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.
Highlights
Erythropoietin (Epo) is a glycoprotein that stimulates erythrocyte production and maturation
These results show that erythropoietin in erythropoietin receptor (EpoR)-positive xenografts through increase of vascular endothelial growth factor (VEGF) and Flt-1 expressions may contribute to tumor development by promoting angiogenesis
We examined the expression of EpoR and Akt in adenocarcinoma cells as well as EpoR, VEGF, Flt-1, and CD31 expression in xenografts
Summary
Erythropoietin (Epo) is a glycoprotein that stimulates erythrocyte production and maturation. It is composed of 166 amino acids of a molecular weight of about 34 kD (depending on carbohydrate content) and is mainly (80–90 %) produced by renal interstitial cells. Colorectal carcinoma is a tremendous social problem. It is the second largest, after lung cancer, threat of modern oncology. The growth rate of colorectal carcinoma incidence in Poland is the highest in Europe. Anemia is a relatively common symptom coexisting with malignancy. It is a significant clinical problem occurring in approximately 60–90 % of patients with cancer, and in nearly 30 % of
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