Darbepoetin promotes tumor growth and angiogenesis of colorectal liver metastases particularly after liver resection

Abstract

Background: After major hepatectomy, postoperative hepatic failure still remains a serious problem. In experimental models, erythropoietin (EPO) and its analogue darbepoetin (DPO) have been shown to improve liver function and liver regeneration. In case of malignant hepatic tumors, the use of EPO is still controversially discussed, suggesting that EPO could stimulate growth of remnant micrometastases leading to early tumor relapse. We therefore studied the influence of DPO-treatment on tumor growth in a model of experimental colorectal liver metastasis. Methods: BALB/c mice received 1×10⁵ syngeneic CT26.WT colorectal cancer cells into the left liver lobe and were randomized into 4 groups: the first group received portalvenous injection (i.p.) of 10μ/kg DPO; the second group received PBS i.p. and served as control; the third group underwent a 50% hepatectomy (Phx) and received PBS i.p.; the fourth group underwent Phx and received 10μ/kg DPO i.p. After 7 days, tumor growth, angiogenesis and leukocyte adhesion were analyzed using intravital fluorescence microscopy. Results: After tumor cell implantation, DPO induced a slight, but not significant increase of tumor volume compared to controls, whereas Phx significantly stimulated tumor growth. Application of DPO after Phx caused an additional stimulation of tumor growth with a significantly increased tumor volume compared to Phx only. DPO also induced tumor angiogenesis and significantly increased microvascular density compared to controls. DPO after Phx also caused an increase of capillary density compared to Phx only. DPO treatment significantly reduced leukocyte adhesion within the tumors as compared to controls. After Phx, leukocyte adhesion within the tumor mass was significantly enhanced, whereas additional DPO treatment again inhibited leukocyte adhesion. Conclusion: Our study indicates that DPO stimulates tumor growth especially after liver resection due to an increase of angiogenesis within the colorectal metastases.