Receptor heterodimerization: A new mechanism for platelet-derived growth factor induced resistance to anti-epidermal growth factor receptor therapy for bladder cancer - Abstract

Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

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.

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.

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.

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.

Written by:
Black PC, Brown GA, Dinney CP, Kassouf W, Inamoto T, Arora A, Gallagher D, Munsell MF, Bar-Eli M, McConkey DJ, Adam L.   Are you the author?

Reference: J Urol. 2011 Feb;185(2):693-700.
doi: 10.1016/j.juro.2010.09.082

PubMed Abstract
PMID: 21168861 Bladder Cancer Section