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Judah Folkman - One of the best experts on this subject based on the ideXlab platform.
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role of angiogenesis in tumor growth and metastasis
Seminars in Oncology, 2002Co-Authors: Judah FolkmanAbstract:Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable new approach to cancer therapy. Avascular tumors are severely restricted in their growth potential because of the lack of a blood supply. For tumors to develop in size and metastatic potential they must make an "angiogenic switch" through perturbing the local balance of proangiogenic and antiangiogenic factors. Frequently, tumors overexpress proangiogenic factors, such as vascular endothelial growth factor, allowing them to make this angiogenic switch. Two strategies used in the development of antiangiogenic agents involve the inhibition of proangiogenic factors (eg, anti-vascular endothelial growth factor monoclonal antibodies) as well as therapy with endogenous inhibitors of angiogenesis, such as endostatin and Angiostatin. Therapy with endogenous angiogenic inhibitors such as endostatin and Angiostatin may reverse the angiogenic switch preventing growth of tumor vasculature. Preclinical studies have shown that endostatin effectively inhibits tumor growth and shrinks existing tumor blood vessels. Phase 1 clinical trials of endostatin and Angiostatin are ongoing, and preliminary results show minimal toxicities.
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viral vector targeted antiangiogenic gene therapy utilizing an Angiostatin complementary dna
Cancer Research, 1998Co-Authors: Toshihide Tanaka, Judah Folkman, Howard A FineAbstract:Despite recent advances in neurosurgery, radiation, and chemotherapy, the prognosis of patients with malignant gliomas remains dismal. Based on the observation that solid tumor growth is angiogenic dependent, and gliomas are among the most angiogenic of all tumors, therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. Angiostatin, an internal peptide fragment of plasminogen, has recently been shown to potently inhibit endothelial proliferation in vitro and tumor growth in vivo. Long-term systemic delivery of proteins, however, poses a number of difficult logistic and pharmacological problems and may not be necessary or optimal for treating locally aggressive tumors such as gliomas. We now demonstrate that retroviral and adenoviral vectors that transduce the Angiostatin cDNA can be used to inhibit endothelial cell growth in vitro and angiogenesis in vivo. Vector-mediated inhibition of tumor-associated angiogenesis results in increased apoptotic tumor cell death, leading to inhibition of tumor growth. These studies support a potential role of vector-mediated transduction of the cDNA encoding Angiostatin as a potential novel therapeutic strategy for the treatment of malignant brain tumors and confirm the antitumor activity of Angiostatin and the concept of dormancy therapy.
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Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin binding motif rgd
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Lena Claessonwelsh, Michael S Oreilly, Michael Welsh, Nobuyuki Ito, Bela Anandapte, Shay Soker, Bruce R Zetter, Judah FolkmanAbstract:Angiostatin, a fragment of plasminogen, has been identified and characterized as an endogenous inhibitor of neovascularization. We show that Angiostatin treatment of endothelial cells in the absence of growth factors results in an increased apoptotic index whereas the proliferation index is unchanged. Angiostatin also inhibits migration and tube formation of endothelial cells. Angiostatin treatment has no effect on growth factor-induced signal transduction but leads to an RGD-independent induction of the kinase activity of focal adhesion kinase, suggesting that the biological effects of Angiostatin relate to subversion of adhesion plaque formation in endothelial cells.
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expression of Angiostatin cdna in a murine fibrosarcoma suppresses primary tumor growth and produces long term dormancy of metastases
Journal of Clinical Investigation, 1998Co-Authors: Evelyn Flynn, Michael S Oreilly, Yihai Cao, Blair Marshall, Judah FolkmanAbstract:Tumor growth and metastasis are angiogenesis dependent. Previously, we reported that Angiostatin, a potent angiogenesis inhibitor, produced by a primary Lewis lung carcinoma suppressed its growth of lung metastases (O'Reilly, M.S., L. Holmgren, Y. Shing, C. Chen, R.A. Rosenthal, M. Moses, W.S. Lane, Y. Cao, E.H. Sage, and J. Folkman. 1994. Cell. 79:315-328). Now we show that a shift of balance of tumor angiogenesis by gene transfer of a cDNA coding for mouse Angiostatin into murine T241 fibrosarcoma cells suppresses primary and metastatic tumor growth in vivo. Implantation of stable clones expressing mouse Angiostatin in C57Bl6/J mice inhibits primary tumor growth by an average of 77%. After removal of primary tumors, the pulmonary micrometastases in approximately 70% of mice remain in a microscopic dormant and avascular state for the duration of the experiments, e.g., 2-5 mo. The tumor cells in the dormant micrometastases exhibit a high rate of apoptosis balanced by a high proliferation rate. Our study, to our knowledge, for the first time shows the diminished growth of lung metastases after removal of the primary tumor, suggesting that metastases are self-inhibitory by halting angiogenesis. Our data may also provide a novel approach for cancer therapy by antiangiogenic gene therapy with a specific angiogenesis inhibitor.
