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Evaluation of the insulin-like growth factor receptor I and Pyk2 kinase in urothelial carcinomas and effect on motility and invasion of urothelial carcinoma-derived cells.

254 Background: We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial-carcinoma-derived cells without affecting cell proliferation, suggesting that the IGF-IR may play a more prominent role in promoting the transition to the invasive phenotype in bladder cancer.


METHODS
IGF-IR levels in cancer and normal bladder tissues were analyzed by immunohistochemistry. IGF-IR and Pyk2 signaling pathways were studied in several urothelial carcinoma-derived cancer cells using biochemical assays and siRNA approaches. Pyk2 expression in a bladder tissue array was analyzed by immunofluorescence and by AQUA (Automated Quantitative Analysis).


RESULTS
In this studywe demonstrated by immunohistochemical analysis that the IGF-IR expression increased with grade in bladder cancer tissues compared to non-malignant controls. Increased IGF-IR expression in non-tumorigenic T24 urothelial carcinoma cells promoted anchorage independent growth, while IGF-IR targeting in metastatic T24T cells inhibited colony formation in soft-agar. We also discovered that the focal adhesion protein Pyk2 is activated by IGF-I in urothelial carcinoma-derived cells. Using siRNA approaches, we demonstrated that Pyk2 is critical for IGF-IR-dependent motility and invasion and regulates IGF-I-dependent activation of the Akt and MAPK pathways in urothelial cancer cells. Using immunofluorescence and AQUA analysis we also discovered that Pyk2 is overexpressed in bladder cancer tissues compared to normal tissue controls. In urothelial carcinoma-derived tissues there is also increased Pyk2 localization in the nucleus compared to normal tissue controls.


CONCLUSIONS
Our results provide the first evidence for a role of the IGF-IR and Pyk2 in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR and Pyk2 may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR and Pyk2 could also serve as novel tumor biomarkers for diagnosis and possibly prognosis of bladder tumors. No significant financial relationships to disclose.