Human erythropoietin increases the pro-angiogenic potential of A2780 ovarian adenocarcinoma cells under hypoxic conditions

Kriška,Ján; Solár,Peter; Varinská,Lenka; Solárová,Zuzana; Kimáková,Patrícia; Mojžiš,Ján; Fedoročko,Peter; Sytkowski,Arthur  J.

doi:10.3892/or.2013.2566

Human erythropoietin increases the pro-angiogenic potential of A2780 ovarian adenocarcinoma cells under hypoxic conditions

Authors:
- Ján Kriška
- Peter Solár
- Lenka Varinská
- Zuzana Solárová
- Patrícia Kimáková
- Ján Mojžiš
- Peter Fedoročko
- Arthur J. Sytkowski
View Affiliations

Affiliations: Institute of Biology and Ecology, Faculty of Science, P.J. Šafárik University, Košice, Slovak Republic, Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovak Republic, Geriatric Nursing Clinic, Faculty of Medicine, P.J. Šafárik University, Košice, Slovak Republic, Oncology Therapeutic Area, Therapeutic Delivery Unit, Quintiles Transnational, Rockville, MD, USA
Published online on: June 26, 2013 https://doi.org/10.3892/or.2013.2566
Pages: 1455-1462

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Erythropoietin (Epo) is a key regulator of erythroid cell proliferation, differentiation and apoptosis. In the form of the recombinant protein, it is widely used to treat various types of anemias, including that associated with cancer and with the myelosuppressive effects of chemotherapy, particularly platinum-based regimens. Our previous studies confirmed the presence of Epo receptors (EpoRs) in ovarian adenocarcinoma cell lines and demonstrated that long-term Epo treatment of A2780 cells resulted in the development of a phenotype exhibiting both enhanced Epo signaling and increased paclitaxel resistance. In the present study, we carried out a series of experiments to analyze the pro-angiogenic potential of Epo-treated A2780 and SKOV-3 cells. Our studies revealed that conditioned media of Epo-treated A2780 cells had a stimulative effect on human umbilical vein endothelial cells (HUVECs). This effect was only seen when A2780 cells were incubated under hypoxic conditions. Furthermore, Epo increased the secretion of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, GM-CSF and interferon-γ by A2780 cells that grew in hypoxic conditions. In this regard, conditioned media of hypoxic and Epo-treated A2780 cells induced a significant phosphorylation of STAT-5 in HUVECs. Our results may have important implications for ovarian cancer patients receiving Epo.

