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 erythropoietin 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.
Highlights
Erythropoietin (Epo) regulates erythropoiesis by binding to its transmembrane receptor, Epo receptor (EpoR) (Wu et al, 1995)
The current study shows for the first time that increased copy number of the Epo and EpoR loci occurs in surprisingly high percentage of primary melanomas; EpoR is functional in a series of in vitro and in vivo assays
No copy number increases of EpoR were found in any of 47 cell lines analyzed by single-nucleotide polymorphism, gain of Epo was identified in 5/47 melanoma cells lines
Summary
Erythropoietin (Epo) regulates erythropoiesis by binding to its transmembrane receptor, Epo receptor (EpoR) (Wu et al, 1995). Following the reports of the results of three additional phase III studies and a phase II trial, all suggesting a statistically significant adverse effect of Epo treatment on survival (Blau, 2007), a ‘black box warning’ was issued for Epo products by the United States Food and Drug Administration (FDA). Some of these studies have been criticized based on inadequate study design and lack of rigorous controls (Jelkmann et al, 2008), a meta-analysis of 57 studies did not find a survival benefit of patients receiving Epo or darbepoetin, but raised the possibility of a negative impact on survival (Bohlius et al, 2009). A more recent meta-analysis of more than 10 000 cancer patients confirmed decreased overall survival in patients treated with Epo (Bennett et al, 2008)
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