Korean J Phys Anthropol.  2015 Dec;28(4):175-184. 10.11637/kjpa.2015.28.4.175.

Thrombospondin-1 and Inhibition of Tumor Growth

• Jeong GB

• KMID: 2150435
• DOI: http://doi.org/10.11637/kjpa.2015.28.4.175

Abstract

Thrmobospondin-1 is the multifunctional protein that modulates endothelial cell and tumor cell behavior via several cell surface receptors and inhibits angiogenesis. In vitro, thrombospondin-1 alters adhesion, proliferation, motility, and survival of endothelial and cancer cells. Studies have confirmed that increased TSP-1 expression suppresses growth or metastasis of some tumors and inhibits angiogenesis. In the past three decades, inhibitors of angiogenesis have been developed as regulators target the vascular endothelial growth factor (VEGF) signaling pathway and small molecule tyrosine kinase inhibitors have been clinically approved. TSP-1 has several functional domain structures and inhibits tumor angiogenesis by engaging receptors CD36 and CD47. TSP-1 binding to CD47 dissociates it from VEGFR2, inhibiting downstream AKT activation and functional responses of endothelial cells to VEGF. Recently, macrophage phagocytosis and cytotoxic T-cell induction of tumor cells mediated by CD47-specific blocking antibodies have been proposed. These findings provide a new therapeutic paradigm for elinination of cancer cells and inhibition of angiogenesis of tumor by TSP-1.

Keyword

Thrombospondin-1; Angiogenesis; Endothelial cells; VEGFR2; CD36; CD47

MeSH Terms

Antibodies, Blocking
Endothelial Cells
Macrophages
Neoplasm Metastasis
Phagocytosis
Protein-Tyrosine Kinases
Receptors, Cell Surface
T-Lymphocytes
Thrombospondin 1
Vascular Endothelial Growth Factor A
Antibodies, Blocking
Protein-Tyrosine Kinases
Receptors, Cell Surface
Thrombospondin 1
Vascular Endothelial Growth Factor A

Figure

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  Fig. 1. Domain structures of human Thrombospondin gene family. The thrombospondins are a family of five extracellular glycoproteins that are composed of multiple well-defined structural motifs. All five members contain the type 2 repeats, the type 3 repeats and a highly conserved C-terminal domain.

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  Fig. 2. The structure of the thrombospondin-1 subunit and its receptors. The TSP-1 peptide consists of six functional domain structures from N- to C-terminal. The NH2-terminal domain stimulates angiogenic response via α3β1 and other integrins. The type 1 repeats contain two distinct anti-angiogenic sequences that interacts with heparan sulfated glycoconjugates, fibronectin, TGF-β, and the receptor CD36. The type 3 repeats contain an RGD sequence that interacts with α5β1 and αvβ3 integrins. The C-terminal domain interacts with CD47. Some CD47-binding peptides derived from this domain inhibit angiogenesis.

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  Fig. 3. Antagonism of angiogenesis by CD36 receptor. Prongio-genic receptors induces proliferation, migraton, and tube formation of endothelial cells by ligand stimulation. In the presence of TSP-1, which interactis with a specific motif[CLESH) of the CD36 receptor, angiogenesis is inhibited. Inhibition is mediated by fyn, p38 MAPK and caspase signaling pathways, resulting in endothe-lial cell apoptosis.

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  Fig. 4. TSP1-CD47 signaling pathways. TSP-1 acts through its re-ceptor CD47 to block sGC activation. TSP-1 also signals through CD36 to inhibit the same response, but CD47 is necessary for these signals to inhibit cGMP signaling. Blockade of TSP1-CD47 signaling with antibodies to TSP-1 and CD47 increases cell surviv-al and enhances angiogenesis.

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  Fig. 5. Macrophage phagocytosis of tumor cells by CD47 antibody. Left, CD47 expression on cancer cells activates SIRPα on macro-phages and prevents macrophage phagocytosis of cancer cells. Right, CD47-blocking therapies to cancer cells prevent inhibitory signaling from SIRPα to augment macrophage phagocytosis.

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