Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urokinase receptor antagonists based on the growth factor domains of both human and murine urokinase which show sub-nanomolar affinities for their homologous receptors have been expressed as recombinant proteins. Further modification of these molecules by preparing fusions with the constant region of human IgG has led to molecules with high affinities and long in vivo half-lives. Smaller peptidic inhibitors have been obtained by a combination of bacteriophage display and peptide analog synthesis. All of these molecules inhibit the binding of the growth factor domain of uPA to the uPA receptor and enhance binding of the uPA receptor to vitronectin. Protein uPA receptor antagonists were tested in an in vivo tumor model using the human breast carcinoma MDAmb231 in immunodeficient mice. Both human and murine receptor antagonists showed significant inhibition of primary tumor growth, demonstrating that in vivo, both tumor and stromal cell uPA receptor dependent plasminogen activation can modulate tumor growth.
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PMID:Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth. 1019 Feb 94

Recombinant adenoviral vectors expressing u-PA, t-PA, PAI-1 and PAI-2 were employed to correlate the expression of components of the fibrinolytic system with the invasiveness of HT 1080 tumor cells. Migration through Transwell inserts in vitro in the presence of plasminogen was increased up to 22% by overexpression of u-PA, whereas t-PA had no effect. Gene transfer of PAI-1 or PAI-2 both reduced migration in a dose-dependent manner by up to 43% with PAI-1 and 29% with PAI-2. Two routes of gene transfer were used to alter metastasis of subcutaneously implanted HT 1080 cells expressing firefly luciferase in nude mice. Infection of cultured tumor cells with adenovirus expressing either PAI-1 or PAI-2 before implantation significantly reduced the incidence of lung metastasis by 60% compared with control virus. However, only PAI-2 reduced the incidence of lung and brain metastasis following liver gene transfer. Although PAI gene transfer by either route reduced primary tumor size, it had little effect on tumor vascularization or host survival. The migratory and metastatic phenotype of HT 1080 tumor cells is thus directly dependent on u-PA expression levels and can be altered by gene transfer of u-PA or plasminogen activator inhibitors.
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PMID:Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors. 1043 7

We have previously reported the identification of the endogenous angiogenesis inhibitor angiostatin, a specific inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. In our original studies, we demonstrated that a Lewis lung carcinoma (LLC-LM) primary tumor could suppress the growth of its metastases by generating angiostatin. Angiostatin, a 38-kDa internal fragment of plasminogen, was purified from the serum and urine of mice bearing LLC-LM, and its discovery provides the first proven mechanism for concomitant resistance (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M. A., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328). Subsequently, we have shown that systemic administration of angiostatin can regress a wide variety of malignant tumors in vivo. However, at the time of our initial discovery of angiostatin, the source of the protein was unclear. We hypothesized that the tumor or stromal cells might produce an enzyme that could cleave plasminogen sequestered by the primary tumor into angiostatin. Alternatively, we speculated that the tumor cells might express angiostatin. By Northern analysis, however, we have found no evidence that the tumor cells express angiostatin or other fragments of plasminogen (data not shown). We now report that gelatinase A (matrix metalloproteinase-2), produced directly by the LLC-LM cells, is responsible for the production of angiostatin, which suppresses the growth of metastases in our original model.
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PMID:Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance. 1050 24

The serine protease urokinase-type plasminogen activator, uPA, when bound to its specific receptor, uPAR (CD87), plays a significant role in tumor cell invasion and metastasis. In breast cancer, enhanced uPA antigen in the primary tumor is correlated with poor prognosis of the patient. In an in vivo nude mouse model, we tested tumor growth and metastasis of human breast carcinoma cells that had been transfected with an expression plasmid encoding a soluble form of uPAR (suPAR). We explored, whether suPAR/uPA interaction reduces the binding of uPA to cell surface-associated uPAR, and, as a consequence, could suppress tumor growth and metastasis of the human breast cancer cell line MDA-MB-231 BAG. Overexpressed, secreted suPAR was shown to bind and thus scavenge the uPA secreted by the transfected lines suPAR3 and suPAR10. In vitro, an overexpression of suPAR did not alter the proliferation rate of the transfected tumor cells, nor did it affect the expression of uPA. Overexpression of suPAR led to a reduction in the plasminogen activation-related proteolytic activity of breast carcinoma cells. Primary tumor growth in the mammary fat pad of nude mice was followed up for 52 days. Overexpression of suPAR correlated with a reduction in tumor growth (from day 21, reaching 30% by day 34) as well as lung colonization (lung metastasis-positive mice in suPAR3: 4 of 17; suPAR10: 3 of 10; parental MDA-MB-231 BAG: 13 of 18). We conclude that suPAR overexpression leading to effective scavenge of uPA impairs proteolysis as well as the tumor growth and metastatic potential of breast carcinoma cells in vivo.
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PMID:Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor (CD87). 1077 Jun 39

