Endothelin B Receptor, a New Target in Cancer Immune Therapy

The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET A R). Their interaction induces tumor...

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Bibliographic Details
Published in:Clinical cancer research 2009-07, Vol.15 (14), p.4521-4528
Main Authors: KANDALAFT, Lana E, FACCIABENE, Andrea, BUCKANOVICH, Ron J, COUKOS, George
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Endothelin B Receptor Antagonists
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Humans
Immunotherapy - methods
Intercellular Adhesion Molecule-1 - metabolism
Medical sciences
Models, Biological
Neoplasms - immunology
Neoplasms - metabolism
Neoplasms - therapy
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Piperidines - pharmacology
Receptor, Endothelin B - metabolism
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
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Summary:The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors overexpress the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ET A R). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angiogenesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ET A R. In this review, we discuss a novel role of the endothelin-B-receptor (ET B R) in tumorigenesis and the effect of its blockade during cancer immune therapy. We highlight key characteristics of the B receptor such as its specific overexpression in the tumor compartment; and specifically, in the tumor endothelium, where its activation by ET-1 suppresses T-cell adhesion and homing to tumors. We also review our recent findings on the effects of ET B R-specific blockade in increasing T-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-08-0543