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Seminars in Thrombosis and Hemostasis Feb 2004The quiescent vascular system in the adult body represents the imbalanced net outcome of overproduction of endogenous angiogenesis inhibitors and reduced levels of... (Review)
Review
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.
Topics: Angiogenesis Inhibitors; Angiostatins; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 15034800
DOI: 10.1055/s-2004-822973 -
Cancer Treatment and Research 2005
Review
Topics: Amino Acid Sequence; Angiostatins; Animals; Humans; Mice; Molecular Sequence Data; Protein Isoforms
PubMed: 16209067
DOI: 10.1007/0-387-24361-5_8 -
Cancer Metastasis Reviews 2000The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several years. The discovery... (Review)
Review
The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several years. The discovery and publication of angiostatin by O'Reilly and colleagues in Judah Folkman's lab in 1994 has greatly contributed to this progress. Angiostatin is a kringle-containing fragment of plasminogen, which is a potent inhibitor of angiogenesis in vivo, and selectively inhibits endothelial cell proliferation and migration in vitro. There have been a number of proposed proteolytic mechanisms by which plasminogen is cleaved to form angiostatin, and the resulting cleavage products contain different NH2 and COOH termini of the angiostatin. Therefore, it is possible that there are more than one angiostatin isoforms (or angiostatin-related proteins) which occur in one or more normal or pathophysiological situations. It is also possible that some of the proteolytic processes which can convert plasminogen to angiostatin-like proteins are simply laboratory artifacts. Angiostatin-related proteins exert potent endothelial cell inhibitory activity, including the induction of apoptosis, and inhibition of migration, and the intact kringle structures are believed to be necessary for the antiangiogenic activity. Efforts are now underway to translate the understanding of the biology of angiostatin to clinical practice, which includes phase 1 clinical trials with recombinant angiostatin K1-3 (kringles 1-3) as well as phase 1 trials of an Angiostatin Cocktail, which induces the direct in vivo conversion of plasminogen to angiostatin 4.5 (kringles 1-4, plus most of kringle 5). The translation of the basic science of angiostatin and angiostatin-related proteins to clinical trial promises to provide an important new tool in the treatment of cancer by inhibition of angiogenesis.
Topics: Amino Acid Sequence; Angiogenesis Inhibitors; Angiostatins; Animals; Antineoplastic Agents; Genetic Therapy; Humans; Models, Molecular; Molecular Sequence Data; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Plasminogen; Protein Conformation
PubMed: 11191071
DOI: 10.1023/a:1026525121027 -
Journal of Cellular Biochemistry Oct 2005Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as "angiogenesis" [Folkman (1971) N Engl J Med... (Review)
Review
Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as "angiogenesis" [Folkman (1971) N Engl J Med 285:1182-1186]. These new vessels arise from local capillaries, arteries, and veins in response to the release of soluble growth factors from the tumor mass, enabling these tumors to grow beyond the diffusion-limited size of approximately 2 mm diameter. Angiostatin, a naturally occurring inhibitor of angiogenesis, was discovered based on its ability to block tumor growth in vivo by inhibiting the formation of new tumor blood vessels [O'Reilly et al. (1994a) Cold Spring Harb Symp Quant Biol 59:471-482]. Angiostatin is a proteolytically derived internal fragment of plasminogen and may contain various members of the five plasminogen "kringle" domains, depending on the exact sites of proteolysis. Different forms of angiostatin have measurably different activities, suggesting that much remains to be elucidated about angiostatin biology. A number of groups have sought to identify the native cell surface binding site(s) for angiostatin, resulting in at least five different binding sites proposed for angiostatin on the surface of endothelial cells (EC). This review will consider the data supporting all of the various reported angiostatin binding sites and will focus particular attention on the angiostatin binding protein identified by our group: F(1)F(O) ATP synthase. There have been several developments in the quest to elucidate the mechanism of action of angiostatin and the regulation of its receptor. The purpose of this review is to describe the highlights of research on the mechanism of action of angiostatin, its' interaction with ATP synthase on the EC surface, modulators of its activity, and issues that should be explored in future research related to angiostatin and other anti-angiogenic agents.
Topics: ATP Synthetase Complexes; Angiostatins; Animals; Annexin A2; Antigens; Humans; Integrin alphaVbeta3; Membrane Proteins; Proteoglycans
PubMed: 16094651
DOI: 10.1002/jcb.20480 -
EXS 1997Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which selectively inhibits endothelial cell proliferation. When given... (Review)
Review
Angiostatin, an internal fragment of plasminogen, is a potent inhibitor of angiogenesis, which selectively inhibits endothelial cell proliferation. When given systemically, angiostatin potently inhibits tumor growth and can maintain metastatic and primary tumors in a dormant state defined by a balance of proliferation and apoptosis of the tumor cells. We identified angiostatin while studying the phenomenon of inhibition of tumor growth by tumor mass and have elucidated one mechanism for this phenomenon. In our animal model, a primary tumor almost completely suppresses the growth of its remote metastases. However, after tumor removal, the previously dormant metastases neovascularize and grow. When the primary tumor is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. Serum and urine from tumor-bearing mice, but not from controls, specifically inhibit endothelial cell proliferation. The activity copurifies with a 38 kD plasminogen fragment which we have sequenced and named angiostatin. Human angiostatin, obtained from a limited proteolytic digest of human plasminogen, has similar activities. Systemic administration of angiostatin, but not intact plasminogen, potently blocks neovascularization and growth of metastases and primary tumors. We here show that the inhibition of metastases by a primary mouse tumor is mediated, at least in part, by the angiogenesis inhibitor angiostatin.
