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  • Review Article
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Endothelin 1 in cancer: biological implications and therapeutic opportunities

Nature Reviews Cancer volume 13, pages 637–651 (2013)Cite this article

Subjects

Key Points

  • Aberrant expression of endothelin 1 (ET1), or overexpression of endothelin receptors or their linked signalling circuits can contribute to tumour initiation and progression through both autocrine and paracrine mechanisms. These alteration mechanisms may arise from genetic and epigenetic changes.

  • An intricate network of crosstalk between ET1 signalling and other growth factor pathways drives tumour progression. This includes crosstalk between the endothelin receptors and epidermal growth factor receptor and vascular endothelial growth factor receptor.

  • ET1 signalling promotes cell proliferation, survival, epithelial-to-mesenchymal transition, neovascularization, response of immune cells and drug resistance in a context-dependent manner. Hence, endothelin receptors have emerged as key targets for cancer therapy.

  • In addition to tumour cells, endothelin receptors are found on tumour-associated host cells, such as blood and lymphatic endothelial cells, fibroblasts and inflammatory cells, thus regulating the contribution of these cell types to cancer progression. Therefore, endothelin receptor antagonists may inhibit tumour progression by blocking crucial signalling events in both the tumour microenvironment and the tumour cells.

  • The activation of ET1 signalling pathways is often negatively correlated with patient outcomes in different types of cancer.

  • Small-molecule antagonists for targeting endothelin receptors have been evaluated in several recent clinical trials. However, the clinical results to date have been disappointing and it is crucial to decipher why the promising preclinical data have not yet been translated to the clinic.

  • Future improved clinical trials might incorporate predictive biomarkers to focus on subsets of patients who are most likely to respond, use other clinical settings or use rational combination therapy with chemotherapeutics or targeted agents.

Abstract

Activation of autocrine and paracrine signalling by endothelin 1 (ET1) binding to its receptors elicits pleiotropic effects on tumour cells and on the host microenvironment. This activation modulates cell proliferation, apoptosis, migration, epithelial-to-mesenchymal transition, chemoresistance and neovascularization, thus providing a strong rationale for targeting ET1 receptors in cancer. In this Review, we discuss the advances in our understanding of the diverse biological roles of ET1 in cancer and describe the latest preclinical and clinical progress that has been made using small-molecule antagonists of ET1 receptors that inhibit ET1-driven signalling.

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Figure 1: The ET1 signalling network.
Figure 2: Crosstalk between ET1 signalling and the β-catenin and HIF1α signalling pathways.
Figure 3: The ET1-regulated tumour–microenvironment interactions in tumour maintenance and progression.
Figure 4: The ET1 axis in immunomodulation.

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Acknowledgements

The authors thank P. G. Natali, V. Di Castro and all members of the laboratory for their constant support and enthusiasm. Work in A.B.'s laboratory is supported in part by Associazione Italiana Ricerca sul Cancro. The authors apologize to their colleagues whose work could not be cited here owing to space limitations.

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  1. Laboratory of Molecular Pathology A, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome, 00144, Italy

    Laura Rosanò, Francesca Spinella & Anna Bagnato

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  1. Laura Rosanò
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  2. Francesca Spinella
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Correspondence to Anna Bagnato.

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Glossary

Nociceptive

Pertaining to nociceptors, which are nerves with specialized receptors that send pain signals to the brain and spinal cord.

Autocrine

A mode of signalling in which a secreted substance acts on surface receptors that are present on the same cell from which the substance was produced.

Paracrine

A form of bioregulation in which a secretion produced by one cell type in a tissue diffuses through the tissue and affects another cell type in the same tissue.

β-arrestins

A family of proteins that interact with the carboxyl termini of G protein-coupled receptors and that help to mediate receptor desensitization, internalization, recycling and signalling.

Lymphangiogenesis

The formation of lymphatic vessels from pre-existing lymphatic vessels, in a way similar to blood vessel development or angiogenesis.

Triple-negative breast cancer

(TNBC). Breast cancer that lacks the expression of oestrogen receptor, progesterone receptor and ERBB2.

Proenzymes

Also known as zymogens. The inactive or nearly inactive precursors of enzymes, which are converted into active enzymes by proteolysis.

Mesothelial

Pertaining to the layer of flat cells of mesodermal origin that lines the embryonic body cavity and that gives rise to the squamous cells of the peritoneum, pericardium and pleura.

Osteoblasts

Cells responsible for bone formation. They express bone sialoprotein and osteocalcin and produce osteoid, which is mainly composed of type I collagen.

Osteoclast

A cell that breaks down mineralized bone and that is responsible for bone resorption.

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Rosanò, L., Spinella, F. & Bagnato, A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 13, 637–651 (2013). https://doi.org/10.1038/nrc3546

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