Paracrine Suppression of VEGF Secretion by Erythropoietin Inhibits Tumor Growth.

Several studies have reported that erythropoietin (Epo) is a pleiotropic cytokine with biological properties in addition to its primary function in regulating maturation, growth and survival along the erythroid lineage. Recently, a number of investigators have reported that various neoplastic tissues and human cancer cell lines express Epo and the Epo receptor (EpoR), raising suspicion for the presence of an autocrine-paracrine Epo-EpoR system. It has been shown that inhibition of vascular endothelial growth factor (VEGF) results in an increase of Epo secretion and increased hematocrit in vivo. In this study, we used an in vivo Lewis lung carcinoma model to examine a converse Epo effect on VEGF production and metastasis. Lewis lung carcinoma (LLC) cells were injected subcutaneously into C57BL mice. The plasma levels of VEGF, the tumor vessel formation, the size of the primary tumors and the extent of lung metastatic disease were determined. In addition, intravenously injected LLC cells seeded in the lungs were assessed. Tumor-bearing animals treated with Epo had 23.6% less VEGF in the plasma compared to saline treated mice (p<0.04). There was no correlation between VEGF concentration and hemoglobin levels in either group of animals. Tumor sections indicated that the number of blood vessels was higher (10.7% for inner and 23.8% for outer, respectively) in tumors obtained from animals treated with saline compared to Epo-treated mice (p>0.05). Using non-parametric analysis, we found that there was a statistically significant difference in tumor growth between saline-treated and Epo-treated animals (p<0.05). However, the number of lung metastases derived from primary tumors was similar in both groups. In assessing size of the metastatic tumors, we found that the average volume of lung nodules was 24.2% higher in saline-injected animals compared to Epo-treated mice. The number of tumors seeded in the lungs following intravenous injection of LLC cells was similar in animals treated with a high dosage of Epo, low dosage of Epo or saline. In addition, the average volume of the nodules was reduced by 42% in animals treated with high and low concentrations of Epo compared to the control group (p = 0.03). In conclusion, Epo exerts a paracrine suppressive effect on VEGF secretion resulting in slower tumor growth in this model.