PharmStatus.com
Oncology Intelligence

TSP-1
TSP-1
TSP-1(12)
TSP-1 is a member of the thrombospondin family, encoded by the THBS1 gene.(1,2) TSP-1 is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions, and plays a role in platelet aggregation, angiogenesis, and tumorigenesis. Both positive and negative modulation of endothelial cell adhesion, motility, and growth have been attributed to TSP1.(1, 3)
TSP1 is a subunit of a disulfide-linked homotrimeric protein. TSP1 contains three type I repeats, only the second two of which have been found to inhibit angiogenesis. The N-terminal end contains a tryptophan-rich motif that blocks bFGF driven angiogenesis. The second region of activity, the CD36 binding region of TSP1, can be found on the carboxy-terminal half of the type I repeats.(4) It has been suggested that activating the CD36 receptor causes an increase in ECs sensitivity to apoptotic signals.(5) Type I repeats have also been shown to bind to heparin, fibronectin, TGF-?, and others, potentially antagonizing the effects of these molecules on ECs.(6) However, CD36 is generally considered to be the dominant inhibitory signaling receptor for TSP1, andEC expression of CD36 is restricted to microvascular ECs.(1, 3) TSP1 can bind to fibrinogen, fibronectin, laminin, type V collagen, INTs, CD36, syndecan, and INT-associated protein (CD47). It also interacts with numerous proteases involved in angiogenesis, including plasminogen, urokinase, MMP, thrombin, cathepsin, elastase, and LRP1.(1,3,9-11)
Various domains of and receptors for TSP1 have been shown to have pro-adhesive and chemotactic activities for cancer cells, suggesting that this molecule may have a direct effect on cancer cell biology independent of its anti-angiogenic properties.(7) By blocking TSP1 from binding to its cell surface receptor (CD47) normal tissue becomes nearly immune to cancer radiation therapy and assists in tumor death.(8)

Drugs/Indications
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
ALT-836 Altor P2: ALI/ARDS, P1: solid trials
trials
MORAb-066 Eisai P1: BC, pancreatic, CRC, NSCLC, adenocarcinoma trials



News
Pharmstatus Pro
Therapeutics in clinical trials updated weekly
Subscription portal TSP-1 therapeutics
References

1. Blake SM, Strasser V, Andrade N, Duit S, Hofbauer R, Schneider WJ, et al. Thrombospondin?1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration. The EMBO journal. 2008;27(22):3069-80.

2. Wolf FW, Eddy RL, Shows TB, Dixit VM. Structure and chromosomal localization of the human thrombospondin gene. Genomics. 1990;6(4):685-91.

3. Thrombospondin_1. [cited]; Available from: http://en.wikipedia.org/wiki/Thrombospondin_1.

4. Iruela-Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD. Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats. Circulation. 1999;100(13):1423-31.

5. Sid B, Sartelet H, Bellon G, El Btaouri H, Rath G, Delorme N, et al. Thrombospondin 1: a multifunctional protein implicated in the regulation of tumor growth. Critical reviews in oncology/hematology. 2004;49(3):245-58.

6. Guo N-h, Zabrenetzky VS, Chandrasekaran L, Sipes JM, Lawler J, Krutzsch HC, et al. Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1. CANCER RESEARCH. 1998;58(14):3154-62.

7. Chandrasekaran S, Guo N-h, Rodrigues RG, Kaiser J, Roberts DD. Pro-adhesive and chemotactic activities of thrombospondin-1 for breast carcinoma cells are mediated by ?3?1 integrin and regulated by insulin-like growth factor-1 and CD98. Journal of Biological Chemistry. 1999;274(16):11408-16.

8. Maxhimer JB, Soto-Pantoja DR, Ridnour LA, Shih HB, DeGraff WG, Tsokos M, et al. Radioprotection in normal tissue and delayed tumor growth by blockade of CD47 signaling. Science translational medicine. 2009;1(3):3ra7-3ra7.

9. Wang S, Herndon ME, Ranganathan S, Godyna S, Lawler J, Argraves WS, et al. Internalization but not binding of thrombospondin?1 to low density lipoprotein receptor?related protein?1 requires heparan sulfate proteoglycans. Journal of cellular biochemistry. 2004;91(4):766-76.

10. Bein K, Simons M. Thrombospondin Type 1 Repeats Interact with Matrix Metalloproteinase 2 REGULATION OF METALLOPROTEINASE ACTIVITY. Journal of Biological Chemistry. 2000;275(41):32167-73.

11. DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA. Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen. Blood. 1989;73(4):976-82.

12. Inhibition_of_Angiogenesis_by_TSP1. [cited]; Available from: http://www.sabiosciences.com/pathway.php?sn=Inhibition_of_Angiogenesis_by_TSP1.