Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three cancer cell lines, IMC-2, IMC-3 and IMC-4, were established from a single tumor of a patient with maxillary cancer. We examined responses to epidermal growth factor (EGF) of these 3 cell lines with regard to cell growth and tumor invasion. The growth rate of IMC-2 in nude mice was markedly faster than that of the IMC-3 and IMC-4 cell lines. Assay for invasion through fibrin gels showed significantly enhanced invasive capacity of IMC-2 cells in response to EGF, but no change for IMC-3 and IMC-4 cells. We examined response to EGF of IMC-2 cells with regard to expression of a growth-related oncogene (c-fos), proteinases and their inhibitors. Expression of c-fos was transiently increased in IMC-2 cells at rates comparable to those seen in the 2 other lines in the presence of EGF. There was no apparent effect of EGF on the expression of urokinase-type plasminogen activator and 72-kDa type-IV collagenase in IMC-2 cells. In contrast, EGF specifically enhanced the expression of plasminogen activator inhibitor-I (PAI-I) and tissue inhibitor of metalloproteinases-I (TIMP-I) in IMC-2 cells. Our data suggest that proteinase inhibitors or other related factors may play an important role in tumor growth and invasion in response to EGF.
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PMID:The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors. 165 98

Although giant cell tumor of bone (GCT) is generally considered to be an uncommon benign neoplasm, it can pursue an aggressive course with local recurrence and metastasis. Attempts to predict the biological behavior of GCT with histopathological parameters, however, have not been successful. The urokinase-type plasminogen activation system has been implicated in tumor invasion and metastasis and abnormalities of the components of this system have been found in several malignancies. In this study we postulated that the urokinase-type plasminogen activation system associated with bone destruction and local invasion is present in GCT. We therefore evaluated the mRNA levels for urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), and plasminogen activator inhibitor type 1 (PAI-1) by using Northern blot analysis and in situ hybridization in four cases of GCT and spindle-shaped mononuclear cells at the 35th passage from a GCT. Our results showed that giant cell tumors of bone contained variable levels of u-PA, u-PAR, and PAI-1 mRNA, respectively, 2.3, 1.4, and 3.2 kb in size. In situ hybridization showed that u-PA, u-PAR, and PAI-1 mRNA were expressed in both the mononuclear cells and the osteoclast-like giant cells; the signal for u-PA mRNA in the spindle-shaped mononuclear cells was more intense than that in the osteoclast-like multinuclear giant cells. Some spherical mononuclear cells (macrophage-like cells) expressed high levels of PAI-1 mRNA in comparison with the spindle-shaped mononuclear cells. In addition, the 35th passaged spindle-shaped mononuclear cells were used to study the gene expression of u-PA during cell proliferation. The results showed that the level of u-PA mRNA increases after adding 10% fetal calf serum to quiescent cells. The induction was maximal at 16 hours and remained high during 48 hours of treatment. In conclusion, even though osteoclast-like cells are ultimately responsible for the bone resorption of GCT, the mononuclear neoplastic cells of GCT may also be involved in degradation of the extracellular matrix during invasive growth by facilitating the urokinase plasminogen activation system. In addition, our observation of upregulation of u-PA mRNA in spindle-shaped mononuclear cells after serum stimulation indicated that u-PA production may be linked to tumor growth.
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PMID:Detection of mRNAs for urokinase-type plasminogen activator, its receptor, and type 1 inhibitor in giant cell tumors of bone with in situ hybridization. 749 80

Recently, a novel class of angiostatic steroids which block angiogenesis in several systems has been described. Since the elaboration of proteases is believed to be an important component of angiogenesis, we tested whether these steroids blocked the fibrinolytic response of endothelial cells to the angiogenic protein, basic fibroblast growth factor [bFGF]). Cultured bovine aortic endothelial (BAE) cells were incubated with bFGF and/or medroxyprogesterone acetate (MPA), an angiostatic steroid which has been shown to inhibit vascularization, collagenolysis, and tumor growth. When bFGF (3 ng/ml) was added to confluent monolayers of BAE cells, plasminogen activator (PA) activity in the medium was increased threefold. In contrast, MPA at 10(-6) M, 10(-7) M, 10(-8) M, and 10(-9) M decreased PA levels in the medium by 83%, 83%, 75%, and 39%, respectively. The stimulation of PA levels in BAE cells by bFGF (3 ng/ml) was abrogated by the presence of 10(-6) M MPA. This decrease in PA activity was found to be mediated by a significant increase in plasminogen activator inhibitor type-1 (PAI-1) production. MPA, therefore, negated one of the important enzymatic activities associated with the angiogenic process. In contrast to the decreased levels of secreted PA in cultures exposed simultaneously to MPA and bFGF, cell-associated PA levels remained high, consistent with earlier observations indicating that PAI-1 does not inhibit cell-associated PA. Thus, angiostatic steroids may exert their inhibitory effects on angiogenesis by increasing the synthesis of PAI-1. This, in turn, inhibits PA activity and, therefore, plasmin generation, which is essential for the invasive aspect of angiogenesis.
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PMID:Mechanism of action of angiostatic steroids: suppression of plasminogen activator activity via stimulation of plasminogen activator inhibitor synthesis. 768 43

