. 819 99

The plasminogen activator urokinase (u-PA) mediates proteolysis by a variety of human tumor cells. Competitive displacement of u-PA from cellular binding sites results in decreased proteolysis in vitro, suggesting that the cell surface is the preferred site for u-PA-mediated protein degradation. We studied the effect of u-PA receptor blockade on the metastatic capacity of human PC3 prostate carcinoma cells, using transfectants which expressed chloramphenicol acetyl-transferase (CAT). Eight weeks after subcutaneous inoculation of these cells into nude mice, CAT activity was detected in regional lymph nodes, femurs, lungs, and brain, thereby mimicking the organ tropism observed for naturally occurring metastases of prostate cancer. In a second transfection, CAT-expressing PC3 cells received cDNA encoding a mutant u-PA (Ser356-->Ala) which lacks enzymatic activity but which retains full receptor binding affinity. Three mutant u-PA expressors, each with < 5% of wild-type cell-associated u-PA activity, were compared in vivo with independently derived controls. Primary tumor growth was similar in each group of animals and all tumors expressed comparable CAT activity. In contrast, metastasis (as assessed by CAT activity) was markedly inhibited when cell surface u-PA activity was blocked. Levels of CAT activity were reduced by a factor of > 300 in regional lymph nodes, 40-100 in brain tissue, and 10-20 in lung tissue. Metastatic capacity was inhibited similarly when animals were given intermittent intraperitoneal injections of a u-PA/IgG fusion protein capable of displacing u-PA activity from the tumor cell surface. Our results indicate that cell surface u-PA activity is essential to the metastatic process. In addition, the assay system employed in these experiments may be generally useful in testing other therapeutic modalities to limit the spread of primary tumors.
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PMID:Prevention of metastasis by inhibition of the urokinase receptor. 838 64

Plasminogen activator (PA) is a serine protease existing in two forms known as tissue-type (t-PA) and urokinase-type (u-PA). To examine whether PA is related to the postoperative clinical course of human breast cancer, total PA activity, t-PA activity, u-PA activity, and immunoreactive t-PA were determined in tissue extracts from 144 breast cancer specimens. The patients were initially divided into four groups according to the postoperative clinical course: Group I (83 patients who are disease-free), Group II (20 patients whose first metastases were found only in bone), Group III (19 patients whose first metastases were found in both bone and lung), and Group IV (22 patients whose first metastases were found only in lung). Total PA activity was significantly lower in Groups, II, III and IV than in Group I. Both t-PA activity and t-PA antigen levels were also significantly lower in Groups II, III and IV than in Group I, while no significant difference was found in u-PA activity among these groups, indicating that low activity of total PA in Groups II, III and IV was due to a decrease in t-PA but not in u-PA. In the multivariate analyses, t-PA activity was found to be an independent prognostic factor for relapse-free survival. When four groups of patients were further analysed in terms of nodal status, both t-PA activity and antigen levels were markedly decreased in the node-negative Group II compared with the node-negative Groups III and IV or with the node-positive Groups II, III and IV. Of additional interest, u-PA activity was significantly higher in node-positive patients than in node-negative patients with any group. The clinico-pathologic analyses of the patients in this series showed that node involvement and lymphatic invasion were more frequently positive in Groups III and IV than in Groups I and II. When 144 breast cancers were categorised in terms of combinations of oestrogen receptor (ER) and progesterone receptor (PgR) status, breast cancers which were positive for both receptors were found to contain the highest t-PA activity and antigen. This study provides provocative evidence suggesting a possible differential significance of t-PA and u-PA expression in human breast cancer.
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PMID:Differential biological significance of tissue-type and urokinase-type plasminogen activator in human breast cancer. 839 31

