Receptor heterodimerization: a new mechanism for platelet-derived growth factor induced resistance to anti-epidermal growth factor receptor therapy for bladder cancer.
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| Abstract | PURPOSE: Human bladder cancer cells resistant to anti-epidermal growth factor receptor therapy often co-express platelet-derived growth factor receptor-β. We determined whether there is functional crosstalk between epidermal growth factor receptor and platelet-derived growth factor receptor-β, and how this regulates biological functions in bladder cancer cases. MATERIALS AND METHODS: We determined heterodimerization and co-localization of epidermal growth factor receptor and platelet-derived growth factor receptor-β by immunoprecipitation and confocal microscopy, respectively. We tested the antiproliferative effects of specific inhibitory monoclonal antibodies to each receptor by (3)H-thymidine uptake assay. We transfected the nonplatelet-derived growth factor receptor-β expressing bladder cancer cell line UMUC5 with the platelet-derived growth factor receptor-β gene. These cells were analyzed in vitro by (3)H-thymidine uptake and by Matrigel™ invasion assay, and in vivo for tumorigenicity, metastatic potential and orthotopic growth. In a treatment study nude mice were inoculated with orthotopic tumors and treated with the inhibitory antibodies alone and in combination. RESULTS: Immunoprecipitation revealed epidermal growth factor receptor/platelet-derived growth factor receptor-β heterodimers in all platelet-derived growth factor receptor-β expressing cell lines. Forced expression of platelet-derived growth factor receptor-β in epidermal growth factor receptor sensitive UMUC5 cells (50% inhibitory concentration less than 10 nM) significantly decreased responsiveness to epidermal growth factor receptor inhibition (50% inhibitory concentration greater than 100 nM) and increased invasive potential 3-fold as well as tumorigenicity. Increased invasiveness was associated with epidermal growth factor triggered platelet-derived growth factor receptor-β transactivation, increased mitogen activated protein kinase and glycogen synthase kinase-3β phosphorylation, and decreased E-cadherin. Inhibition of epidermal growth factor receptor and platelet-derived growth factor receptor-β receptors blocked cell invasion, decreased cell proliferation, reduced xenograft tumor growth and increased E-cadherin expression. CONCLUSIONS: In epidermal growth factor receptor expressing bladder cancer co-expression of platelet-derived growth factor receptor-β has implications for tumor biology. Thus, it should be further evaluated as a strategy involving dual receptor targeting.
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| Authors | Peter C Black, Gordon A Brown, Colin P Dinney, Wassim Kassouf, Teruo Inamoto, Ameeta Arora, David Gallagher, Mark F Munsell, Menashe Bar-Eli, David J McConkey, Liana Adam |
| Journal | The Journal of urology (J Urol) Vol. 185 Issue 2 Pg. 693-700 (Feb 2011) ISSN: 1527-3792 [Electronic] United States |
| PMID | 21168861 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved. |
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