title: Erythropoietin accelerates tumor growth through increase of erythropoietin receptor (EpoR) as well as by the stimulation of angiogenesis in DLD-1 and Ht-29 xenografts.
abstract: Anemia is a relatively common symptom coexisting with colorectal carcinoma. Besides having a positive impact on hematological parameters, erythropoietin (Epo) has the serious adverse effect of promoting the neoplastic process. The role of Epo in colon cancer has not been clearly shown. The aim of this study was to assess the effects of Epo therapy on colorectal carcinoma cells both in in vitro and in animal models. Human colon adenocarcinoma cells DLD-1 and Ht-29 were cultured in medium with Epo beta in normoxia. Cell proliferation was measured with an automated cell counter. Expression of erythropoietin receptor (EpoR) mRNA, Akt mRNA, and their proteins were assessed by RT-PCR and confocal microscopy, respectively. Nude mice were inoculated with adenocarcinoma cells and treated with a therapeutic dose of Epo. Expression of EpoR, VEGF, Flt-1 and CD31 was evaluated in xenograft tumors. We identified that Epo through EpoR activates Akt, which promotes colon cancer cell growth and proliferation. Epo, and high levels of phosphorylated EpoR, directly accelerates tumor growth through its proliferative and proangiogenic effects. This study demonstrated that Epo had enhanced carcinogenesis through increase of EpoR and Flt-1 expression, and thereby contributed to tumor development. These results suggest that both EpoR-positive and EpoR-negative cancer cells could be regulated by exogenous Epo. However, an increased response to erythropoietin was observed in the EpoR-positive cells. Thus, erythropoietin increases the risk of tumor progression in colon cancer and should not be used to treat anemia in this type of cancer.
authors.affiliation: Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland. aniatan@poczta.onet.pl.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-5189-3334
authors.initials: A
authors.lastname: Tankiewicz-Kwedlo
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.|Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Hermanowicz
authors.affiliation: Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Surażynski
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Rożkiewicz
authors.affiliation: Department of Pathomorphology, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Pryczynicz
authors.affiliation: Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Domaniewski
authors.affiliation: Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Pawlak
authors.affiliation: Department of Pathomorphology, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Kemona
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, Bialystok, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Pawlak
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D017467:Receptors, Erythropoietin / Q000378:metabolism*
chemical_list: C554270:EPO protein, human; D009363:Neoplasm Proteins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin
keywords: Colon cancer; Erythropoietin; Erythropoietin receptor; Vascular endothelial growth factor receptor