Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1519670 (tumor angiogenesis)
 6,052 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiostatin4.5 (AS4.5) is a naturally occurring human angiostatin isoform, consisting of plasminogen kringles 1-4 plus 85% of kringle 5 (amino acids Lys78 to Arg529). Prior studies indicate that plasminogen is converted to AS4.5 in a two-step reaction. First, plasminogen is activated to plasmin. Then plasmin undergoes autoproteolysis within the inner loop of kringle 5, which can be induced by a free sulfhydryl donor or an alkaline pH. We now demonstrate that plasminogen can be converted to AS4.5 in a cell membrane-dependent reaction. Actin was shown previously to be a surface receptor for plasmin(ogen). We now show that beta-actin is present on the extracellular membranes of cancer cells (PC-3, HT1080, and MDA-MB231), and beta-actin can mediate plasmin binding to the cell surface and autoproteolysis to AS4.5. In the presence of beta-actin, no small molecule-free sulfhydryl donor is needed for generation of AS4.5. Antibodies to actin reduced membrane-dependent generation of AS4.5 by 70%. In a cell-free system, addition of actin to in vitro-generated plasmin resulted in stoichiometric conversion to AS4.5. Annexin II and alpha-enolase have been reported to be plasminogen receptors, but we did not demonstrate a role for these proteins in conversion of plasminogen to AS4.5. Our data indicate that membrane-associated beta-actin, documented previously as a plasminogen receptor, is a key cell membrane receptor capable of mediating conversion of plasmin to AS4.5. This conversion may serve an important role in regulating tumor angiogenesis, invasion, and metastasis, and surface beta-actin may also serve as a prognostic marker to predict tumor behavior.
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PMID:Cell surface-dependent generation of angiostatin4.5. 1472 20

The quiescent vascular system in the adult body represents the imbalanced net outcome of overproduction of endogenous angiogenesis inhibitors and reduced levels of angiogenic factors. While some endogenous inhibitors are expressed under physiological conditions, they can also be generated in association with tumor growth. Angiostatin is such a specific angiogenesis inhibitor produced by tumors. It inhibits primary and metastatic tumor growth by blocking tumor angiogenesis. Having demonstrated potent antitumor activity in animal studies, angiostatin is now in clinical trials for human cancer therapy. Angiostatin is not a novel protein molecule coded by novel DNA sequences. Instead, it is an internal proteolytic fragment of a known protein, plasminogen. Surprisingly, most kringle domains of plasminogen only inhibit angiogenesis when cleaved as fragments from their parent protein that lacks antiangiogenic activity. These findings suggest that they are cryptic fragments hidden in large protein molecules. Thus, proteolytic processing plays a critical role in down-regulation of angiogenesis. Despite proteolytic processing, the antiangiogenic mechanism of angiostatin remains an enigma. Without knowing the mechanisms, it is difficult to predict the ultimate outcome of ongoing clinical trials. In this article, we discuss what is known about angiostatin and how this molecule specifically inhibits angiogenesis. We hope that the information will be useful for further development of angiostatin and its related inhibitors as therapeutic agents.
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PMID:Angiostatin. 1503

Angiostatin, a proteolytic fragment of plasminogen consisting of the first 3 or 4 kringle domains, reduces tumor growth by specifically inhibiting tumor angiogenesis. Angiostatin is generated in vitro in a 2-step process. First, plasminogen is converted to plasmin by plasminogen activators. Next, plasmin excises the angiostatin fragment from plasminogen, a process requiring molecules that are able to donate a free sulfhydryl group. In this study, we investigated whether stimulation of in vivo angiostatin generation by administration of plasminogen activator and a free sulfhydryl group donor (FSD) has anti-tumor activity. First, we determined the optimal conditions for in vitro angiostatin generation by incubating murine plasma with different concentrations of plasminogen activator and/or the FSD captopril. Angiostatin generation was monitored by western blot analysis. Our results were extrapolated to the in vivo situation by administering the optimal dose of tissue-type plasminogen activator (tPA, i.v. injection 3 times/week) and captopril (in drinking water) to mice and analyzing the presence of angiostatin in the circulation. Angiostatin was readily detectable in mice receiving both tPA and captopril, but not in mice receiving either one of the agents. Finally, the anti-tumor activity of the tPA/captopril treatment was tested in a human melanoma xenograft model. Administration of tPA alone had only a marginal effect on tumor growth. Captopril alone reduced tumor growth by about 60%, whereas treatment with both captopril and tPA resulted in 83% inhibition of tumor growth.
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PMID:Anti-tumor activity of a combination of plasminogen activator and captopril in a human melanoma xenograft model. 1535 48