Topics: Angiostatins; Animals; Antineoplastic Agents; Apoptosis; Cornea; Endothelium, Vascular; Humans; Mice; Models, Structural; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neovascularization, Pathologic; Neovascularization, Physiologic; Peptide Fragments; Plasminogen
PubMed: 9002223
DOI: No ID Found -
Journal of Thrombosis and Haemostasis :... Jan 2004Originally discovered in 1994 by Folkman and coworkers, angiostatin was identified through its antitumor effects in mice and later shown to be a potent inhibitor of... (Review)
Review
Originally discovered in 1994 by Folkman and coworkers, angiostatin was identified through its antitumor effects in mice and later shown to be a potent inhibitor of angiogenesis. An internal fragment of plasminogen, angiostatin consists of kringle domains that are known to be lysine-binding. The crystal structure of angiostatin was the first multikringle domain-containing structure to be published. This review will focus on what is known about the structure of angiostatin and its implications in function from the current literature.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Binding Sites; Humans; Kringles; Models, Molecular; Protein Binding; Protein Conformation
PubMed: 14717962
DOI: 10.1111/j.1538-7836.2004.00544.x -
Translational Psychiatry May 2022Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of...
Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of Alzheimer's disease (AD). However, whether there are pathological changes in angiostatin levels in individuals with AD dementia is unclear, and whether plasma angiostatin has a relationship with major AD pathological processes and cognitive impairment remains unknown. To examine plasma angiostatin levels in patients with AD dementia and investigate the associations of angiostatin with blood and cerebrospinal fluid (CSF) AD biomarkers, we conducted a cross-sectional study including 35 cognitively normal control (CN) subjects and 59 PiB-PET-positive AD dementia patients. We found that plasma angiostatin levels were decreased in AD dementia patients compared to CN subjects. Plasma angiostatin levels were negatively correlated with plasma Aβ42 and Aβ40 levels in AD dementia patients and positively correlated with CSF total tau (t-tau) levels and t-tau/Aβ42 in AD dementia patients with APOE-ε4. In addition, plasma angiostatin levels had the potential to distinguish AD from CN. These findings suggest a link between angiostatin and AD pathogenesis and imply that angiostatin might be a potential diagnostic biomarker for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiostatins; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Humans; Peptide Fragments; tau Proteins
PubMed: 35538065
DOI: 10.1038/s41398-022-01962-6 -
Recent Progress in Hormone Research 2004Many diseases have abnormal quality and/or quantity of vascularization as a characteristic feature. Cancer cells elicit the growth of new capillaries during... (Review)
Review
Many diseases have abnormal quality and/or quantity of vascularization as a characteristic feature. Cancer cells elicit the growth of new capillaries during neovascularization in a process termed angiogenesis. In diabetics, pathologic angiogenesis in various tissues is a clinical feature of many common complications. Therefore, the diabetic cancer patient warrants special consideration and extra care in the design of anti-angiogenic treatments without adverse side effects. Some treatment regimens that look promising in vitro, in animal models, or in early clinical trials may be contra-indicated for diabetics. This chapter will review the common complications of diabetes, with emphasis on the angiogenic pathology. Recent research related to the mechanism of action and basis for specificity of the anti-angiogenic peptide, angiostatin, will be the focus. The aim is to shed light on areas in which more research is needed with respect to angiostatin and other anti-angiogenic agents and the microenvironmental conditions that affect their activities, in order to develop improved therapeutic strategies for diabetic cancer patients.
Topics: Angiostatins; Animals; Diabetes Complications; Diabetic Retinopathy; Disease Models, Animal; Endothelium, Vascular; Humans; Neoplasms; Neovascularization, Pathologic
PubMed: 14749498
DOI: 10.1210/rp.59.1.73 -
Endothelium : Journal of Endothelial... 2002Tumor growth, local invasion, and metastatic dissemination are dependent on the formation of new microvessels. The process of angiogenesis is regulated by a balance... (Review)
Review
Tumor growth, local invasion, and metastatic dissemination are dependent on the formation of new microvessels. The process of angiogenesis is regulated by a balance between pro-angiogenic and anti-angiogenic factors, and the shift to an angiogenic phenotype (the "angiogenic switch") is a key event in tumor progression. The use of anti-angiogenic agents to restore this balance represents a promising approach to cancer treatment. Known physiological inhibitors include trombospondin, several interleukins, and the proteolytic break-down products of several proteins. Angiostatin, an internal fragment of plasminogen, is one of the more potent of this latter class of angiogenesis inhibitors. Like endostatin, another anti-angiogenic peptide derived from collagen XVIII, angiostatin can induce tumor vasculature regression, leading to a complete cessation of tumor growth. Inhibitors of angiogenesis target normal endothelial cells, therefore the development of resistance to these drugs is unlikely. The efficacy of angiostatin has been demonstrated in animal models for many different types of solid tumors. Anti-angiogenic cancer therapy with angiostatin requires prolonged administration of the peptide. The production of the functional polypeptides is expensive and technical problems related to physical properties and purity are frequently encountered. Gene transfer represents an alternative method to deliver angiostatin. Gene therapy has the potential to produce the therapeutic agent in high concentrations in a local area for a sustained period, thereby avoiding the problems encountered with long-term administration of recombinant proteins, monoclonal antibodies, or anti-angiogenic drugs. In this review we compare the different gene therapy strategies that have been applied to angiostatin, with special regard to their ability to provide sufficient angiostatin at the target site.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Genetic Therapy; Genetic Vectors; Humans; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Plasminogen; Recombinant Proteins
PubMed: 12901356
DOI: 10.1080/10623320210712 -
Hepatology (Baltimore, Md.) Mar 2003
Topics: Angiostatins; Animals; Carcinoma, Hepatocellular; Genetic Therapy; Humans; Liver Neoplasms; Peptide Fragments; Plasminogen
PubMed: 12601345
DOI: 10.1053/jhep.2003.50125