The plasminogen activation system is considered to play an important role in cancer growth and metastasis. Both plasminogen activators (PAs) and their fast-acting inhibitors are produced in tumor cells and their surrounding tissues. In order to clarify the influence of the existence of malignant tumor in urinary tract on the systemic fibrinolytic activity, we designed a study in which we compared the plasma levels of PAs and their inhibitors between before and after radical resection of tumors. Fourteen patients with renal cell carcinoma and 14 patients with transitional cell carcinoma participated in the study. In both groups, plasma levels of tissue-type plasminogen activator and urokinase-type plasminogen activator before the operation were higher than those 15 days after operation. The plasma level of plasminogen activator inhibitor 1 (PAI-1), however, did not change after the operation in the renal cell carcinoma group, and it decreased slightly in the transitional cell carcinoma group although it was not significant. When these values of the groups with or without metastasis were compared to other organs or lymph nodes, the PAI-1 level before operation was significantly higher in the group with metastasis than that without metastasis. In the three groups divided by the degree of atypia, PAI-1 level in the most atypical group was the highest. These results suggest that the fibrinolytic system in the plasma of cancer patients may play an important role in tumor growth and metastasis.
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PMID:Plasminogen activators and plasminogen activator inhibitor 1 in urinary tract cancer. 814 Jun 79

Proteolytic enzymes are required to mediate tumor cell invasion and metastasis. The urokinase plasminogen activator (uPA) is commonly overexpressed by many human cancers. Therefore, uPA is a logical target to inhibit cancer invasion and metastasis. However, uPA inhibitors also reduce tumor growth. We used a mutated form of plasminogen activator inhibitor type 1 to conform a correlation between the inactivation of uPA and tumor size; we have compared these results with the action of p-aminobenzamidine and amiloride, known inhibitors of uPA. Our results show that blocking uPA by uPA inhibitors reduces tumor size in experimental animals. Our molecular simulation of docking inhibitors to the urokinase reveals that all tested small molecule inhibitors bind in proximity of uPA's specificity pocket, a critical site for future search of novel anticancer uPA inhibitors.
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PMID:Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combined immunodeficient mice. 904 24

Glucocorticoid (GC) use is known to induce or enhance the growth of Kaposi's sarcoma (KS) in many clinical settings including human immunodeficiency virus infection, collagen vascular disease, lymphoproliferative disorders, and renal transplantation. Because GCs may induce immune suppression and thus tumor growth, we determined whether GCs had a direct effect on KS growth. We found that GCs directly induce the growth of KS cell lines. In examining the mechanism of action of GCs, we did not observe induction of known autocrine growth factors for KS including interleukin-1 (IL-1), IL-6, oncostatin-M, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). We thus examined factor(s) that inhibit KS growth. Transforming growth factor-beta (TGF-beta) is produced by KS cells and has pleiotropic effects, including inhibiting the growth of hematopoietic and endothelial cells. We show that TGF-beta is produced by KS cells in both the latent and active forms, and that TGF-beta is an autocrine growth inhibitory factor. We then studied the effects of GCs on the regulation of TGF-beta and found that GCs do not inhibit TGF-beta transcription, but significantly inhibit TGF-beta activation. This effect is mediated through regulation of the TGF-beta activation pathway. TGF-beta is activated by plasmin which is positively regulated by plasminogen activator (PA) and PA receptor (PAR), and negatively regulated by plasminogen activator inhibitor (PAI). GCs downregulated PAR and upregulated PAI. Thus, glucocorticoids enhance KS cell growth through the regulation of TGF-beta activation.
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PMID:Glucocorticoids induce Kaposi's sarcoma cell proliferation through the regulation of transforming growth factor-beta. 905 28

Our understanding of the role of matrix degrading proteases in cancer has dramatically expanded over the last two decades. From correlative observations linking proteases to cancer progression, we have accumulated evidence supporting a causal role for proteases in various steps of tumor progression and have become increasingly aware of the complex interactions that exist among proteases. Specific natural inhibitors of these proteases have also been identified and their role as potent cytostatic agents in cancer has been suggested. In this article some of the concepts on the role of proteases in cancer are discussed and examples of cooperation between matrix metalloproteinases and the plasmin/plasminogen activators system are presented. The role of protease inhibitors such as tissue inhibitor of metalloproteinases-2 (TIMP-2) and plasminogen activator inhibitor-2 (PAI-2) as inhibitors of tumor growth, invasion and metastasis is discussed.
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PMID:Proteases and protease inhibitors in tumor progression. 943 92