Angiogenesis and tumor expansion are associated with extracellular matrix remodeling and involve various proteases such as the plasminogen (Plg)/plasminogen activator (PA) system. Recently, several experimental data have implicated the plasminogen activator inhibitor-1 (PAI-1) in tumor angiogenesis in murine systems. However, little is known about PAI-1 functions in human skin carcinoma progression. By generating immunodeficient mice (in Rag-1-/- or nude background) deleted for PAI-1 gene (PAI-1-/-), we have evaluated the impact of host PAI-1 deficiency on the tumorigenicity of two malignant human skin keratinocyte cell lines HaCaT II-4 and HaCaT A5-RT3 forming low-grade and high-grade carcinomas, respectively. When using the surface transplantation model, angiogenesis and tumor invasion of these two cell lines are strongly reduced in PAI-1-deficient mice as compared to the wild-type control animals. After subcutaneous injection in PAI-1-/- mice, the tumor incidence is reduced for HaCaT II-4 cells, but not for those formed by HaCaT A5-RT3 cells. These data indicate that PAI-1 produced by host cells is an important contributor to earlier stages of human skin carcinoma progression. It exerts its tumor-promoting effect in a tumor stage-dependent manner, but PAI-1 deficiency is not sufficient to prevent neoplastic growth of aggressive tumors of the human skin.
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PMID:Host plasminogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner. 1572 Aug 17

Angiostatin, an inhibitor of tumor angiogenesis, is produced by the actions of matrix metalloproteinases (MMP) on plasminogen. Recently, we reported that angiostatin levels are increased in a model of inadequate coronary collateral growth and angiogenesis in response to ischemia, despite high levels of vascular endothelial growth factor (VEGF). We hypothesized that angiostatin levels are negatively associated with collateral formation in patients. Coronary angiograms from 37 patients undergoing coronary bypass surgery were evaluated for the absence of angiographically visible collaterals (Rentrop scores of 0) or the presence of Rentrop classification grade 3 (well developed) collaterals. Pericardial fluid was obtained from each patient during the bypass procedure, and the sample was analyzed for angiostatin, plasminogen, and VEGF (Western analysis) and for combined activities of MMP-2 and MMP-9 (zymographic analysis). In patients with no collaterals, angiostatin level was greater compared with that in patients with well-developed collaterals (3.1 +/- 0.2 vs. 2.3 +/- 0.1 optical density units, P < 0.05). Neither MMP activities nor VEGF levels were different between the two groups of patients. The higher levels of angiostatin in patients with no visible collaterals were reflective of a higher concentration of plasmin/plasminogen (6.2 +/- 0.7 vs. 4.2 +/- 0.5 optical density units, P < 0.05) compared with those in patients with well-developed collateral vessels. Our results support the concept that the growth inhibitor angiostatin may have a negative impact on coronary collateral growth in patients. Perhaps therapies attempting to provoke coronary collateral growth should incorporate approaches to limit or neutralize the effects of growth inhibitors.
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PMID:Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease. 1584 Sep 2

Transforming growth factor-beta (TGF-beta), a key modulator of endothelial cell apoptosis, must be activated from the latent form (LTGF-beta) to induce biological responses. In the present study, we report activation of TGF-beta by functional and physical co-operation of the mannose-6-phosphate/insulin-like-growth-factor-II receptor (CD222) and the urokinase-type plasminogen activator receptor (CD87). We show that endothelial cells express CD222 and CD87 in a membrane complex and demonstrate that the association of these two receptors is essential for the release of active TGF-beta in the transduced mouse fibroblast used as model cells. By contrast, smooth-muscle cells, which express CD222 and CD87 at similar density to endothelial cells but not in complexed form, do not activate TGF-beta. We also have found that mini-plasminogen is a high-affinity ligand for CD222 and is essential for the activation of TGF-beta by the CD87-CD222 complex to induce apoptosis in endothelial cells. This specific mechanism of TGF-beta-mediated apoptosis in endothelial cells is thus a potential novel target to be considered for treatment of pathological vascular disorders (e.g. tumor angiogenesis).
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PMID:TGF-beta-induced apoptosis in endothelial cells mediated by M6P/IGFII-R and mini-plasminogen. 1617 14

