Effect of erythropoietin on human tumor growth in xenograft models

Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan. .
Molecular Medicine Reports (Impact Factor: 1.55). 01/2009; 3(1):95-101. DOI: 10.3892/mmr_00000224
Source: PubMed


Recombinant human erythropoietin (rhEPO) has been used in the EU and the United States for the treatment of anemia in cancer patients after myelosuppressive chemotherapy or radiotherapy. However, several conflicting results have been reported concerning the detrimental effect of rhEPO on survival benefit in cancer patients. In experimental studies, contradictory results were also reported in in vitro tumor cell proliferation studies and in vivo tumor growth studies using tumor cells expressing EPO-receptor (EPO-R). Therefore, we tried to clarify the effect of epoetin β, a product of rhEPO, on tumor growth in xenograft models using five EPO-R-positive human cancer cell lines, namely the MCF7 breast, 786-O renal, SCH gastric, A549 lung and SK-OV-3 ovarian cancer cell lines. Epoetin β was administered once a week for 3 weeks at doses of 1,000, 3,000 and 10,000 IU/kg in accordance with the clinical administration schedule and dosages. As a result, no enhancement of tumor growth from the administration of epoetin β was observed in any of the xenograft models throughout the experiment duration. The effect of epoetin β on the antitumor activity of bevacizumab, an anti-angiogenic agent, was additionally examined using A549 and MCF7 xenograft models, since rhEPO reportedly stimulates tumor neovascularization. Epoetin β showed no significant effect on the antitumor activity of bevacizumab in either xenograft model. These findings suggest that epoetin β is not involved in in vivo tumor growth promotion.

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    • "One report indicated that rHuEpo alone had no effect on MCF-7 cell growth in animals, but that tumor size increased in trastuzumab-treated animals [66]. However, as noted above, MCF-7 cells express minimal levels of EpoR and in studies by other groups, treating MCF-7 cells with Epo failed to interfere with the antiproliferative and/or cytotoxic effects of either bevacizumab or paclitaxel [67, 68]. "
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    ABSTRACT: Testing for the presence of specific cell-surface receptors (such as EGFR or HER2) on tumor cells is an integral part of cancer care in terms of treatment decisions and prognosis. Understanding the strengths and limitations of these tests is important because inaccurate results may occur if procedures designed to prevent false-negative or false-positive outcomes are not employed. This review discusses tests commonly used to identify and characterize cell-surface receptors, such as the erythropoietin receptor (EpoR). First, a summary is provided on the biology of the Epo/EpoR system, describing how EpoR is expressed on erythrocytic progenitors and precursors in the bone marrow where it mediates red blood cell production in response to Epo. Second, studies are described that investigated whether erythropoiesis-stimulating agents could stimulate tumor progression in cancer patients and whether EpoR is expressed and functional on tumor cells or on endothelial cells. The methods used in these studies included immunohistochemistry, Northern blotting, Western blotting, and binding assays. This review summarizes the strengths and limitations of these methods. Critically analyzing data from tests for cell-surface receptors such as EpoR requires understanding the techniques utilized and demonstrating that results are consistent with current knowledge about receptor biology.
    Annals of Hematology 12/2013; 93(2). DOI:10.1007/s00277-013-1947-2 · 2.63 Impact Factor
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    • "Indeed, some in vitro studies have demonstrated that Epo enhances tumor proliferation [Westenfelder and Baranowski, 2000; Acs et al., 2001; Yasuda et al., 2003; Feldman et al., 2006]. However, others have demonstrated that no effects of Epo on tumor growth were observed in vitro [Dunlop et al., 2006; Jeong et al., 2008], and in vivo [Kataoka et al., 2010]. Our current study failed to reveal any stimulatory effects of Epo on tumor growth, however, we did find that Epo inhibits PCa cell apoptosis. "
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    ABSTRACT: Erythropoietin (Epo) is used in clinical settings to enhance hematopoietic function and to improve the quality of life for patients undergoing chemotherapy by reducing fatigue and the need for transfusions. However, several meta-analyses have revealed that Epo treatments are associated with an increased risk of mortality in cancer patients. In this study, we examined the role of Epo in prostate cancer (PCa) progression, using in vitro cell culture systems and in vivo bone metastatic assays. We found that Epo did not stimulate the proliferation of PCa cell lines, but did protect PCa cells from apoptosis. In animal models of PCa metastasis, no evidence was found to support the hypothesis that Epo enhances metastasis. Together, these findings suggest that Epo may be useful for treating severe anemia in PCa patients without increasing metastatic risk. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 11/2013; 114(11). DOI:10.1002/jcb.24592 · 3.26 Impact Factor
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    ABSTRACT: Erythropoiesis-stimulating agents (ESAs) stimulate formation of red blood cells by binding to and activating Epo receptors (EpoR) on erythroid progenitor cells. Beyond successful treatment of anemia, ESAs have been reported to reduce damage following insult to organs, including the kidney, possibly via direct activation of EpoR. However, data on ESA effects outside hematopoietic functions are conflicting. Furthermore, limited use of appropriate EpoR-positive and EpoR-negative controls and lack of specific anti-EpoR antibodies make interpretation of data difficult. Recently positive and negative control cell types were validated and a sensitive and specific anti-EpoR antibody (A82) that detects low levels of EpoR protein was described. A82 was used to measure EpoR protein levels in tissues, human renal cells and human cell lines by western blot analysis. Surface EpoR was examined on renal cells by measuring binding of [125I]-rHuEpo or antibodies. Renal cells and cell lines were treated with rHuEpo to see if phosphorylation of signaling proteins or proliferation/survival could be induced. Small inhibitory RNA (siRNA) were used to determine if EpoR knockdown affected cell viability. Total EpoR protein was low to undetectable in tissues and renal cells with no detectable EpoR on cell surfaces. EpoR knockdown had no effect on viability of renal cell lines. RHuEpo had no detectable effect on intracellular signaling on renal cell lines with no growth-promoting or survival effect on primary human renal cells. These results suggest that functional EpoR protein is absent on renal cells and that non-EpoR mechanisms should be explored to explain non-hematopoietic effects of ESAs.
    Nephrology Dialysis Transplantation 12/2011; 27(7):2733-45. DOI:10.1093/ndt/gfr698 · 3.58 Impact Factor
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