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endostatin an endogenous inhibitor of angiogenesis and tumor growth
Cell, 1997Co-Authors: Michael S Oreilly, Evelyn Flynn, Thomas Boehm, Yuen Shing, Naomi Fukai, George Vasios, William S Lane, James R Birkhead, Bjorn Olsen, Judah FolkmanAbstract:We previously identified the angiogenesis inhibitor Angiostatin. Using a similar strategy, we have identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin specifically inhibits endothelial proliferation and potently inhibits angiogenesis and tumor growth. By a novel method of sustained release, E. coli-derived endostatin was administered as a nonrefolded suspension. Primary tumors were regressed to dormant microscopic lesions. Immunohistochemistry revealed blocked angiogenesis accompanied by high proliferation balanced by apoptosis in tumor cells. There was no toxicity. Together with Angiostatin data, these findings validate a strategy for identifying endogenous angiogenesis inhibitors, suggest a theme of fragments of proteins as angiogenesis inhibitors, and demonstrate dormancy therapy.
Steven D Shapiro - One of the best experts on this subject based on the ideXlab platform.
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macrophage elastase matrix metalloproteinase 12 suppresses growth of lung metastases
Cancer Research, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Dean R Hautamaki, Jay L Grisolano, Mary Baumann, Leslie C Nehring, Lynn A Cornelius, Steven D ShapiroAbstract:Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in macrophage elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely macrophage derived in this model, being expressed by tumor-associated macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic>angiogenic tumor microenvironment that retards lung tumor growth independent of the production of Angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics. (Cancer Res 2006; 66(12): 6149-55)
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macrophage elastase matrix metalloproteinase 12 suppresses growth of lung metastases
Cancer Research, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Dean R Hautamaki, Jay L Grisolano, Mary Baumann, Leslie C Nehring, Lynn A Cornelius, Steven D ShapiroAbstract:Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in macrophage elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely macrophage derived in this model, being expressed by tumor-associated macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic>angiogenic tumor microenvironment that retards lung tumor growth independent of the production of Angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics.
Stephen Gately - One of the best experts on this subject based on the ideXlab platform.
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Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix enhanced plasminogen activation
Biochemical Journal, 1999Co-Authors: M S Stack, Stephen Gately, Jan J Enghild, L M Bafetti, Gerald A SoffAbstract:Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The mechanism(s) responsible for the anti-angiogenic properties of Angiostatin are unknown. We now report that human Angiostatin blocks plasmin(ogen)-enhanced in vitro invasion of tissue plasminogen activator (t-PA)-producing endothelial and melanoma cells. Kinetic analyses demonstrated that Angiostatin functions as a non-competitive inhibitor of extracellular-matrix (ECM)-enhanced, t-PA-catalysed plasminogen activation, with a Ki of 0.9+/-0.03 microM. This mechanism suggests that t-PA has a binding site for the inhibitor Angiostatin, as well as for its substrate plasminogen that, when occupied, prevents ternary complex formation between t-PA, plasminogen and matrix protein. Direct binding experiments confirmed that Angiostatin bound to t-PA with an apparent Kd [Kd(app)] of 6.7+/-0.7 nM, but did not bind with high affinity to ECM proteins. Together, these data suggest that Angiostatin in the cellular micro-environment can inhibit matrix-enhanced plasminogen activation, resulting in reduced invasive activity, and suggest a biochemical mechanism whereby Angiostatin-mediated regulation of plasmin formation could influence cellular migration and invasion.
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the mechanism of cancer mediated conversion of plasminogen to the angiogenesis inhibitor Angiostatin
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Stephen Gately, Francis J. Castellino, Przemyslaw Twardowski, Sharon M Stack, Deborah L Cundiff, Davida K Grella, Jan J Enghild, Hau C Kwaan, Robert Kramer, Olga V VolpertAbstract:Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to Angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for Angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-l-cysteine, d-penicillamine, captopril, l-cysteine, or reduced glutathione] generate Angiostatin from plasminogen. An essential role of plasmin catalytic activity for Angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to Angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate Angiostatin. Cell-free derived Angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated Angiostatin generation and permit large-scale production of bioactive Angiostatin for investigation and potential therapeutic application.
