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Article

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells

  • Authors:
    • Chisato Tomida
    • Naoko Yamagishi
    • Hikaru Nagano
    • Takayuki Uchida
    • Ayako Ohno
    • Katsuya Hirasaka
    • Takeshi Nikawa
    • Shigetada Teshima-Kondo
  • View Affiliations / Copyright

    Affiliations: Department of Physiological Nutrition, Institute of Medical Nutrition, University of Tokushima Graduate School, Kuramoto, Tokushima 770-8503, Japan, Department of Anatomy and Cell Biology, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama 641-8509, Japan, Department of Clinical Nutrition, Osaka Prefecture University Graduate School, Habikino, Osaka 583-8555, Japan, Graduate School of Fisheries Science and Environmental Studies, Nagasaki University, Nagasaki, Nagasaki 852-8521, Japan
  • Pages: 1350-1362
    |
    Published online on: February 28, 2018
       https://doi.org/10.3892/ijo.2018.4291
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Abstract

Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) are important treatments for a number of human malignancies, including colorectal cancers. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. The mechanism by which the cancer cells become resistant remains unclear. One potential mechanism is that VEGF/VEGF-R blockers directly act on tumor cells independently of anti-angiogenic effects. In this study, the direct effects of an anti-VEGF antibody (bevacizumab) and a VEGF-R tyrosine kinase inhibitor (sunitinib) on the evasive adaptation of colon cancer cells were compared. HCT116 and RKO human colon cancer cell lines were chronically exposed (3 months) to bevacizumab or sunitinib in vitro to establish bevacizumab- and sunitinib-adapted cells, respectively. Transwell migration and invasion assays, western blotting, reverse transcription-quantitative polymerase chain reaction, co-immunoprecipitation analysis, cell survival assays and ELISAs were conducted to analyze the adapted cells. Compared with the control vehicle-treated cells, the two cell models exhibited increased migration and invasion activities to different degrees and through different mechanisms. The bevacizumab-adapted cells, but not in the sunitinib-adapted cells, exhibited redundantly increased expression levels of VEGF/VEGF-R family members, including VEGF-A, placental growth factor, VEGF-C, VEGF-R1 and VEGF-R3. In addition, the phosphorylation levels of VEGF-R1 and VEGF-R3 were increased in the bevacizumab-adapted cells compared with the control cells. Thus, the inhibition of VEGF-R1 and VEGF-R3 decreased the evasive activities of the cells, suggesting that they remained dependent on redundant VEGF/VEGF-R signaling. By contrast, the sunitinib-adapted cells exhibited increased neuropilin-1 (NRP1) expression levels compared with the control cells. In the sunitinib-adapted cells, NRP1 interacted with phosphorylated cMet, and the cMet activation was dependent on NRP1. Thus, NRP1 or cMet blockade suppressed the evasive activation of the sunitinib-adapted cells. These results suggest that the sunitinib-adapted cells switched from a VEGF-R-dependent pathway to an alternative NRP1/cMet-dependent one. The findings of the present study indicate that VEGF/VEGF-R inhibitors directly act on colon cancer cells and activate their evasive adaptation via different mechanisms.
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Copy and paste a formatted citation
Spandidos Publications style
Tomida C, Yamagishi N, Nagano H, Uchida T, Ohno A, Hirasaka K, Nikawa T and Teshima-Kondo S: VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. Int J Oncol 52: 1350-1362, 2018.
APA
Tomida, C., Yamagishi, N., Nagano, H., Uchida, T., Ohno, A., Hirasaka, K. ... Teshima-Kondo, S. (2018). VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. International Journal of Oncology, 52, 1350-1362. https://doi.org/10.3892/ijo.2018.4291
MLA
Tomida, C., Yamagishi, N., Nagano, H., Uchida, T., Ohno, A., Hirasaka, K., Nikawa, T., Teshima-Kondo, S."VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells". International Journal of Oncology 52.4 (2018): 1350-1362.
Chicago
Tomida, C., Yamagishi, N., Nagano, H., Uchida, T., Ohno, A., Hirasaka, K., Nikawa, T., Teshima-Kondo, S."VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells". International Journal of Oncology 52, no. 4 (2018): 1350-1362. https://doi.org/10.3892/ijo.2018.4291
Copy and paste a formatted citation
x
Spandidos Publications style
Tomida C, Yamagishi N, Nagano H, Uchida T, Ohno A, Hirasaka K, Nikawa T and Teshima-Kondo S: VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. Int J Oncol 52: 1350-1362, 2018.
APA
Tomida, C., Yamagishi, N., Nagano, H., Uchida, T., Ohno, A., Hirasaka, K. ... Teshima-Kondo, S. (2018). VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells. International Journal of Oncology, 52, 1350-1362. https://doi.org/10.3892/ijo.2018.4291
MLA
Tomida, C., Yamagishi, N., Nagano, H., Uchida, T., Ohno, A., Hirasaka, K., Nikawa, T., Teshima-Kondo, S."VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells". International Journal of Oncology 52.4 (2018): 1350-1362.
Chicago
Tomida, C., Yamagishi, N., Nagano, H., Uchida, T., Ohno, A., Hirasaka, K., Nikawa, T., Teshima-Kondo, S."VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells". International Journal of Oncology 52, no. 4 (2018): 1350-1362. https://doi.org/10.3892/ijo.2018.4291
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