Thrombospondins (TSP) are secreted proteins with the ability to inhibit angiogenesis.
Importance
The thrombospondins (TSP) are a family of multifunctional proteins. The family consists of thrombospondins 1-5 and can be divided into 2 subgroups: A, which contains TSP-1 and -2, and B, which contains TSP-3, -4 and -5 (also designated cartilage oligomeric protein or COMP). TSP-1 and -2 are homotrimers, consisting of three identical subunits, whereas TSP-3, -4 and -5 are homopentamers. TSP-1 is encoded by THBS1. It was first isolated from platelets that had been stimulated with thrombin, and so was designated 'thrombin-sensitive protein'. Since its first recognition, functions for TSP-1 have been found in multiple biological processes including angiogenesis, apoptosis, activation of TGF-beta and Immune regulation. As such, TSP-1 is designated a multifunctional protein. TSP-1 has multiple receptors, among which CD36, CD47 and integrins are of particular note. TSP-1 acts to inhibit angiogenesis, inhibiting the proliferation and migration of endothelial cells by interactions with CD36 expressed on their surface of these cells. Inhibitory peptides and fragments of TSP1 bind to CD36, leading to the expression of FAS ligand (FasL), which activates the expression of Fas. This leads to the activation of caspases and apoptosis of the cell. Since tumors overexpressing TSP-1 typically grow slower, exhibit less angiogenesis, and have fewer metastases, TSP1 is an attractive target for cancer treatment. Because TSP1 is extremely large (~120 kDa monomer), not very abundant and exerts multiple actions, its clinical usefulness is questionable. However, small-molecules based on a CD36-binding peptide sequence from TSP1 are being tested. One analog, ABT-510, exhibits potent proapoptotic activity in cultured cells, while clinically it is very well tolerated with therapeutic benefits reported against several malignancies [1]. ABT-510 is being evaluated in phase II clinical trials for the treatment of several types of cancer [2]. TSP-1 and TSP-2 are produced by immature astrocytes during brain development, which promotes the development of new synapses.[3]
References
- ^ Haviv F, Bradley MF, Kalvin DM, et al. Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumor growth: design, synthesis, and optimization of pharmacokinetics and biological activities. J Med Chem 2005;48:2838–46
- ^ Sorbera L, Bayes M. ABT-510: oncolytic Angiogenesis Inhibitor. Drugs of the Future 2005;30:1081–6
- ^ Christopherson KS, Ullian EM, Stokes CC,Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. (2005). "Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.". Cell 120 (3): 421-33. PMID 15707899.
