Erythropoietin receptor contributes to melanoma cell survival in vivo

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.

Erythropoietin Stimulates Tumor Growth via EphB4

“…Epo is a pleiotropic cytokine that regulates erythropoiesis, angiogenesis, cytoprotection, and proliferation (Foley, 2008; Glaspy, 2009b). Alarmingly, a growing number of studies have demonstrated that ESA-based treatment can compromise overall survival of cancer patients (Crouch and DeSantis, 2009; Kumar et al, 2012; Tovari et al, 2008; Wang et al, 2011), raising the possibility of growth-stimulatory effects on cancer cells via the canonical Epo receptor (EpoR) (Aapro et al, 2012; Chateauvieux et al, 2011; Hedley et al, 2011; McKinney and Arcasoy, 2011; Rathod and Salahudeen, 2011). However, EpoR expression on cancer cells has largely failed to explain the effects of rhEpo on tumor growth.…”

Characterization of the erythropoietin/erythropoietin receptor axis in a rat model of liver damage and cholangiocarcinoma development

“…However, the functional role of EPO in tumor biology is still far from being fully understood. In spite of a growing amount of in vitro and in vivo studies (Shi et al 2010;Kumar et al 2011) that associate the presence of EpoR with the promotion of cancer cells proliferation and invasion, a linear correlation between EpoR activation and an efficient responsiveness to exogenous EPO administration has not been established.…”

VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells

“…The WM35 cell line was originally derived from a melanoma lesion at the Radial Growth Phase when presumably most of the melanoma cells have not acquired the ability to form metastases, while the A2058 cell line was derived from a metastatic lymph node36. A striking difference between WM35 and A2058 cell lines is that the former does not form tumors in xenograft models in mice, while the latter is capable of growing tumors in an immune-compromised mouse model3738. Furthermore, previous studies from our group have characterized these melanoma cell lines based on cell invasiveness and adhesiveness and found that these characteristics correlate with metastatic potential39.…”