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Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling

Oncogene volume 27, pages 3923–3934 (2008)Cite this article

Abstract

The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the ‘stemness’-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction. In HOS, these changes are associated with the transformation of a non-tumorigenic osteosarcoma SP fraction to a highly tumorigenic phenotype. Inhibition of Flt1 led to complete reduction of tumorigenicity in the HOS SP fraction, and reduction of clonogenic capacity and expression of stemness genes in the SK-N-BE(2) and RH-4 SP fractions. Treatment with U0126, a specific inhibitor of MAPK/ERK1,2 completely downregulates CDDP-induced VEGF and Flt1 expression and induction/expansion of SP fraction in all three cell lines, indicating that these effects are mediated through MAPK/ERK1,2 signaling. In conclusion, we report a novel mechanism of CDDP-induced tumor progression, whereby the activation of VEGF/Flt1 autocrine signaling leads to the survival and expansion of a highly tumorigenic SP fraction.

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Acknowledgements

This work is supported by the National Cancer Institute of Canada, the Andrew Mizzoni Cancer Research Fund and the Harry and Hannah Fisher Research Fund. RT and BD are supported in part by awards of the Hospital for Sick Children's Research Training Centre and the National Cancer Institute of Canada Fellowship with funds from the Terry Fox Foundation. We thank Dr Meredith Irwin for critical review of the manuscript; Sherry Zhao, Shamim Lotif, Micky Tsui, Reza Mokhtari, Michael Ho, Suzanne McGovern and Ana Novokmet for technical assistance; and the staff of the animal facility of the Hospital for Sick Children for their technical support.

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Author notes

  1. R Tsuchida and B Das: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

    R Tsuchida, B Das, S Baruchel & D Malkin

  2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    B Das, G Koren, S Baruchel & D Malkin

  3. Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada

    H Yeger & P S Thorner

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    H Yeger & P S Thorner

  5. Department of Genetics, Division of Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    M Shibuya

  6. Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada

    S Baruchel & D Malkin

  7. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    D Malkin

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  1. R Tsuchida
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Correspondence to D Malkin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Tsuchida, R., Das, B., Yeger, H. et al. Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling. Oncogene 27, 3923–3934 (2008). https://doi.org/10.1038/onc.2008.38

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