Thrombospondin (TSP-1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP-1, the following observations suggest that TSP-1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP-1 and inhibited by anti-TSP-1 antibodies. (2) TSP-1 promotes tumor cell adhesion, migration and invasion. (3) TSP-1 promotes angiogenesis in the rat aorta model. (4) TSP-1 up-regulates the plasminogen activator system through a mechanism involving the activation of TGF-beta 1. (5) Human tumors express increased levels of the CSVTCG-specific TSP-1 receptor. (6) Tumor stroma is enriched in TSP-1. (7) Cancer patients have high blood levels of TSP-1. (8) Poor patient survival correlates with a higher expression of the CSVTCG-specific TSP-1 receptor on tumor cells. In this paper we discuss the evidence that TSP-1 promotes tumor progression and present a hypothetical scheme for its mechanism of action.
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PMID:The role of thrombospondin-1 in tumor progression and angiogenesis. 859 67

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

Tumor cell invasion and metastasis is a complex, multistep process that is postulated to require degradation of extracellular matrix at several steps. Urokinase-type plasminogen activator (uPA) is expressed on the cell surface of B16 murine melanoma cells and is thought to contribute to the pericellular proteolysis necessary for tumor cell migration. In vitro modification of B16 melanoma cell surface uPA activity has been shown to alter the invasive and metastatic potential of these murine melanoma cells in vivo. Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of both uPA and tissue-type plasminogen activator (tPA) is the major physiologic regulator of plasminogen activator activity. To test the role of host PAI-1 in the invasive and metastatic capacity of B16 melanoma cells we analyzed local tumor growth and pulmonary metastasis in transgenic mice engineered to overexpress murine PAI-1 in multiple tissues including lung, and in mice completely deficient in PAI-1. No significant difference in the number of pulmonary metastases was observed after intravenous inoculation of tumor cells into PAI-1-overexpressing and PAI-1-deficient mice when compared with wild-type controls. Similarly, in a spontaneous metastasis model, PAI-1-overexpressing and PAI-1-deficient mice demonstrated no difference in primary tumor size or overall survival. These data demonstrate that wide variations of host PAI-1 expression, from complete absence to marked overexpression, does not significantly influence the metastatic potential of B16 melanoma cells in a murine model.
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PMID:Lack of plasminogen activator inhibitor-1 effect in a transgenic mouse model of metastatic melanoma. 863 41

Epithelial ovarian carcinoma, the leading cause of gynecologic cancer death, is characterized by widespread intra-abdominal metastases mediated primarily by surface shedding of tumor cells and peritoneal implantation. Whereas hematogenous metastasis is known to involve cellular adhesion, extracellular matrix proteolysis and cell migration, the role of these processes in the intraperitoneal dissemination of ovarian cancer remains unclear. To analyze further the role of adhesion and proteolysis in ovarian carcinoma dissemination, we have characterized the adhesive profiles of 4 primary cultures of ovarian carcinoma cells and 5 ovarian carcinoma cell lines. Our data demonstrate preferential adhesion of ovarian carcinoma cells to interstitial type I collagen. Analysis of adhesion molecule expression demonstrated the presence of the alpha2 and beta1 integrin subunits by cell surface ELISA, immunoprecipitation and immunohistochemistry. Furthermore, antibodies directed against the alpha2 and beta1 subunits inhibited adhesion of ovarian carcinoma cells to type I collagen by 56% and 95%, respectively. Plasminogen activator and matrix metalloproteinase production by adherent cells was not altered as a consequence of adhesion to individual extracellular matrix proteins; however, adhesion to an extracellular matrix comprised primarily of interstitial collagen increased plasminogen activator activity in 5 of 5 cell lines. Since the ovarian carcinoma micro-environment is rich in type I collagen, our data suggest that preferential adhesion to type I collagen followed by secretion of serine and metalloproteinases may represent a biochemical mechanism by which the intraperitoneal dissemination of ovarian carcinoma is mediated.
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PMID:Evidence for preferential adhesion of ovarian epithelial carcinoma cells to type I collagen mediated by the alpha2beta1 integrin. 878 61


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