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Erythropoietin receptor contributes to melanoma cell survival in vivo

Oncogene volume 31, pages 1649–1660 (2012)Cite this article

Abstract

Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.

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Acknowledgements

We are grateful to M Herlyn from the Wistar Institute for providing melanoma cell lines. Financial support was provided by CA-093372, CA-116103, AR-054593 and Melanoma Research Foundation (to X Xu) and CA-100844 (to MO Arcasoy).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    S M Kumar, A Pushparajan & X Xu

  2. The Wistar Institute, Philadelphia, PA, USA

    G Zhang

  3. Departments of Dermatology and Pathology, University of California, San Francisco, CA, USA

    B C Bastian

  4. Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    M O Arcasoy

  5. Departments of Chemical and Biological Engineering, Rensselaer Polytechnology Institute, Troy, NY, USA

    P Karande

  6. Departments of Anatomic Pathology and Women's Oncology, Moffitt Cancer, Center, Tampa, FL, USA

    G Acs

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Correspondence to X Xu.

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Kumar, S., Zhang, G., Bastian, B. et al. Erythropoietin receptor contributes to melanoma cell survival in vivo. Oncogene 31, 1649–1660 (2012). https://doi.org/10.1038/onc.2011.366

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