Blockade of the vascular endothelial growth factor-receptor 2 pathway inhibits the growth of human renal cell carcinoma, RBM1-IT4, in the kidney but not in the bone of nude mice

  • Authors:
    • Takashi Karashima
    • Keji Inoue
    • Satoshi Fukata
    • Tatsuo Iiyama
    • Atsushi Kurabayashi
    • Chiaki Kawada
    • Taro Shuin
  • View Affiliations

  • Published online on: April 1, 2007     https://doi.org/10.3892/ijo.30.4.937
  • Pages: 937-945
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Abstract

Primary and metastatic RCCs are consistently resistant to radiotherapy, chemotherapy, or immunotherapy. As recurrent or metastatic RCC after surgery is related with poor prognosis and cancer-related death, development of therapeutic modalities that can control RCC and improve patient survival is urgently needed. We determined whether blockade of the vascular endothelial growth factor-receptor 2 (VEGF-R2) signaling pathway inhibits the growth of human renal cell carcinoma cells in the kidney and bone of nude mice. Male nude mice implanted with 1x106 RBM1-IT4 cells in the kidney or in the tibia were treated with oral administrations of TSU-68, anti-VEGF-R2 tyrosine kinase inhibitor beginning 5 days after implantation. The tumor incidence, tumor weight and bone destruction were determined at twelve weeks after commencing the therapy. VEGF production by RCCs was determined by ELISA and alterations in VEGF production related with genetic instability were also analysed. VEGF-R expression of mouse osteoclast precursors (mOCPs) and human umbilical vascular endothelial cell (HUVEC) was determined by RT-PCR and Western immunoblotting. in vitro, the effects of TSU-68 on the cellular proliferation of HUVEC, normal human renal proximal tubule epithelial cell (RPTEC) and mOCPs were determined. RBM1-IT4 cells had loss of heterozygosity and frame shift mutation on chromosome 3p, inactivating the von Hippel-Lindau (VHL) tumor suppressor gene and resulting in the production of relatively higher levels of VEGF than the RCCs without VHL mutation. TSU-68 significantly inhibited the growth of RBM1-IT4 in the kidney (p<0.05). In contrast, TSU-68 did not inhibit the growth of RBM1-IT4 in the tibia or bone lysis. Although HUVEC, RPTEC and mOCPs expressed VEGF-R2, TSU-68 directly inhibited the VEGF-stimulated cell growth of HUVEC and RPTEC but not the mOCPs in vitro. These data indicate that the VEGF-VEGF-R2 pathway is not required for survival of the osteoclasts and anti-VEGF-R2 therapy did not contribute to the suppression of metastatic RCC growth in the bone.

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April 2007
Volume 30 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Karashima, T., Inoue, K., Fukata, S., Iiyama, T., Kurabayashi, A., Kawada, C., & Shuin, T. (2007). Blockade of the vascular endothelial growth factor-receptor 2 pathway inhibits the growth of human renal cell carcinoma, RBM1-IT4, in the kidney but not in the bone of nude mice. International Journal of Oncology, 30, 937-945. https://doi.org/10.3892/ijo.30.4.937
MLA
Karashima, T., Inoue, K., Fukata, S., Iiyama, T., Kurabayashi, A., Kawada, C., Shuin, T."Blockade of the vascular endothelial growth factor-receptor 2 pathway inhibits the growth of human renal cell carcinoma, RBM1-IT4, in the kidney but not in the bone of nude mice". International Journal of Oncology 30.4 (2007): 937-945.
Chicago
Karashima, T., Inoue, K., Fukata, S., Iiyama, T., Kurabayashi, A., Kawada, C., Shuin, T."Blockade of the vascular endothelial growth factor-receptor 2 pathway inhibits the growth of human renal cell carcinoma, RBM1-IT4, in the kidney but not in the bone of nude mice". International Journal of Oncology 30, no. 4 (2007): 937-945. https://doi.org/10.3892/ijo.30.4.937