Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
Ann Surg. 2010 Jul;252(1):131-41. doi: 10.1097/SLA.0b013e3181e33915.
Liver insufficiency after major hepatectomy still represents a serious challenge in liver surgery. Although some previous studies indicate that erythropoietin (EPO) and its analogue darbepoetin-alpha (DPO) may improve liver function and liver regeneration, little is known on their effect on tumor growth after hepatectomy. Because EPO may promote tumor progression, we herein studied the effect of DPO on tumor growth after major hepatectomy.
CT26.WT colorectal cancer cells were implanted into the left liver lobe of BALB/c mice. Animals underwent 50% hepatectomy (Phx) and received 10 microg/kg DPO-treatment. Additional Phx animals received only saline treatment. Nonhepatectomized animals with DPO-treatment or saline treatment served as controls. One week after hepatectomy angiogenic blood vessel formation, leukocyte-endothelial cell interaction, tumor cell proliferation, apoptotic cell death, and tumor growth were studied using intravital fluorescence microscopy, histology, Immunohistochemistry, and Western blot analysis.
Phx significantly enhanced the growth of liver metastases. This was associated with an increase of tumor capillary density and tumor cell proliferation. In nonhepatectomized animals, DPO only slightly affected metastatic growth. In hepatectomized animals, however, DPO significantly enhanced the Phx-induced stimulation of tumor growth. This was associated with an increased tumor capillary density, a decreased leukocyte-endothelial cell interaction, and a reduced cleaved caspase-3 expression of the CT26.WT cells.
: Our data indicate that DPO significantly enhances the hepatectomy-induced stimulation of colorectal liver metastatic growth by increasing neovascularization, suppressing intratumoral leukocyte recruitment, and reducing tumor cell apoptosis. Thus, EPOs may not be used in patients undergoing hepatectomy for malignant tumor resection.
大肝切除术后的肝功能不全仍然是肝外科的一个严重挑战。尽管一些先前的研究表明促红细胞生成素（EPO）及其类似物达贝泊汀-α（DPO）可能改善肝功能和肝再生，但对于其对肝切除术后肿瘤生长的影响知之甚少。由于 EPO 可能促进肿瘤进展，我们在此研究了 DPO 对大肝切除术后肿瘤生长的影响。
将 CT26.WT 结直肠癌细胞植入 BALB/c 小鼠的左肝叶。动物接受 50%肝切除术（Phx）并接受 10μg/kg DPO 治疗。接受 Phx 的其他动物仅接受生理盐水治疗。接受 DPO 治疗或生理盐水治疗的非肝切除动物作为对照。肝切除后 1 周，使用活体荧光显微镜、组织学、免疫组织化学和 Western blot 分析研究血管生成、白细胞-内皮细胞相互作用、肿瘤细胞增殖、细胞凋亡和肿瘤生长。
Phx 显著增强了肝转移的生长。这与肿瘤毛细血管密度和肿瘤细胞增殖的增加有关。在非肝切除动物中，DPO 仅轻微影响转移性生长。然而，在肝切除动物中，DPO 显著增强了 Phx 诱导的肿瘤生长刺激。这与肿瘤毛细血管密度增加、白细胞-内皮细胞相互作用减少和 CT26.WT 细胞裂解 caspase-3 表达减少有关。
DPO 通过增加新生血管形成、抑制肿瘤内白细胞募集和减少肿瘤细胞凋亡，显著增强了 Phx 诱导的结直肠肝转移生长刺激。因此，EPO 可能不适用于接受恶性肿瘤切除术的肝切除术患者。