Mouse macrophage metalloelastase (MME) has been associated with the generation of angiostatin, an internal fragment of plasminogen, which inhibits angiogenesis. To clarify whether tumor cells that consistently generate MME can suppress angiogenesis and, therefore, inhibit the growth of primary tumors in vivo, we transfected a cDNA coding for MME into murine B16-BL6 melanoma cells that grow rapidly and are MME deficient. The generation of active MME in MME-transfected clones was confirmed by immunoprecipitation followed by in vitro cleavage of plasminogen. Subcutaneous implantation of these stable clones in C57BL/6 mice inhibited primary tumor growth by an average of 73% (P = 0.00002), which directly correlated with a significant reduction of blood vessel formation (approximately 76%) in such tumors. Microangiography revealed massive angiogenesis in control tumors (mock and vector); however, in MME-transfected primary tumors it demonstrated a decreased and disrupted vascular network. Western blot analysis using a specific anti-mouse angiostatin antibody demonstrated a strong 38-kDa immunoreactive band in MME-transfected tumors and in the serum of mice bearing those tumor cells. These results show that placing MME gene directly into B16-BL6 melanoma cells is an effective approach to suppress primary tumor growth in vivo because it halts angiogenesis. Our data provide a feasible and promising strategy for gene therapy of cancer by targeting tumor vasculature.
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PMID:Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis. 1081 82

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) have been observed in many cancers and may contribute to progression and metastasis. In our study, we examined the expression of the 5 proteins by immunohistochemistry in 59 consecutive primary colorectal cancers (CRC) and correlated the protein expression with patient outcome. In addition, we determined the effect of down-regulation of uPAR on the invasive/metastatic capability of CRC cells, by measuring antisense-uPAR transfected HCT116 and control cell lines, in terms of uPAR expression, uPA-binding activity, invasiveness through Matrigel in vitro and metastasis after cecal orthotopic implantation in nude mice in vivo. We found that higher expression of uPA or uPAR in primary tumor tissues was positively correlated with distant metastasis of CRC (Mann-Whitney, p < 0.02) and negatively correlated with both patient overall survival (OS) and cancer-specific survival (CSS; Cox model, p < 0.04). The prognostic value of uPA and uPAR for both OS and CSS was independent of other variables (multivariate Cox model, p < 0. 007). Antisense-uPAR transfected HCT116 cells, which expressed significantly lower levels of total cellular and cell surface uPAR proteins and uPA-binding activity compared with either wild-type or cells transfected with vector alone (Bonferroni, p < 0.05/3), consistently showed decreased invasiveness through Matrigel (Bonferroni, p < 0.05/3) and decreased metastasis formation in nude mice (Fisher, p < 0.05). Our data suggest that uPAR and uPA are independent prognostic factors in CRC; anti-uPAR treatment, which affects both uPAR and uPA levels, may have potential for new treatment of the disease.
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PMID:Urokinase-type plasminogen activator and its receptor in colorectal cancer: independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets. 1100 5

