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‘Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma’

Oncogene volume 28, pages 4147–4161 (2009)Cite this article

Abstract

Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein that displays broad anti-tumor activity based on dual targeting of the tumor microenvironment (anti-angiogenic action) and the tumor cells (direct anti-tumor action). Here, we show that PEDF expression is high in melanocytes, but it is lost during malignant progression of human melanoma. Using a high-throughput analysis of the data from microarray studies of molecular profiling of human melanoma, we found that PEDF expression is lost in highly invasive melanomas. In paired cell lines established from the same lesion but representing the high and low extremes of malignant potential, abundant PEDF expression was restricted to the poorly aggressive counterparts. We used RNA interference to directly address the functional consequences of PEDF silencing. PEDF knockdown in poorly aggressive melanoma cell lines augmented migration, invasion and vasculogenic mimicry, which translated into an increased in vivo metastatic potential. PEDF interference also significantly enhanced the migratory and invasive capability of normal melanocytes and moderately increased their proliferative potential. Our results show that loss of PEDF enables melanoma cells to acquire an invasive phenotype and, therefore, modulation of this multifunctional factor could be critical for the malignant progression of human melanoma.

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Acknowledgements

We acknowledge with gratitude all researchers that contributed with cell lines: M Herlyn, PF Peñas, F Vidal-Vanaclocha, GN Van Muijen, AM Valverde, M Garcia and M del Rio. We also thank P Fernández for her technical assistance in lentivirus production. Supported by grants: Ministerio de Educación y Ciencia grant SAF2007-62292 (BJ), Comunidad de Madrid SAL-0311-2006 (BJ), NIH grant RO1 HL68033 (OV), NIH merit grant CA59702 (MJCH). JL Orgaz has been supported by a Ministerio de Educación y Ciencia fellowship, O Ladhani by an NIH/NCI training grant T32CA009560 and A Fernández-Barral by a Consejo Superior de Investigaciones Científicas fellowship.

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Authors and Affiliations

  1. Department of Biochemistry, Universidad Autónoma de Madrid and Instituto de Investigaciones Biomédicas CSIC-UAM, Madrid, Spain

    J L Orgaz, A Fernández-Barral, O Aguilera & B Jiménez

  2. Department of Urology, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    O Ladhani & O V Volpert

  3. Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland

    K S Hoek

  4. Department of Pathology, University Hospital of Zürich, Zürich, Switzerland

    D Mihic

  5. Children's Memorial Research Center, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    E A Seftor & M J C Hendrix

  6. Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain

    A Bernad

  7. Department of Pathology, Hospital Universitario 12 de Octubre de Madrid, Madrid, Spain

    J L Rodríguez-Peralto

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  1. J L Orgaz
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Correspondence to B Jiménez.

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

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Orgaz, J., Ladhani, O., Hoek, K. et al. ‘Loss of pigment epithelium-derived factor enables migration, invasion and metastatic spread of human melanoma’. Oncogene 28, 4147–4161 (2009). https://doi.org/10.1038/onc.2009.284

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  • DOI: https://doi.org/10.1038/onc.2009.284

Keywords

  • PEDF
  • melanoma progression
  • vasculogenic mimicry
  • anti-angiogenic factors

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