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The endothelin axis: emerging role in cancer

Nature Reviews Cancer volume 3, pages 110–116 (2003)Cite this article

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Key Points

  • Studies have demonstrated the role of the ET axis in a wide variety of diseases, including cancer.

  • ETA-receptor activation by ET-1 contributes to tumour growth and progression, inducing cell proliferation, survival, angiogenesis and metastatic spread, indicating that ETA-receptor blockade might improve cancer treatment.

  • In Phase I and II clinical studies, ETA-receptor antagonists can be administered orally, once a day, and have a favourable tolerability profile.

  • Preliminary data from clinical trials are promising.

  • Studies are underway to better define the role and ET-receptor antagonists in the treatment of malignant diseases.

Abstract

Collectively, the endothelins and their receptors — referred to as the endothelin (ET) axis — have key physiological functions in normal tissue, acting as modulators of vasomotor tone, tissue differentiation, development, cell proliferation and hormone production. Based on new data, the ET axis also functions in the growth and progression of various tumours. Preliminary results from clinical trials, such as those with atrasentan — an ETA-receptor antagonist — in prostate cancer, are encouraging. The place of ET-receptor antagonists in cancer therapy for a range of malignancies merits further investigation.

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Figure 1
Figure 2: Endothelins and their receptor-mediated functions.
Figure 3: Endothelin-induced signal-transduction pathways.
Figure 4: Endothelin-1 activity in bone remodelling.

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Change history

  • 03 February 2005

    'a' added to first page numbers for references 40 and 53; acknowledgement added

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Acknowledgements

A.B. is grateful to the Associazione Italiana Ricerca sul Cancro for supporting her work.

Author information

Authors and Affiliations

  1. University of Pittsburgh School of Medicine, 5200 Centre Avenue, Pittsburgh, 15232, PA, USA

    Joel Nelson

  2. Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158, Rome, Italy

    Anna Bagnato

  3. Quebec Heart and Lung Institute, Laval Hospital Research Center, 2725 Chemin Ste-Foy

    Bruno Battistini

  4. Laval University, Ste-Foy, G1V 4G5, Quebec, Canada

    Bruno Battistini

  5. Abbott Laboratories, Abbott Park, Illinois, 60064, USA

    Perry Nisen

Authors
  1. Joel Nelson
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  2. Anna Bagnato
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  3. Bruno Battistini
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  4. Perry Nisen
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Corresponding author

Correspondence to Joel Nelson.

Related links

Related links

DATABASES

Cancer.gov

breast carcinoma

cervical carcinoma

Kaposi's sarcoma

ovarian cancer

prostate cancer

renal-cell carcinoma

LocusLink

BCL2

EGF

EGFR

ET-1

ET-2

ET-3

ETA

ETB

FASL

FGF1

FGF2

FOS

GRB2

HIF-1α

insulin-like growth factor-1

JUN

MAPK

MMP-2

MYC

NEP

phosphatidylinositol 3-kinase

PKC

platelet-derived growth factor

RAS

SHC

transforming growth factor-β

uPA

VEGF

FURTHER INFORMATION

The Cancer Web Project. The On-Line Medical Dictionary

InteliHealth Medical Dictionary

Kimball's Biology Pages

Glossary

OSTEOBLAST

A bone-forming cell.

VASCULAR RESTENOSIS

A renarrowing or renewed blockage of an artery at the site where previous treatment, such as angioplasty, has already been performed.

BENIGN PROSTATIC HYPERPLASIA

Hyperplasia of the periurethral part of the prostate gland that usually occurs in men over 50 years old and might obstruct urination by constricting the urethra.

FAS LIGAND

Apoptosis antigen ligand is the ligand for FAS. Interaction of FAS with its ligand is crucial in triggering apoptosis in some types of cells.

AKT

A serine/threonine protein kinase.

PROSTATE-SPECIFIC ANTIGEN

(PSA). A serine protease that is secreted into seminal fluid by prostatic epithelial cells and that is found in the serum. Almost exclusively a product of prostate cells, PSA measurement in blood is useful as a tumour marker for the diagnosis of prostate cancer and for monitoring the effectiveness of treatment.

OSTEOCLAST

Large multinucleate cells that are associated with areas of bone resorption.

ALKALINE PHOSPHATASE

An enzyme that is found on the cell surface of osteoblasts and that is used as a serum marker of increased osteoblast activity.

OSTEOCALCIN

A protein constituent of bone; circulating levels are used as a marker of increased bone turnover.

PERICYTE

A cell of the connective tissue that abuts capillaries or other small blood vessels.

ZYMOGEN

An inactive precursor of an enzyme, particularly a proteolytic enzyme.

XENOGRAFT

A surgical graft of tissue or cells from one species to another. In cancer research, most xenografts are human cancer cell lines or human tumours that have been transplanted into immune-deficient rodents.

ADENOCARCINOMA

A malignant tumour of epithelial tissue in which the tumour cells form glands or gland-like structures.

HUMAN PAPILLOMAVIRUS

A virus that causes various human warts, including some that are associated with the development of cancer.

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Nelson, J., Bagnato, A., Battistini, B. et al. The endothelin axis: emerging role in cancer. Nat Rev Cancer 3, 110–116 (2003). https://doi.org/10.1038/nrc990

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