Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions

Taraboletti, Giulia; Benelli, Roberto; Borsotti, Patrizia; Rusnati, Marco; Presta, Marco; Giavazzi, Raffaella; Ruco, Luigi; Albini, Adriana

doi:10.1002/(sici)1096-9896(199905)188:1<76::aid-path312>3.0.co;2-a

Cited by 50 publications

(41 citation statements)

References 33 publications

(52 reference statements)

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“…This was confirmed by experimental competition experiments and is in agreement with our previous observation that intact TSP-1 as well as a recombinant fragment comprising the type III repeats inhibited the binding of FGF-2 to HSPG on the surface of endothelial cells and in the extracellular matrix (12)(13)(14). The biological importance of this interaction in FGF-2 bioavailability and activity suggests that DD15 mimics might be developed as inhibitors of FGF-2 biological functions.…”

Section: Discussionsupporting

confidence: 90%

“…Biological, Antiangiogenic Activity of the New Leads in Vitro and in Vivo-The high affinity interaction of lead molecules with FGF-2 suggested they might retain the antiangiogenic activity of the entire TSP-1 and the type III repeats (12,14). Indeed, both sm27 and sm8, although not sm10, inhibited the binding of FGF-2 to endothelial cells (Fig.…”

Section: Nmr Analysis Of Dd15-fgf-2 Interaction-mentioning

confidence: 95%

“…Proliferation of endothelial cells exposed to 5 ng/ml FGF-2 in the presence of the small molecules was assessed with a colorimetric assay (14). One small molecule (sm27) was also tested for ability to affect angiogenesis in the chicken embryo chorioallantoic membrane assay using fertilized White Leghorn chicken eggs, where angiogenesis is induced by sterilized gelatin sponges loaded with FGF-2 with or without the small molecule (38).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, using recombinant portions of TSP-1, we identified a previously undescribed antiangiogenic site in the type III repeats of TSP-1 and demonstrated that binding of the angiogenic factor FGF-2 to this site inhibits angiogenesis by sequestration of FGF-2 (12). Binding of FGF-2 to TSP-1 and its type III repeats is of high affinity and involves a yet unidentified sequence sensitive to calcium and heparin (12)(13)(14). Each antiangiogenic TSP-1 sequence offers a potential tool for the design of new angiogenesis inhibitors (10,15), as exemplified by ABT-510, a synthetic nonapeptide based on the sequence GVITRIR in the second type I repeat that was the first TSP-1-based antiangiogenic compound to reach clinical testing (16).…”

mentioning

confidence: 99%

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Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Colombo

Margosio

Ragona

et al. 2010

Journal of Biological Chemistry

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Endogenous inhibitors of angiogenesis, such as thrombospondin-1 (TSP-1), are promising sources of therapeutic agents to treat angiogenesis-driven diseases, including cancer. TSP-1 regulates angiogenesis through different mechanisms, including binding and sequestration of the angiogenic factor fibroblast growth factor-2 (FGF-2), through a site located in the calcium binding type III repeats. We hypothesized that the FGF-2 binding sequence of TSP-1 might serve as a template for the development of inhibitors of angiogenesis. Using a peptide array approach followed by binding assays with synthetic peptides and recombinant proteins, we identified a FGF-2 binding sequence of TSP-1 in the 15-mer sequence DDDDDNDKIPD-DRDN. Molecular dynamics simulations, taking the full flexibility of the ligand and receptor into account, and nuclear magnetic resonance identified the relevant residues and conformational determinants for the peptide-FGF interaction. This information was translated into a pharmacophore model used to screen the NCI2003 small molecule databases, leading to the identification of three small molecules that bound FGF-2 with affinity in the submicromolar range. The lead compounds inhibited FGF-2-induced endothelial cell proliferation in vitro and affected angiogenesis induced by FGF-2 in the chicken chorioallantoic membrane assay. These small molecules, therefore, represent promising leads for the development of antiangiogenic agents. Altogether, this study demonstrates that new biological insights obtained by integrated multidisciplinary approaches can be used to develop small molecule mimics of endogenous proteins as therapeutic agents.Inhibitors of angiogenesis, aimed at preventing the deregulated formation of new blood vessels, are emerging as a successful approach to treat an array of diseases, including cancer (1). Antiangiogenic strategies are designed to reestablish the balance between angiogenic factors and endogenous inhibitors, restoring the physiologically quiescent condition of the vasculature (2). A strategy to achieve this is to exploit the activity of endogenous inhibitors of angiogenesis (3).Thrombospondin-1 (TSP-1) 2 was the first endogenous inhibitor of angiogenesis identified (4, 5). Of the five members that constitute the TSP family in mammals, the homotrimeric TSP-1 and TSP-2 share domain organization and the ability to inhibit angiogenesis. Like other thrombospondins, TSP-1 is a multi-modular protein. Each monomer consists of an N-terminal globular domain followed by the coiled-coil oligomerization domain, a von Willebrand factor type C repeat, three properdin-like type I repeats, two TSP-type epidermal growth factor (EGF)-like or type II repeats, and a signature domain comprising a third EGF-like repeat, the calcium binding wire or type III repeats, and the lectin-like C-terminal globular domain (6).TSP-1 has been classified functionally as a matricellular protein, i.e. an extracellular protein that acts to regulate cell interactions with the environment (7). TSP-1 binds to a variety of ...

