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VEGF receptor expression and signaling in human bladder tumors

Oncogene volume 22, pages 3361–3370 (2003)Cite this article

Abstract

Overexpression of vascular endothelial growth factor receptors (VEGFRs) has been reported in a variety of tumor types. Here we find that 11 out of the 14 bladder tumor cell lines examined express one or more VEGF receptors. Analysis of the T24 bladder tumor cell line reveals a functional autocrine loop involving VEGF and the Flk-1 receptor. Blocking VEGF expression in T24 cells results in a decrease in DNA synthesis. The Flk-1 receptor in T24 cells is phosphorylated in response to VEGF-121 or VEGF-165, and an Flk-1 inhibitor blocks VEGF to ERK signaling. We report that VEGF stimulation of T24 cells results in activation of H- and N-Ras and this is dependent on cellular sphingosine kinase 1 (SPK1) activity. Previously, we found VEGF-induced activation of Ras appears to be independent of a Ras-guanine nucleotide exchange factors (GEFs). Here we report that sphingosine can stimulate Ras-GTPase activating protein (GAP) activity in vitro, and sphingosine-1-phosphate (SPP) can block the stimulatory effects of sphingosine. We present a model where the balance between sphingosine and SPP regulates Ras-GAP activity such that stimulation of SPK1 favors downregulation of Ras-GAP and thereby the activation of Ras proteins. These data highlight a VEGF pathway that may be involved in the survival and proliferation of bladder tumor cells as well as other tumor cell types.

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References

  • Bollag G and McCormick F . (1991). Nature, 351, 576–579.

  • Bollag G and McCormick F . (1995). Methods Enzymol., 255, 161–170.

  • Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF and Senger DR . (1993). Am. J. Pathol., 143, 1255–1262.

  • Byzova TV, Goldman CK, Pampori N, Thomas KA, Bett A, Shattil SJ and Plow EF . (2000). Mol. Cell, 6, 851–860.

  • Carmeliet P and Collen D . (2000). Ann. NY Acad. Sci., 902, 249–262; discussion 262–264.

  • Crew JP, O'Brien T, Bradburn M, Fuggle S, Bicknell R, Cranston D and Harris AL . (1997). Cancer Res., 57, 5281–5285.

  • Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA and Rafii S . (2000). J. Clin. Invest., 106, 511–521.

  • Edsall LC, Van Brocklyn JR, Cuvillier O, Kleuser B and Spiegel S . (1998). Biochemistry, 37, 12892–12898.

  • Ferrara N . (1999). J. Mol. Med., 77, 527–543.

  • Ferrer FA, Miller LJ, Lindquist R, Kowalczyk P, Laudone VP, Albertsen PC and Kreutzer DL . (1999). Urology, 54, 567–572.

  • Golubic M, Tanaka K, Dobrowolski S, Wood D, Tsai MH, Marshall M, Tamanoi F and Stacey DW . (1991). EMBO J., 10, 2897–2903.

  • Guerrin M, Moukadiri H, Chollet P, Moro F, Dutt K, Malecaze F and Plouet J . (1995). J. Cell Physiol., 164, 385–394.

  • Guo D, Jia Q, Song HY, Warren RS and Donner DB . (1995). J. Biol. Chem., 270, 6729–6733.

  • Han JW, McCormick F and Macara IG . (1991). Science, 252, 576–579.

  • Kroll J and Waltenberger J . (1997). J. Biol. Chem., 272, 32521–32527.

  • Liu B, Earl HM, Baban D, Shoaibi M, Fabra A, Kerr DJ and Seymour LW . (1995). Biochem. Biophys. Res. Commun., 217, 721–727.

  • Marais R, Light Y, Mason C, Paterson H, Olson MF and Marshall CJ . (1998). Science, 280, 109–112.

  • Martiny-Baron G, Kazanietz MG, Mischak H, Blumberg PM, Kochs G, Hug H, Marme D and Schachtele C . (1993). J. Biol. Chem., 268, 9194–9197.

  • Masood R, Cai J, Zheng T, Smith DL, Naidu Y and Gill PS . (1997). Proc. Natl. Acad. Sci. USA, 94, 979–984.

  • Meister B, Grunebach F, Bautz F, Brugger W, Fink FM, Kanz L and Mohle R . (1999). Eur. J. Cancer, 35, 445–449.

  • Oberg-Welsh C, Sandler S, Andersson A and Welsh M . (1997). Mol. Cell Endocrinol., 126, 125–132.

  • Podar K, Tai YT, Lin BK, Narsimhan RP, Sattler M, Kijima T, Salgia R, Gupta D, Chauhan D and Anderson KC . (2002). J. Biol. Chem., 277, 7875–7881.

  • Price DJ, Miralem T, Jiang S, Steinberg R and Avraham H . (2001). Cell Growth Differ., 12, 129–135.

  • Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T and Shibuya M . (2001). Blood, 97, 785–791.

  • Selheim F, Holmsen H and Vassbotn FS . (2002). FEBS Lett., 512, 107–110.

  • Shu X, Wu W, Mosteller RD and Broek D . (2002). Mol. Cell. Biol., 22, 7758–7768.

  • Soker S, Takashima S, Miao HQ, Neufeld G and Klagsbrun M . (1998). Cell, 92, 735–745.

  • Sondell M, Lundborg G and Kanje M . (1999). Brain Res., 846, 219–228.

  • Strawn LM, McMahon G, App H, Schreck R, Kuchler WR, Longhi MP, Hui TH, Tang C, Levitzki A, Gazit A, Chen I, Keri G, Orfi L, Risau W, Flamme I, Ullrich A, Hirth KP and Shawver LK . (1996). Cancer Res., 56, 3540–3545.

  • Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G, Puntoni R, Mutti L and Procopio A . (2001). J. Pathol., 193, 468–475.

  • Takahashi T, Shirasawa T, Miyake K, Yahagi Y, Maruyama N, Kasahara N, Kawamura T, Matsumura O, Mitarai T and Sakai O . (1995). Biochem. Biophys. Res. Commun., 209, 218–226.

  • Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M and Wigler M . (1982). Nature, 300, 762–765.

  • Veikkola T, Karkkainen M, Claesson-Welsh L and Alitalo K . (2000). Cancer Res., 60, 203–212.

  • von Marschall Z, Cramer T, Hocker M, Burde R, Plath T, Schirner M, Heidenreich R, Breier G, Riecken EO, Wiedenmann B and Rosewicz S . (2000). Gastroenterology, 119, 1358–1372.

  • Zucker S, Mirza H, Conner CE, Lorenz AF, Drews MH, Bahou WF and Jesty J . (1998). Int. J. Cancer, 75, 780–786.

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Acknowledgements

This work was supported by NIH RO1 Grant # CA50261. We are grateful to Dr Peter Jones at the USC/Norris Comprehensive Cancer Center for providing the cell lines. We are grateful to Dr Darryl Shibata at the USC/Norris Comprehensive Cancer Center for his assistance with genetic identification of T24 cell line.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine at the University of Southern California, 90089, CA, USA

    Weicheng Wu, Xiaodong Shu, Harut Hovsepyan, Raymond D Mosteller & Daniel Broek

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  1. Weicheng Wu
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  2. Xiaodong Shu
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Correspondence to Daniel Broek.

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Wu, W., Shu, X., Hovsepyan, H. et al. VEGF receptor expression and signaling in human bladder tumors. Oncogene 22, 3361–3370 (2003). https://doi.org/10.1038/sj.onc.1206285

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