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  • Review Article
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Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies

Nature Reviews Cancer volume 9, pages 182–194 (2009)Cite this article

Key Points

  • Nitric oxide (NO) mediates pro-angiogenic activities of vascular endothelial growth factor A (VEGFA) and a number of additional angiogenic factors that support the neovascularization of tumours. This signalling involves activation of soluble guanylate cyclase and downstream targets of cyclic GMP.

  • Thrombospondin 1 (TSP1) and TSP2 are endogenous angiogenesis inhibitors. Their expression is frequently lost during cancer progression, and overexpression suppresses tumour growth. TSP1 is a potent antagonist of NO signalling in vascular endothelial cells, vascular smooth muscle cells and platelets. TSP2 is substantially less active.

  • Antagonism of NO signalling can be mediated by TSP1 binding to two of its receptors, CD36 and CD47. CD47 mediates inhibition at much lower concentrations of TSP1, and CD47 is also required for signalling through CD36.

  • TSP1 signalling through CD47 redundantly inhibits NO signalling at the level of soluble guanylate cyclase and cGMP-dependent protein kinase.

  • In addition to long-term inhibition of angiogenesis, antagonism of NO signalling by TSP1 results in acute inhibition of tissue perfusion and acceleration of platelet haemostasis. Consequently, TSP1 and CD47 limit recovery of blood flow and tissue survival following ischaemic injuries. By contrast, tumour vasculature is resistant to acute vasodilation by NO, and increased circulating TSP1 produced by tumour stroma may instead indirectly increase tumour perfusion by limiting blood flow elsewhere.

  • These activities of TSP1 parallel the hypertensive and pro-thrombotic activities that are emerging as frequent side effects of therapeutic angiogenesis inhibitors, and both can be explained by inhibition of NO signalling.

  • TSP1 signalling through CD47 also limits soft tissue survival after radiation injury. Disruption of this pathway is a possible strategy to permit delivery of higher therapeutic radiation doses to tumours while selectively protecting surrounding healthy tissues.

Abstract

In addition to long-term regulation of angiogenesis, angiogenic growth factor signalling through nitric oxide (NO) acutely controls blood flow and haemostasis. Inhibition of this pathway may account for the hypertensive and pro-thrombotic side effects of the vascular endothelial growth factor antagonists that are currently used for cancer treatment. The first identified endogenous angiogenesis inhibitor, thrombospondin 1, also controls tissue perfusion, haemostasis and radiosensitivity by antagonizing NO signalling. We examine the role of these and other emerging activities of thrombospondin 1 in cancer. Clarifying how endogenous and therapeutic angiogenesis inhibitors regulate vascular NO signalling could facilitate development of more selective inhibitors.

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Figure 1: The central role of nitric oxide (NO) signalling in angiogenesis, vascular tone and haemostasis.
Figure 2: CD47 and CD36 mediate inhibition of nitric oxide (NO)–cyclic GMP signalling by thrombospondin 1 (TSP1).
Figure 3: Vascular responses outside the tumour primarily determine effects of thrombospondin 1 (TSP1) on tumour perfusion.
Figure 4: Convergence of angiogenesis inhibitor signalling on the nitric oxide (NO)–cyclic GMP cascade.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (D.D.R.). Gema Martin-Manso is recipient of a grant BEFI from Instituto de Salud Carlos III (Spanish Ministry of Heath).

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Authors and Affiliations

  1. Hemostasis and Vascular Biology Research Institute and the Department of Medicine, University of Pittsburgh, Pittsburgh, 15260, Pennsylvania, USA

    Jeff S. Isenberg

  2. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Gema Martin-Manso, Justin B. Maxhimer & David D. Roberts

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DATABASES

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Glossary

Hypertension

A condition in which blood pressure is chronically increased.

Thrombosis

Formation of a blood clot (thrombus) inside a blood vessel that obstructs blood flow.

Vessel tone

An assessment of vessel resistance to blood flow. Vessel tone is decreased by NO-mediated vasodilation and increased by activity of autonomic innervation and the presence of vasopressors.

Tissue perfusion

The volume of blood that flows through a unit quantity of tissue.

Haemostasis

The physiological process that arrests bleeding at a site of injury by formation of a haemostatic plug, resolves this plug during healing and maintains circulating blood in a fluid state in the absence of injury.

Nitric oxide synthase

Mammalian genomes encode three nitric oxide synthases: NOS1 (nNOS) is constitutively expressed in neuronal tissues, NOS2 (iNOS) is an inducible enzyme in phagocytic cells that can also be induced by inflammatory mediators in vascular cells, and NOS3 (eNOS) is a constitutively expressed but highly regulated enzyme in endothelium and platelets.

Mechanical shear

A physical force exerted on endothelial cells in blood vessels as a result of blood flow, which regulates the activity of NOS3 in endothelium.

Acetylcholine

A neurotransmitter in the autonomic nervous system that activates NOS3 in endothelial cells by increasing cytoplasmic calcium levels.

α-Granule

A major secretory organelle in platelets. The primary source for purification of thrombospondin 1.

Innate immunity

Cells and mechanisms that defend the host from pathogens or tumours in a non-specific manner. Innate anti-tumour immunity involves primarily macrophages and natural killer cells.

Corneal angiogenesis

The corneal angiogenesis assay is a standard method to assess pro- and anti-angiogenic factors by implanting slow-releasing polymer pellets containing the factors into the avascular cornea, usually of mice, rats or rabbits.

Vasodilator-stimulated phosphoprotein

A protein that controls actin polymerization. It is a well-characterized substrate for phosphorylation by cGMP-dependent protein kinase

Signature domain

Conserved C-terminal region of thrombospondins that includes EGF-like repeats, Ca2+-binding repeats and the C-terminal globular domain. In TSP1 it contains the binding site for CD47.

Partial fixed ischaemia

A partial but sustained loss of tissue blood flow.

Total ischaemia

A sustained total loss of tissue blood flow.

Hyperthermia therapy

The use of heat to damage or kill cancer cells and to make cancer cells more sensitive to the effects of radiation and certain anticancer drugs.

BOLD-MRI

(Blood oxygen level-dependent magnetic resonance imaging). An imaging technique that assesses blood oxygenation by detecting oxygen bound to haemoglobin.

Alopecia

A temporary or permanent loss of hair. Alopecia typically occurs several weeks after high-dose irradiation for tumour treatment.

Wet desquamation

Skin damage leading to broken skin or infection due to a fluid-filled abscess created by blocked ducts or capillaries, which is a characteristic side effect of high-dose irradiation.

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Isenberg, J., Martin-Manso, G., Maxhimer, J. et al. Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies. Nat Rev Cancer 9, 182–194 (2009). https://doi.org/10.1038/nrc2561

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