Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action

Abstract

Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic growth factors and effectors in the extracellular environment, and directly, by inducing an antiangiogenic program in endothelial cells following engagement of specific receptors including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics, gene therapy strategies, and agents that up-regulate TSP-1 expression. This review discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and therapeutic potential, drawing our experience with angiogenic growth factor-interacting TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic agents.

Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization

“…SPARC can abrogate focal adhesions and lead to migration and metastasis (232). However, it can also bind and interact with growth factors to promote cell cycle arrest and reduce angiogenesis (233). This dichotomy is borne out in the literature, summarized nicely by Podhajcer et.al., where SPARC is noted to be highly expressed in a wide range of very aggressive human tumors, but is also noted to be antitumorigenic in many other models (234).…”

Expression and localization of members of the thrombospondin family during final follicle maturation and corpus luteum formation and function in the bovine ovary

“…Considerable work has been done on the function of THBS1 and THBS2 in cell-matrix interactions and on their potential role as inhibitors of angiogenesis [13, 14]. The cellular effects of the THBS ligands are mediated through interactions with the cell-surface receptors CD36 and CD47 [15,16,17]; in particular, those of THBS1 and THBS2 are mediated by interactions with CD36, which leads to increased caspase-3 activity and finally to apoptosis [18]. THBS1 is the predominant form expressed in luteal endothelial cells (EC), whereas the major form in luteinized granulosa cells (GC) is THBS2 [19].…”

459 The FGF-2 binding domain of thrombospondin-1: functional characterization and exploitation to design antiangiogenic compounds

“…Different therapeutic approaches have been proposed to exploit the antiangiogenic properties of TSP-1 (reviewed in [33][34][35]). Increased levels of TSP-1 have been obtained by gene therapy approaches, based on viral and non-viral vectors, designed to grant the constant delivery of the antiangiogenic factors necessary for an effective control of angiogenesis [36,37].…”

“…Increased levels of TSP-1 have been obtained by gene therapy approaches, based on viral and non-viral vectors, designed to grant the constant delivery of the antiangiogenic factors necessary for an effective control of angiogenesis [36,37]. Alternatively, different classes of antiangiogenic compounds stimulate TSP-1 production, including fenofibrate, thrichostatin-A, retinoic acid, inhibitors of DNA methyltransferases and histone deacetylases (see [33,34] and references therein). Interestingly, an increase in TSP-1 production has been indicated as the main mechanism of the antiangiogenic activity of metronomic chemotherapy, the frequent administration of low dose chemotherapy proposed to optimize the antiangiogenic property of chemotherapeutics [38,39].…”