View Figures

View References

1	Sytkowski AJ: Erythropoietin: Blood, Brain and Beyond. Wiley-VCH; Weinheim: 2004, View Article : Google Scholar
2	Miller CP, Lowe KA, Valliant-Saunders K, et al: Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. Stem Cells. 27:2353–2361. 2009. View Article : Google Scholar
3	Swift S, Ellison AR, Kassner P, et al: Absence of functional EpoR expression in human tumor cell lines. Blood. 115:4254–4263. 2010. View Article : Google Scholar : PubMed/NCBI
4	Jeong JY, Feldman L, Solar P, Szenajch J and Sytkowski AJ: Characterization of erythropoietin receptor and erythropoietin expression and function in human ovarian cancer cells. Int J Cancer. 122:274–280. 2008. View Article : Google Scholar : PubMed/NCBI
5	Paragh G, Kumar SM, Rakosy Z, Choi SC, Xu X and Acs G: RNA interference-mediated inhibition of erythropoietin receptor expression suppresses tumor growth and invasiveness in A2780 human ovarian carcinoma cells. Am J Pathol. 174:1504–1514. 2009. View Article : Google Scholar
6	Solar P, Hrckova G, Varinska L, et al: Location and the functionality of erythropoietin receptor(s) in A2780 cells. Oncol Rep. 28:141–146. 2012.PubMed/NCBI
7	Szenajch J, Wcislo G, Jeong JY, Szczylik C and Feldman L: The role of erythropoietin and its receptor in growth, survival and therapeutic response of human tumor cells From clinic to bench - a critical review. Biochim Biophys Acta. 1806:82–95. 2010.PubMed/NCBI
8	Anagnostou A, Lee ES, Kessimian N, Levinson R and Steiner M: Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci USA. 87:5978–5982. 1990. View Article : Google Scholar : PubMed/NCBI
9	Carlini RG, Dusso AS, Obialo CI, Alvarez UM and Rothstein M: Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. Kidney Int. 43:1010–1014. 1993. View Article : Google Scholar : PubMed/NCBI
10	Carlini RG, Reyes AA and Rothstein M: Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int. 47:740–745. 1995. View Article : Google Scholar : PubMed/NCBI
11	Anagnostou A, Liu Z, Steiner M, et al: Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA. 91:3974–3978. 1994.PubMed/NCBI
12	Yamaji R, Okada T, Moriya M, et al: Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA. Eur J Biochem. 239:494–500. 1996. View Article : Google Scholar : PubMed/NCBI
13	Yasuda Y, Masuda S, Chikuma M, Inoue K, Nagao M and Sasaki R: Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem. 273:25381–25387. 1998.PubMed/NCBI
14	Ribatti D, Presta M, Vacca A, et al: Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood. 93:2627–2636. 1999.PubMed/NCBI
15	Haroon ZA, Amin K, Jiang X and Arcasoy MO: A novel role for erythropoietin during fibrin-induced wound-healing response. Am J Pathol. 163:993–1000. 2003. View Article : Google Scholar : PubMed/NCBI
16	Kertesz N, Wu J, Chen TH, Sucov HM and Wu H: The role of erythropoietin in regulating angiogenesis. Dev Biol. 276:101–110. 2004. View Article : Google Scholar : PubMed/NCBI
17	Yasuda Y, Fujita Y, Musha T, et al: Expression of erythropoietin in human female reproductive organs. Ital J Anat Embryol. 106(Suppl 2): S215–S222. 2001.PubMed/NCBI
18	Yasuda Y, Fujita Y, Masuda S, et al: Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs. Carcinogenesis. 23:1797–1805. 2002. View Article : Google Scholar
19	Nakamatsu K, Nishimura Y, Suzuki M, Kanamori S, Maenishi O and Yasuda Y: Erythropoietin/erythropoietin-receptor system as an angiogenic factor in chemically induced murine hepatic tumors. Int J Clin Oncol. 9:184–188. 2004. View Article : Google Scholar : PubMed/NCBI
20	Nico B, Annese T, Guidolin D, Finato N, Crivellato E and Ribatti D: Epo is involved in angiogenesis in human glioma. J Neurooncol. 102:51–58. 2011. View Article : Google Scholar : PubMed/NCBI
21	Kumar SM, Zhang G, Bastian BC, et al: Erythropoietin receptor contributes to melanoma cell survival in vivo. Oncogene. 31:1649–1660. 2012. View Article : Google Scholar : PubMed/NCBI
22	Okazaki T, Ebihara S, Asada M, Yamanda S, Niu K and Arai H: Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival of tumor-bearing mice by enhancing angiogenesis. Neoplasia. 10:932–939. 2008.PubMed/NCBI
23	Ribatti D, Marzullo A, Gentile A, et al: Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma. Histopathology. 50:591–596. 2007. View Article : Google Scholar : PubMed/NCBI
24	Ribatti D, Nico B, Perra MT, et al: Erythropoietin is involved in angiogenesis in human primary melanoma. Int J Exp Pathol. 91:495–499. 2010. View Article : Google Scholar : PubMed/NCBI
25	Li HG, Li JS, Chen WL, Wang L, Wu DH and Lin ZY: Prognostic significance of erythropoietin and erythropoietin receptor in tongue squamous cell carcinoma. Br J Oral Maxillofac Surg. 47:470–475. 2009. View Article : Google Scholar : PubMed/NCBI
26	Ribatti D: Erythropoietin and tumor angiogenesis. Stem Cells Dev. 19:1–4. 2010. View Article : Google Scholar
27	Wang L, Li HG, Xia ZS, Wen JM and Lv J: Prognostic significance of erythropoietin and erythropoietin receptor in gastric adenocarcinoma. World J Gastroenterol. 17:3933–3940. 2011. View Article : Google Scholar : PubMed/NCBI