Blockade of angiogenesis is a promising strategy to suppress tumor growth, invasion, and metastasis. Vascular endothelial growth factor (VEGF), which binds to tyrosine kinase receptors [VEGF receptors (VEGFR) 1 and 2], is the mediator of angiogenesis and mitogen for endothelial cells. Cyclooxygenase-2 (COX-2) plays an important role in the promoting action of nicotine on gastric cancer growth. However, the action of nicotine and the relationship between COX-2 and VEGF/VEGFR system in tumorigenesis remain undefined. In this study, the effects of nicotine in tumor angiogenesis, invasiveness, and metastasis were studied with sponge implantation and Matrigel membrane models. Nicotine (200 microg/mL) stimulated gastric cancer cell proliferation, which was blocked by SC-236 (a highly selective COX-2 inhibitor) and CBO-P11 (a VEGFR inhibitor). This was associated with decreased VEGF levels as well as VEGFR-2 but not VEGFR-1 expression. Topical injection of nicotine enhanced tumor-associated vascularization, with a concomitant increase in VEGF levels in sponge implants. Again, application of SC-236 (2 mg/kg) and CBO-P11 (0.4 mg/kg) partially attenuated vascularization by approximately 30%. Furthermore, nicotine enhanced tumor cell invasion through the Matrigel membrane by 4-fold and promoted migration of human umbilical vein endothelial cells in a cocultured system with gastric cancer cells. The activity of matrix metalloproteinases 2 and 9 and protein expressions of plasminogen activators (urokinase-type plasminogen activator and its receptor), which are the indicators of invasion and migration processes, were increased by nicotine but blocked by COX-2 and VEGFR inhibitors. Taken together, our results reveal that the promoting action of nicotine on angiogenesis, tumor invasion, and metastasis is COX-2/VEGF/VEGFR dependent.
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PMID:Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. 1631 86

Cancer patients often show a clinical tendency to thromboembolic events. This tendency is due to tumor cell-related factors together with the damage of the vascular endothelial exerted by chemotherapy treatment. Gastrointestinal tumors especially contribute to these types of events. More recently, the implication of tumor angiogenesis in clotting/fibrynolisys and plasminogen systems activation has been addressed in cancer patients. Finally, some hemostasis and angiogenesis-related factors such as platelets, von Willebrand factor, fibrinogen, plasminogen activator inhibitor type-1, D dimer, and vascular endotelial growth factor have been highlighted as new potential response and survival predictors in colorectal cancer patients. In this review article, the current evidence supporting the use of these proteins in assessing prognosis in colorectal cancer patients is critically exposed and discussed.
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PMID:[New prognostic and predictive factors in advanced colorectal cancer]. 1675 7

Recently, increasing evidence has been found demonstrating direct effects of angiostatin on tumor cells themselves. We have applied the plasminogen derivatives K1-4 and K1-5 to a lung cancer model to analyse indirect angiostatic effects against endothelial and direct effects against tumor cells. In accordance with preceding findings both derivatives inhibited endothelial cell functions in vitro. Additionally K1-4 and K1-5 have also shown substantial anti-proliferative and pro-apoptotic effects in tumor cells and have inhibited tumor growth. In addition our data supports the recent conclusion that plasminogen derivatives have a dual antitumor mechanism affecting both tumor angiogenesis and tumor cells.
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PMID:Plasminogen derivatives encoding kringles 1-4 and kringles 1-5 exert indirect antiangiogenic and direct antitumoral effects in experimental lung cancer. 1856 68

Previous studies showed that the mouse macrophage metalloelastase (MME) generates the angiogenesis inhibitor angiostatin from plasminogen in vitro. This study aimed to determine whether tumor cells engineered with MME could generate angiostatin and suppress tumor angiogenesis in vivo. Murine CT-26 colon cancer cells stably transfected with MME were inoculated subcutaneously. A radioisotope tracer, immunoblotting, immunofluorescence and immunohistochemistry were used to explore the pathway of the angiostatin generation. The results showed that tumors derived from MME-transfected cells demonstrated a less microvessel density compared with control tumors derived from vector-transfected and non-transfected cells (P<0.001). The expression of vascular endothelial growth factor (VEGF) was significantly lower in the MME-transfected group compared with that of the controls. The growth of MME-transfected tumors was significantly retarded compared with the control tumors (P<0.001). Western blot analysis, using a specific anti-mouse plasminogen (1-4 Kringle) antibody, demonstrated two strong immunoreactive bands (38- and 35-kDa) in MME-transfected tumors. gamma-ray counting data demonstrated that plasminogen cleavage occurred mostly in tumors formed by cells forced to express. We concluded that MME was demonstrated to be an efficient angiostatin-producing MMP and its presence was negatively correlated with the growth of colon cancer in tumor-bearing mice. These findings provide direct evidence that MME generates angiostatin in tumor-bearing mice and the therapeutic application of MME against tumors.
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PMID:Mouse macrophage metalloelastase generates angiostatin from plasminogen and suppresses tumor angiogenesis in murine colon cancer. 1857 22


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