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human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor Angiostatin
Cancer Research, 1996Co-Authors: Stephen Gately, Przemyslaw Twardowski, Sharon M Stack, Deborah L Cundiff, Olga V Volpert, Matthew Patrick, Lisa N Boggio, William H Schnaper, Laird D Madison, Noel P BouckAbstract:Angiostatin is an inhibitor of angiogenesis and metastatic growth that is found in tumor-bearing animals and can be generated in vitro by the proteolytic cleavage of plasminogen. The mechanism by which Angiostatin is produced in vivo has not been defined. We now demonstrate that human prostate carcinoma cell lines (PC-3, DU-145, and LN-CaP) express enzymatic activity that can generate bioactive Angiostatin from purified human plasminogen or plasmin. Affinity purified PC-3-derived Angiostatin inhibited human endothelial cell proliferation, basic fibroblast growth factor-induced migration, endothelial cell tube formation, and basic fibroblast growth factor-induced corneal angiogenesis. Studies with proteinase inhibitors demonstrated that a serine proteinase is necessary for Angiostatin generation. These data indicate that bioactive Angiostatin can be generated directly by human prostate cancer cells and that serine proteinase activity is necessary for Angiostatin generation.
Jan J Enghild - One of the best experts on this subject based on the ideXlab platform.
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Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix enhanced plasminogen activation
Biochemical Journal, 1999Co-Authors: M S Stack, Stephen Gately, Jan J Enghild, L M Bafetti, Gerald A SoffAbstract:Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The mechanism(s) responsible for the anti-angiogenic properties of Angiostatin are unknown. We now report that human Angiostatin blocks plasmin(ogen)-enhanced in vitro invasion of tissue plasminogen activator (t-PA)-producing endothelial and melanoma cells. Kinetic analyses demonstrated that Angiostatin functions as a non-competitive inhibitor of extracellular-matrix (ECM)-enhanced, t-PA-catalysed plasminogen activation, with a Ki of 0.9+/-0.03 microM. This mechanism suggests that t-PA has a binding site for the inhibitor Angiostatin, as well as for its substrate plasminogen that, when occupied, prevents ternary complex formation between t-PA, plasminogen and matrix protein. Direct binding experiments confirmed that Angiostatin bound to t-PA with an apparent Kd [Kd(app)] of 6.7+/-0.7 nM, but did not bind with high affinity to ECM proteins. Together, these data suggest that Angiostatin in the cellular micro-environment can inhibit matrix-enhanced plasminogen activation, resulting in reduced invasive activity, and suggest a biochemical mechanism whereby Angiostatin-mediated regulation of plasmin formation could influence cellular migration and invasion.
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Angiostatin binds atp synthase on the surface of human endothelial cells
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Tammy L Moser, Sharon M Stack, Jan J Enghild, William H Schnaper, Iain R Asplin, Peter Hojrup, Lorraine Everitt, Susan C Hubchak, Salvatore V PizzoAbstract:Angiostatin, a proteolytic fragment of plasminogen, is a potent antagonist of angiogenesis and an inhibitor of endothelial cell migration and proliferation. To determine whether the mechanism by which Angiostatin inhibits endothelial cell migration and/or proliferation involves binding to cell surface plasminogen receptors, we isolated the binding proteins for plasminogen and Angiostatin from human umbilical vein endothelial cells. Binding studies demonstrated that plasminogen and Angiostatin bound in a concentration-dependent, saturable manner. Plasminogen binding was unaffected by a 100-fold molar excess of Angiostatin, indicating the presence of a distinct Angiostatin binding site. This finding was confirmed by ligand blot analysis of isolated human umbilical vein endothelial cell plasma membrane fractions, which demonstrated that plasminogen bound to a 44-kDa protein, whereas Angiostatin bound to a 55-kDa species. Amino-terminal sequencing coupled with peptide mass fingerprinting and immunologic analyses identified the plasminogen binding protein as annexin II and the Angiostatin binding protein as the α/β-subunits of ATP synthase. The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis. Angiostatin also bound to the recombinant α-subunit of human ATP synthase, and this binding was not inhibited by a 2,500-fold molar excess of plasminogen. Angiostatin’s antiproliferative effect on endothelial cells was inhibited by as much as 90% in the presence of anti-α-subunit ATP synthase antibody. Binding of Angiostatin to the α/β-subunits of ATP synthase on the cell surface may mediate its antiangiogenic effects and the down-regulation of endothelial cell proliferation and migration.
