Induction of tumor proliferation and metastasis by expression of vascular endothelial growth factor receptor 2 in prostate carcinomas
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Vascular endothelial growth factor receptor 2 (VEGFR2) was first discovered on the cells of blood vessels, and has thus been referred to as an endothelial receptor. However, recent evidence suggests that some tumor cells may express VEGFR2 as well. We examine the function of the lowly metastatic human prostate cancer cell line PC3M and its highly metastatic lymph node variant PC3M-LN4. We discovered that PC3M-LN4 cells express high levels of VEGFR2. In vivo, PC3M-LN4 tumors are larger, more metastatic, and more vascularized than PC3M tumors. To further demonstrate the function of VEGFR2, PC3M cells were transfected with a VEGFR2 plasmid and G418 resistant cells were selected then grown as clones. PC3M-VEGFR2 cells were analyzed by Western blot analysis, a migration assay, and a proliferation assay. Cells expressing high levels of VEGFR2 were selected through Western blotting. A Transwell migration assay examining PC3M-VEGFR2.28 revealed greater cell migration towards VEGF-treated media as compared to VEGF-untreated media. A proliferation assay for this same clone showed greater cell proliferation with increasing concentrations of VEGF in both SF and 1% FBS media. These data suggest a direct relationship between VEGFR2 expression and tumor proliferation and metastasis. Furthermore, we noticed that an elongated cell morphology may be a characteristic of metastatic cells. Immunohistochemical analysis of prostate cancer patient biopsies reveals VEGFR2 expression on both tumor cells and endothelial cells. Interestingly, we noticed that this expression is heterogeneous between different patients and even varies within the same biopsy. Our data suggests that anti-VEGFR2 therapies may target both the tumor and blood vessels to inhibit prostate cancer disease progression in those patients that express the receptor.
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