Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma

Aims: To correlate microvascular density and erythropoietin (Epo)/Epo‐receptor (EpoR) expression in endothelial and tumour cells with histopathological type in hepatocellular carcinoma (HCC). Methods and results: Specimens of primary HCC obtained from 50 patients who had undergone curative hepatectomy were investigated immunohistochemically by using anti‐CD31, anti‐Epo and anti‐EpoR antibodies. Poorly differentiated HCC had a higher degree of vascularization than other stages and Epo/EpoR expression in both tumour and endothelial cells increased in parallel with grade of malignancy and was highly correlated with the extent of angiogenesis. Conclusions: Epo/EpoR levels correlate with angiogenesis and progression of patients with HCC and these findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by hepatic tumour cells and it affects vascular endothelial cells via its receptors and promotes angiogenesis in a paracrine manner. It is thus suggested that Epo is an important factor in hepatic tumour angiogenesis. Understanding the mechanisms of HCC angiogenesis provides a basis for a rational approach to the development of antiangiogenic therapy in patients with hepatic cancer.