The plasminogen activation system plays an important role in enhancing pericellular proteolysis of tumor invasion/metastasis and in autocrine/paracrine tumor growth stimulation. To investigate the prognostic significance of the plasminogen activation system in human chondrosarcoma, the immunohistochemical expression of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor, 1 (PAI-1) and 2 (PAI-2) were analyzed in 28 patients with chondrosarcoma. In multivariate survival analysis, histological grade (p = 0.0008) and location (p = 0.02) were independent risk factors for local relapse. For metastasis-free survival, uPA index (p = 0.006) and PAI-2 index (p = 0.04) were independent prognostic factors. PAI-2 index (p = 0.02), uPAR index (p = 0.02) and histological grade (p = 0.03) predicted total survival. These results demonstrated the usefulness of uPA, uPAR and PAI-2 expression as biological prognostic indicator and the importance of the plasminogen activation system in tumor progression and metastasis in chondrosarcoma.
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PMID:Prognostic relevance of urokinase type plasminogen activator, its receptor and inhibitors in chondrosarcoma. 1106 19

This study was designed to investigate the relationship of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor type-1 (PAI-1) to invasion and metastasis of hepatocellular carcinoma (HCC). The expression of uPA, uPAR, and PAI-1 in HCC was determined by immunohistochemistry, Northern blot, and an LCI-D20 nude mouse metastatic model of HCC. The overexpression of uPA, uPAR, and PAI-1 was found in HCC, especially in the patients with portal cancer embolus, tumor invasion, and metastasis. Immunohistochemistry results showed that the rate of positive staining of uPA, uPAR, and PAI-1 were higher in HCC than those in the control groups consisting of cancer-adjacent tissue and normal liver tissue. In the case of HCC invasion, positive uPA and uPAR were seen in 16 and 19 out of 22 patients, respectively (P<0.01 and P<0.001, respectively, as compared with the patients without invasion). In those with portal cancer embolus and tumor metastasis, positive uPAR was eight out of eight and six out of six patients. In those with tumor recurrence, positive uPAR was 15 out of 17 patients (P<0.01 vs. no recurrence). In patients who died within 2 years after surgery, positive uPAR was 12 out of 12 patients (P<0.01 vs. survival), and positive PAI-1 was nine out of 12 patients (P<0.05 vs. survival). In those in which uPA, uPAR, and PAI-1 were all positive staining, stronger cancer invasiveness and higher mortality were found (P<0.05 vs. patients with all negative staining). In 30 patients tested with Northern blot analysis, the results were similar to those tested with immunohistochemistry. Higher expression of uPA mRNA and PAI-1 mRNA were detected in tumor tissues and embolus. In the patients with positive signals of uPA mRNA and PAI-1 mRNA, invasive cases were found in seven out of 19 and eight out of 18 patients, respectively, which were significantly higher than those showing negative signals (P<0.05). In the LCI-D20 nude mouse metastatic model of HCC (MMHCC), PAI-1 activity in plasma and tumor tissue increased with tumor growth, invasion, and metastasis. At an advanced stage of MMHCC, PAI-1 activity rose to 15.4+/-0.7 Au/ml in plasma and 0.8+/-0.3 Au/mg in tumor extracts, which was significantly higher than 6.2+/-1.8 Au/ml in plasma and 0.4+/-0.1 Au/mg in extracts at an early stage (P<0.05). PAI-1 activity related to the changes of serum AFP and tumor progress were r = 0.9544 and r = 0.9648, respectively (P<0.05). The data suggest that the expression of uPA, uPAR, and PAI-1 is increased in HCC, and related to the invasiveness, metastasis, and prognosis of HCC.
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PMID:Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator, its receptor and inhibitor. 1107 28

To understand the fundamental determinants of urokinase plasminogen activator (uPA) driven angiogenesis in cancer we studied how inhibition of uPA activity could reduce neovascularization and consequently reduce tumor size in experimental animals. Proteolytic enzymes are required to mediate tumor cell invasion to adjacent tissues and initiate the metastatic process. Many different human cancers commonly overexpress the urokinase plasminogen activator system, one of the proteolytic enzyme systems. Reduction of urokinase activity in cancer cells is evidently associated with diminished invasion and metastasis. However, it has been shown recently that inhibitors of uPA could reduce tumor size also. The mechanism of action leading to decline in tumor growth rate is not clear. Proteolysis is responsible for degradation of proteins, for invasion or metastasis, but not for the proliferate properties of the cancer cells. It is difficult to envision that diminishing the size of tumor is due to simply blocking of uPA activity of cancer cells. Instead, inhibitors of uPA may be interacting with the elements of the extracellular matrix, such the neovascular bed surrounding tumors that has been reported to contain high amounts of uPA and its receptor. Overall these data strongly suggest that inhibitors of urokinase limit cancer growth by inhibiting angiogenesis. However, it is possible also that uPA inhibitors could act on cancer cells directly or prevent angiogenesis by alternative mechanisms that are not related to uPA inhibition. Therefore, we examined if plasminogen activator inhibitor (PAI-1) could limit angiogenesis. If it does, it will provide definitive evidence of uPA/PAI-1 involvement in reduction of cancer growth. Indeed, our study demonstrates that exogenously applied 14-1b PAI-1 is a powerful inhibitor of angiogenesis in three different in vitro models and is a powerful anti-cancer agent in a SCID mice model inoculated with human LNCaP prostate cancer cells.
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PMID:Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostate cancer xenografts in SCID mice. 1129 64


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