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 3H-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 3H- 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.
Original language | English (US) |
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Pages (from-to) | 693-700 |
Number of pages | 8 |
Journal | Journal of Urology |
Volume | 185 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2011 |
Externally published | Yes |
Keywords
- drug resistance
- epidermal growth factor
- receptor, platelet-derived growth factor beta
- urinary bladder
- urinary bladder neoplasms
ASJC Scopus subject areas
- Urology