The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapy

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Date: Aug. 2008
Publisher: NRC Research Press
Document Type: Clinical report
Length: 8,896 words
Lexile Measure: 1520L

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Abstract: The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and 2 G protein-coupled receptor subtypes, [ET.sub.A]R and ETBR, promotes growth and progression of a variety of tumors, such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, lung, bladder, endometrial carcinoma, Kaposi's sarcoma, brain tumors, and melanoma. Acting on selective receptors, ET-1 regulates mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptors, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion, and metastatic dissemination. At the molecular level, endothelin receptor antagonists, besides providing ideal tools for dissecting the ET axis, have demonstrated their potential in developing novel therapeutic strategies. Emerging experimental and clinical data demonstrate that interfering with endothelin receptors provides an opportunity for the development of rational combinatorial approaches using endothelin receptor antagonists in combination with chemotherapy or molecularly targeted therapy.

Key words: endothelin, endothelin receptor antagonist, G protein-coupled receptor, antitumor therapy.

Resume : L'axe endotheline (ET), qui comprend les endothelines Et-1, Et-2 et ET-3, et deux recepteurs couples aux proteines G, les recepteurs A ([R.sub.A]ET) et B ([R.sub.B]ET), favorise la croissance tumorale et la progression de diverses tumeurs, telles que les carcinomes prostatique, ovarien, renal, pulmonaire, colorectal, cervical, mammaire, bronchique, vesical et endometrial, le sarcome de Kaposi, les tumeurs cerebrales et les melanomes. Agissant sur un recepteur selectif, l'ET-1 regule la mitogenese, la survie des cellules, l'angiogenese, le remodelage osseux, la stimulation des nocicepteurs, les cellules immunitaires infiltrant les tumeurs, la transition epitheliale-mesenchymateuse, l'invasion des metastases et leur dissemination. Sur le plan moleculaire, les antagonistes des recepteurs de l'endotheline, en plus d'etre des outils ideaux pour l'analyse de l'axe ET, ont demontre leur potentiel dans l'elaboration d'une nouvelle strategie threrapeutique. Des donnees cliniques et experimentales emergentes demontrent que l'interference avec un recepteur endotheline permet de developper des approches combinatoires rationnelles en utilisant des antagonistes des recepteurs de l'endotheline en association avec la chimiotherapie ou une therapie ciblee.

Mots-cles : endotheline, antagoniste des recepteurs de l'endotheline, recepteur couple aux proteines G, therapie antitumorale.

[Traduit par la Redaction]

Introduction

The endothelins (ETs) comprise a family of 3 peptides, ET-1, ET-2, and ET-3, that are potent vasoconstricting peptides involved in the pathophysiology of many human malignancies (Levin 1995; Masaki 2000). Biological activity is mediated by the activation of 2 G protein-coupled receptor (GPCR) subtypes, ETA and ETB. Emerging experimental and clinical data increasingly underscore the role of GPCRs in cancer progression and metastasis. Malignant cells often hijack the normal physiologic function of GPCRs to proliferate autonomously, evade immune detection, increase their nutrients and oxygen supply, invade their surrounding tissues, and disseminate to others organs. The aberrant expression of GPCRs, such as endothelin receptors, and their autocrine and paracrine activation by agonists released by tumor or stromal cells represent the most frequent tactics used by tumor cells to stimulate GPCRs and their signaling networks (Dorsam and Gutkind 2007). The endothelin axis has a relevant role in a wide spectrum of malignancies (Nelson et al. 2003; Bagnato and Catt 1998) through the triggering of a highly interconnected signaling network that ultimately activates the "hallmarks of cancer"...

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Gale Document Number: GALE|A185488019