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Section: Discussionsupporting

confidence: 90%

Section: Nmr Analysis Of Dd15-fgf-2 Interaction-mentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Colombo

Margosio

Ragona

et al. 2010

Journal of Biological Chemistry

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“…Several proteolytic enzymes, including the neutrophil elastase, thrombin plasmin, trypsin, and cathepsin G, generate two fragments of TSP-1 of 25 and 140 kDa (Hogg et al, 1993a, b). Most of the antiangiogenic activity of TSP-1 has been located in the 140 kDa carboxy-terminal fragment of TSP-1 and it occurs through the TSP-1 receptor CD36 (Tolsma et al, 1993;Taraboletti et al, 1997). A positive effect on angiogenesis has been detected on the heparin binding 25 kDa fragment of TSP-1 (Taraboletti et al, 2000).…”

Section: Proangiogenic Factorsmentioning

confidence: 99%

Molecular basis of angiogenesis and cancer

2003

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Angiogenesis is a term that describes the formation of new capillaries from a pre-existing vasculature. This process is very important in physiologic conditions because it helps healing injured tissues, and in female populations it helps forming the placenta after fertilization and reconstructs the inside layer of the uterus after menstruation. Angiogenesis is the result of an intricate balance between proangiogenic and antiangiogenic factors and is now very well recognized as a powerful control point in tumor development. In this particular environment, the fine modulation among proangiogenic and antiangiogenic factors is disrupted, leading to inappropriate vessels growth. In this review, we discuss the molecular basis of angiogenesis during tumor growth and we also illustrate some of the molecules that are involved in this angiogenic switch.

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Role of transforming growth factor ?1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome

et al. 2000

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Primary human microvascular endothelial cells (MVEC) of restricted lineage undergo apoptosis when exposed to plasma from patients with thrombotic thrombocytopenic purpura (TTP) and sporadic hemolytic-uremic syndrome (HUS). This reflects the pathology and tissue distribution of lesions in vivo. As extracellular matrix (ECM) is critical to MVEC survival, and cytokines which regulate ECM, such as transforming growth factor (TGF)-beta1, have been reported anecdotally to be altered in TTP/HUS, we examined the role of TGF-beta1 and two ECM proteins, fibronectin and thrombospondin (TSP), in these disorders. Levels of active TGF-beta1 were elevated in acute but not convalescent phases of TTP/sporadic HUS, as well as TTP associated with human immunodeficiency virus infection and use of the anti-platelet drug ticlopidine. MVEC from tissues susceptible to TTP-mediated apoptosis showed little active TGF-beta1 production when exposed to TTP plasmas. In contrast, pulmonary MVEC and large-vessel EC, which are resistant to TTP-linked pathology, showed marked induction of TGF-beta1 following TTP plasma exposure. Exogenous TGF-beta1 suppressed TTP plasma-mediated apoptosis in susceptible MVEC in association with blockade of cell entry into S phase. Soluble TSP, devoid of detectable bound TGF-beta1, had a similar effect, which paralleled its ability to induce TGF-beta1 production in MVEC. In vivo, TSP deposition was diminished markedly in involved tissues of TTP patients. These data highlight the role of TGF-beta1 and ECM in TTP and suggest that differential production of TGF-beta1 by MVEC may play a role in their sensitivity or resistance to TTP/sporadic HUS-mediated apoptosis in vitro and in vivo.

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Thrombospondin-1 inhibits Kaposi's sarcoma (KS) cell and HIV-1 Tat-induced angiogenesis and is poorly expressed in KS lesions

Cited by 50 publications

References 33 publications

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Molecular basis of angiogenesis and cancer

Role of transforming growth factor ?1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome

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