Several studies have indicated an interaction between tumor cells and infiltrating stromal cells regarding the urokinase plasminogen activation (uPA) system. By developing combined uPA gene-disrupted and immunodeficient mice, we have studied the role of stromal uPA for the growth of the MDA-MB-435 BAG human tumor xenograft. Subcutaneous tumor growth and lung metastasis were compared between wild-type immunodeficient mice and mice with the combined deficiencies. Tumor growth was evaluated by volume measurements and plasma beta-galactosidase activity and metastasis was evaluated by counting lung surface metastases. Although no differences appeared in primary tumor take between the two groups of mice, a significant difference was observed in primary tumor growth, with tumors in uPA-/- mice growing significantly more slowly. In addition, a nonsignificant trend toward fewer lung metastases in uPA-/- mice was observed. The present data points to a critical role of stromal-derived uPA in the primary tumor growth of MDA-MB-435 BAG xenografts, whereas only a trend toward fewer lung metastases in uPA gene-disrupted mice was found.
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PMID:Direct evidence of the importance of stromal urokinase plasminogen activator (uPA) in the growth of an experimental human breast cancer using a combined uPA gene-disrupted and immunodeficient xenograft model. 1121 46

A primary inoculum of human pancreatic cancer cells (BxPC-3) has the ability to inhibit the growth of a secondary tumor in an in vivo animal model. Such ability suggests that the primary tumor is producing inhibitors that act at the site of the secondary tumor. Accordingly we attempted to discover which inhibitors are produced by pancreatic cancer cells. We determined that pancreatic cancer cells process angiostatin isoforms from plasminogen. Additionally, we isolated and characterized an uncleaved "latent" antiangiogenic antithrombin (aaAT) molecule processed from systemically available AT by pancreatic cancer cells as well as a cleaved form of aaAT processed from systemically available AT by pancreatic cancer cells. Human AT, cleaved with human neutrophil elastase, inhibits angiogenesis in the chorioallantoic membrane assay. This human aaAT molecule is able to inhibit the growth of pancreatic tumors in immune-compromised mice. Our work represents the first demonstration of multiple angiogenesis inhibitors from a single tumor and suggests that antiangiogenic therapies may provide an avenue for future treatment of pancreatic cancer.
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PMID:Generation of multiple angiogenesis inhibitors by human pancreatic cancer. 1158 69

The content of urokinase- and tissue-type plasminogen activators and plasminogen activator inhibitor PAI-1 in the cytosol of primary and metastatic melanomas and benign skin pigment neoplasms was estimated by enzyme immunoassay. It was shown that local growth and invasion of melanomas are related to suppressed expression of tissue plasminogen activator. The content of urokinase plasminogen activator increases in patients with distant metastases and large thickness of the primary tumor.
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PMID:Tissue- and urokinase-type plasminogen activators and type 1 plasminogen activator inhibitor in melanomas and benign skin pigment neoplasms. 1168 50

Clinical studies have shown that metastatic spread is associated with hypoxia in the primary tumor. The mechanism behind this association has not been identified and, in fact, it has not been established whether hypoxia induces metastasis or whether the most metastatic cell phenotypes develop the most hypoxic tumors. The present study demonstrates that hypoxia promotes spontaneous lymph node metastasis in R-18 human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor (uPAR). Pimonidazole was used as a hypoxia marker, and hypoxia and uPAR expression were detected by immunohistochemistry. R-18 cells were capable of up-regulating uPAR under hypoxic conditions in vitro, as revealed by Western and Northern blot analyses, and uPAR-positive regions showed a high degree of colocalization with hypoxic regions in R-18 tumors. There was a strong correlation between uPAR-positive fraction and hypoxic fraction in individual tumors (P < 0.00001). Incidence of metastases, hypoxic fraction, and uPAR-positive fraction increased with the size of the primary tumor with similar kinetics. Metastatic tumors showed approximately 1.5-fold higher hypoxic fraction (P = 0.00004) and approximately 1.4-fold higher uPAR-positive fraction (P = 0.0003) than nonmetastatic tumors of the same size. Moreover, treatment with neutralizing antibody against uPAR prevented metastasis almost completely. Only 1 of 30 treated mice developed metastases, whereas 14 of 30 control mice were metastasis positive, suggesting that functional uPAR is a prerequisite for lymph node metastasis in R-18 tumors. The study reported here suggests that metastatic spread may be promoted by hypoxia in the primary tumor and identifies the plasminogen activation system as an important target for the treatment of malignant melanoma.
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PMID:Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. 1191 64


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