28	Van Hinsbergh VW, Sprengers ED and Kooistra T: Effect of thrombin on the production of plasminogen activators and PA inhibitor-1 by human foreskin microvascular endothelial cells. Thromb Haemost. 57:148–153. 1987.PubMed/NCBI
29	Defilippi P, van Hinsbergh V, Bertolotto A, Rossino P, Silengo L and Tarone G: Differential distribution and modulation of expression of alpha 1/beta 1 integrin on human endothelial cells. J Cell Biol. 114:855–863. 1991. View Article : Google Scholar : PubMed/NCBI
30	Arcasoy MO, Jiang X and Haroon ZA: Expression of erythropoietin receptor splice variants in human cancer. Biochem Biophys Res Commun. 307:999–1007. 2003. View Article : Google Scholar : PubMed/NCBI
31	Westenfelder C and Baranowski RL: Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int. 58:647–657. 2000. View Article : Google Scholar : PubMed/NCBI
32	Lai SY, Childs EE, Xi S, et al: Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene. 24:4442–4449. 2005. View Article : Google Scholar
33	Feldman L, Wang Y, Rhim JS, Bhattacharya N, Loda M and Sytkowski AJ: Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells. Prostate. 66:135–145. 2006. View Article : Google Scholar : PubMed/NCBI
34	Selzer E, Wacheck V, Kodym R, et al: Erythropoietin receptor expression in human melanoma cells. Melanoma Res. 10:421–426. 2000. View Article : Google Scholar : PubMed/NCBI
35	Ferrara N: VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2:795–803. 2002. View Article : Google Scholar : PubMed/NCBI
36	Solar P, Koval J, Mikes J, et al: Erythropoietin inhibits apoptosis induced by photodynamic therapy in ovarian cancer cells. Mol Cancer Ther. 7:2263–2271. 2008. View Article : Google Scholar : PubMed/NCBI
37	Karar J and Maity A: PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 4:512011. View Article : Google Scholar : PubMed/NCBI
38	Solar P, Feldman L, Jeong JY, Busingye JR and Sytkowski AJ: Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel-resistant phenotype. Int J Cancer. 122:281–288. 2008. View Article : Google Scholar
39	Hale SA, Wong C and Lounsbury KM: Erythropoietin disrupts hypoxia-inducible factor signaling in ovarian cancer cells. Gynecol Oncol. 100:14–19. 2006. View Article : Google Scholar : PubMed/NCBI
40	Haller H, Christel C, Dannenberg L, Thiele P, Lindschau C and Luft FC: Signal transduction of erythropoietin in endothelial cells. Kidney Int. 50:481–488. 1996. View Article : Google Scholar : PubMed/NCBI
41	Janmaat ML, Heerkens JL, de Bruin AM, Klous A, de Waard V and de Vries CJ: Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood. 115:1453–1460. 2010. View Article : Google Scholar
42	Sonoda T, Kobayashi H, Kaku T, Hirakawa T and Nakano H: Expression of angiogenesis factors in monolayer culture, multicellular spheroid and in vivo transplanted tumor by human ovarian cancer cell lines. Cancer Lett. 196:229–237. 2003. View Article : Google Scholar : PubMed/NCBI
43	Lidor YJ, Xu FJ, Martinez-Maza O, et al: Constitutive production of macrophage colony-stimulating factor and interleukin-6 by human ovarian surface epithelial cells. Exp Cell Res. 207:332–339. 1993. View Article : Google Scholar : PubMed/NCBI
44	Di Blasio AM, Carniti C, Vigano P and Vignali M: Basic fibroblast growth factor and ovarian cancer. J Steroid Biochem Mol Biol. 53:375–379. 1995.PubMed/NCBI
45	Versnel MA, Haarbrink M, Langerak AW, et al: Human ovarian tumors of epithelial origin express PDGF in vitro and in vivo. Cancer Genet Cytogenet. 73:60–64. 1994. View Article : Google Scholar : PubMed/NCBI
46	Negus RP, Stamp GW, Relf MG, et al: The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer. J Clin Invest. 95:2391–2396. 1995. View Article : Google Scholar
47	Savarese TM, Mitchell K, McQuain C, et al: Coexpression of granulocyte colony stimulating factor and its receptor in primary ovarian carcinomas. Cancer Lett. 162:105–115. 2001.PubMed/NCBI
48	Glezerman M, Mazot M, Maymon E, et al: Tumor necrosis factor-alpha and interleukin-6 are differently expressed by fresh human cancerous ovarian tissue and primary cell lines. Eur Cytokine Netw. 9:171–179. 1998.PubMed/NCBI
49	Gorelik E, Landsittel DP, Marrangoni AM, et al: Multiplexed immunobead-based cytokine profiling for early detection of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 14:981–987. 2005. View Article : Google Scholar
50	Muller L and Pawelec G: Cytokines and antitumor immunity. Technol Cancer Res Treat. 2:183–194. 2003. View Article : Google Scholar : PubMed/NCBI
51	Coward J, Kulbe H, Chakravarty P, et al: Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res. 17:6083–6096. 2011. View Article : Google Scholar
52	Kohno T, Mizukami H, Suzuki M, et al: Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer. Cancer Res. 63:5091–5094. 2003.PubMed/NCBI
53	Volpert OV, Fong T, Koch AE, et al: Inhibition of angiogenesis by interleukin 4. J Exp Med. 188:1039–1046. 1998. View Article : Google Scholar : PubMed/NCBI
54	Akhtar N, Padilla ML, Dickerson EB, et al: Interleukin-12 inhibits tumor growth in a novel angiogenesis canine hemangiosarcoma xenograft model. Neoplasia. 6:106–116. 2004. View Article : Google Scholar : PubMed/NCBI