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the mechanism of cancer mediated conversion of plasminogen to the angiogenesis inhibitor Angiostatin
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Stephen Gately, Francis J. Castellino, Przemyslaw Twardowski, Sharon M Stack, Deborah L Cundiff, Davida K Grella, Jan J Enghild, Hau C Kwaan, Robert Kramer, Olga V VolpertAbstract:Angiostatin, a potent naturally occurring inhibitor of angiogenesis and growth of tumor metastases, is generated by cancer-mediated proteolysis of plasminogen. Human prostate carcinoma cells (PC-3) release enzymatic activity that converts plasminogen to Angiostatin. We have now identified two components released by PC-3 cells, urokinase (uPA) and free sulfhydryl donors (FSDs), that are sufficient for Angiostatin generation. Furthermore, in a defined cell-free system, plasminogen activators [uPA, tissue-type plasminogen activator (tPA), or streptokinase], in combination with one of a series of FSDs (N-acetyl-l-cysteine, d-penicillamine, captopril, l-cysteine, or reduced glutathione] generate Angiostatin from plasminogen. An essential role of plasmin catalytic activity for Angiostatin generation was identified by using recombinant mutant plasminogens as substrates. The wild-type recombinant plasminogen was converted to Angiostatin in the setting of uPA/FSD; however, a plasminogen activation site mutant and a catalytically inactive mutant failed to generate Angiostatin. Cell-free derived Angiostatin inhibited angiogenesis in vitro and in vivo and suppressed the growth of Lewis lung carcinoma metastases. These findings define a direct mechanism for cancer-cell-mediated Angiostatin generation and permit large-scale production of bioactive Angiostatin for investigation and potential therapeutic application.
Salvatore V Pizzo - One of the best experts on this subject based on the ideXlab platform.
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endothelial cell surface f1 fo atp synthase is active in atp synthesis and is inhibited by Angiostatin
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Tammy L Moser, Daniel J. Kenan, Timothy A Ashley, Michael D Goodman, U K Misra, Dennis J Cheek, Salvatore V PizzoAbstract:Angiostatin blocks tumor angiogenesis in vivo, almost certainly through its demonstrated ability to block endothelial cell migration and proliferation. Although the mechanism of Angiostatin action remains unknown, identification of F1-FO ATP synthase as the major Angiostatin-binding site on the endothelial cell surface suggests that ATP metabolism may play a role in the Angiostatin response. Previous studies noting the presence of F1 ATP synthase subunits on endothelial cells and certain cancer cells did not determine whether this enzyme was functional in ATP synthesis. We now demonstrate that all components of the F1 ATP synthase catalytic core are present on the endothelial cell surface, where they colocalize into discrete punctate structures. The surface-associated enzyme is active in ATP synthesis as shown by dual-label TLC and bioluminescence assays. Both ATP synthase and ATPase activities of the enzyme are inhibited by Angiostatin as well as by antibodies directed against the α- and β-subunits of ATP synthase in cell-based and biochemical assays. Our data suggest that Angiostatin inhibits vascularization by suppression of endothelial-surface ATP metabolism, which, in turn, may regulate vascular physiology by established mechanisms. We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of Angiostatin, indicating that these antibodies function as Angiostatin mimetics.
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Angiostatin binds atp synthase on the surface of human endothelial cells
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Tammy L Moser, Sharon M Stack, Jan J Enghild, William H Schnaper, Iain R Asplin, Peter Hojrup, Lorraine Everitt, Susan C Hubchak, Salvatore V PizzoAbstract:Angiostatin, a proteolytic fragment of plasminogen, is a potent antagonist of angiogenesis and an inhibitor of endothelial cell migration and proliferation. To determine whether the mechanism by which Angiostatin inhibits endothelial cell migration and/or proliferation involves binding to cell surface plasminogen receptors, we isolated the binding proteins for plasminogen and Angiostatin from human umbilical vein endothelial cells. Binding studies demonstrated that plasminogen and Angiostatin bound in a concentration-dependent, saturable manner. Plasminogen binding was unaffected by a 100-fold molar excess of Angiostatin, indicating the presence of a distinct Angiostatin binding site. This finding was confirmed by ligand blot analysis of isolated human umbilical vein endothelial cell plasma membrane fractions, which demonstrated that plasminogen bound to a 44-kDa protein, whereas Angiostatin bound to a 55-kDa species. Amino-terminal sequencing coupled with peptide mass fingerprinting and immunologic analyses identified the plasminogen binding protein as annexin II and the Angiostatin binding protein as the α/β-subunits of ATP synthase. The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis. Angiostatin also bound to the recombinant α-subunit of human ATP synthase, and this binding was not inhibited by a 2,500-fold molar excess of plasminogen. Angiostatin’s antiproliferative effect on endothelial cells was inhibited by as much as 90% in the presence of anti-α-subunit ATP synthase antibody. Binding of Angiostatin to the α/β-subunits of ATP synthase on the cell surface may mediate its antiangiogenic effects and the down-regulation of endothelial cell proliferation and migration.